Enantioselective nickel-catalyzed electrochemical reductive conjugate alkenylation of α,β-unsaturated ketones

Abstract

Catalytic electrochemical asymmetric catalysis is emerging as a promising strategy for the synthesis of chiral compounds. Herein, we report an asymmetric electrochemical nickel-catalysed reductive conjugate addition of alkenyl bromides/aryl iodides to α,β-unsaturated ketones in an undivided cell, leading to addition products with high yields and excellent enantioselectivities (up to 96% yield and 96% ee).

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Introduction

Catalytic enantioselective conjugate addition to α,β-unsaturated carbonyl compounds, forming carbon–carbon bonds, constitutes one of the central pillars of modern-day organic synthesis.¹ This important transformation has been extensively developed in the last few decades and widely used in the synthesis of chiral products.² Among various catalytic systems, chiral copper-based complex catalysts have successfully promoted asymmetric conjugate additions of organometallic reagents to various Michael acceptors.³ However, this approach requires prior synthesis of reactive organometallic reagents from the corresponding organohalides, is sensitive to both air and humidity and presents a narrow scope for both alkenylation and arylation reactions. In contrast, rhodium catalysis has been successfully applied in the asymmetric conjugate alkenylation of alkenylboronic,⁴ silicon,⁵ zirconium,⁶ tin⁷ and potassium organotrifluoroborate nucleophiles.⁸ Nevertheless, most of these reactions require harsh conditions and additional steps for the synthesis of alkenyl reagents. Recently, Zhou et al. were the first to report on the nickel- and cobalt-catalysed enantioselective reductive conjugate addition of aryl/alkenyl halides to enones.^9–11 This transformation requires the use of super-stoichiometric amounts of zinc or manganese powder and must be carried out under an inert atmosphere in a glove box.

With the resurgence of organic electrolysis,¹² asymmetric electrocatalysis involving anodic oxidation has attracted considerable attention in recent years.¹³ However, catalytic asymmetric electrochemical reduction reactions have received comparatively less attention (Scheme 1b). Chiral nickel based catalytic systems for the enantioselective coupling of alkenyl and benzyl halides,¹⁴ α-chloroesters,¹⁵ aryl aziridines,^16,17 and Nozaki–Hiyama–Kishi coupling¹⁸ without the need for super-stoichiometric metal powder reductants have been developed by the groups of Reisman, Baran, Mei and Nevado.

Scheme 1 Design of enantioselective electrochemical reductive conjugate addition.

Additionally, Mei et al. reported enantioselective nickel-catalysed electrochemical reductive homocoupling of aryl bromides.¹⁹ The recent report by Zhang et al. represents a significant advance in this area,²⁰ but limited examples of alkenylations emphasise the current challenges faced by this chemistry. Electroreductive alkenylations remain challenging due to the potential for side reactions, such as electrochemical difunctionalisation of alkenes, due to the presence of double bonds in both the starting materials and the resulting alkene products.²¹ Herein, we present enantioselective nickel-catalysed electrochemical conjugate alkenylation of α,β-unsaturated ketones with alkenyl bromides/aryl iodides (Scheme 1c).

Results and discussion

We started our investigation (Table 1) by exploring the asymmetric electrochemical reductive conjugated addition of trans-chalcone 1a with 2-bromopropene 2a in the presence of a catalyst derived from the combination of a nickel salt and Quinox-L1 in an undivided electrochemical cell (IKA Electrasyn 2.0). After systematic evaluation of the reaction parameters (see the ESI†), we were delighted to find that the desired product 3a could be obtained in 72% yield and 96% ee (entry 1) when employing zinc as the anode and reticulated vitreous carbon (RVC) as the cathode in the presence of 5 mol% NiBr₂·DME, 6 mol% chiral quinoline–oxazoline (Quinox) ligand L1, 1.5 equiv. of ^tBuOH and 1.0 equiv. of ⁿBu₄NBF₄ in DMSO/DMF as solvent under 10 mA constant current electrolysis. Further investigation of different chiral quinoline–oxazoline ligands revealed that Quinox-L2 with a bulky tert-butyl substituent allows for a similar outcome, while with isopropyl (L3) and phenyl (L4) substituents the corresponding product was obtained with a decreased yield and enantiopurity. Other chiral ligands such as pyridine-oxazoline (L5), phosphine-oxazoline (L6) and bis-oxazolines (L7 and L8) all afforded the addition product 3a with lower yields.

Table 1 Optimisation of the reaction conditions for the nickel-catalysed electrochemical reductive conjugate alkenylation of 1a to 2a^a

Entry	Deviation from reaction conditions	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), NiBr2 DME (5 mol%), chiral ligand L* (6 mol%), additive (0.3 mmol, 1.5 equiv.), electrolyte (0.2 mmol, 1.0 equiv.) in DMSO/DMF (0.1 M, 2 mL, 1 : 1) under a N2 atmosphere and 10 mA constant current in an undivided cell at room temperature. b The yield of 3a was determined from the H NMR spectra of the reaction crude. Isolated yield is reported in parentheses. c Enantiomeric excess (ee) was determined by SFC with a chiral stationary phase. d In this case 1a (0.4 mmol, 1.0 equiv.) and 2a (0.8 mmol, 2.0 equiv.) were used.
1	None	72	96
2	8 h instead of 6 h	41	95
3	4 h instead of 6 h	61	94
4	NaBr instead of ^nBu4NBF4, 4 h	12	94
5	MgBr2 instead of ^nBu4NBF4, 4 h	17	92
6	^nBu4NBr instead of ^nBu4NBF4, 4 h	12	94
7	^nBu4NPF6 instead of ^nBu4NBF4, 4 h	55	95
8	H2O instead of ^tBuOH	71	94
9	EtOH instead of ^tBuOH	40	95
10	^iPrOH instead of ^tBuOH	74	96
11	^iPrOH instead of ^tBuOH, 0.06 M	49	95
12	^i PrOH instead of ^t BuOH, 0.2 M	75 (74)	96

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To improve the results further, we examined other reaction parameters. When the reaction was extended beyond 6 hours or stopped before 6 hours, lower yields were obtained (entries 2 and 3). The use of different supporting electrolytes such as NaBr, MgBr₂, ⁿBu₄NBr, or ⁿBu₄NPF₆ also proved detrimental to the reaction outcome (entries 4–7). At this point, we investigated the effect of additives. While reactions with H₂O and EtOH resulted in a reduced yield of 3a (entries 8 and 9), ⁱPrOH was found to be the most suitable additive for this reaction, yielding 74% of 3a with 96% ee (entry 10). Reducing the concentration to 0.06 M did not improve the reaction results (entry 11). A slight increase in yield was achieved when the reaction was performed on a 0.4 mmol scale with a concentration of 0.2 M (entry 12).

Based on these results, we adopted the following optimised reaction conditions for further substrate scope studies: NiBr₂·DME (5 mol%) and Quinox-L1 (6 mol%) as chiral nickel catalysts, with ⁱPrOH (1.5 equiv.) as the additive and ⁿBu₄NBF₄ as the electrolyte in a DMSO/DMF (0.2 M) solvent mixture. The reaction was carried out under a N₂ atmosphere using a zinc anode and an RVC cathode in an undivided cell with 10 mA constant current electrolysis for 6 hours at room temperature.

With the optimised reaction conditions in hand, we explored the scope of this transformation with respect to α,β-unsaturated ketone substrates (Table 2(a)). First, the reaction was successfully scaled up to 1.2 mmol, yielding product 3a in 68% yield with 95% ee. A wide range of aryl, heteroaryl, and alkyl substituents at the β-position of chalcones were well tolerated. Methyl substituents at the meta or para positions were compatible, yielding products 3b and 3c in 88% and 43% yields, respectively, hardly affecting the enantioselectivity. However, using the aryl moiety with an ortho-methyl substituent resulted in the corresponding product 3d with a lower yield and enantiopurity (12% yield and 54% ee). In contrast, this transformation exhibited minimal sensitivity to the electronic nature of substituents on the aromatic ring.

Table 2 Product scope of enantioselective nickel-catalysed electrochemical reductive conjugate addition of enones^a

a Reaction conditions: 1a (0.4 mmol, 1.0 equiv.), alkenyl bromides 2 (0.8 mmol, 2.0 equiv.), NiBr₂·DME (5 mol%), chiral ligand L1 (6 mol%), ⁱPrOH (0.6 mmol, 1.5 equiv.), ⁿBu₄NBF₄ (0.4 mmol, 1.0 equiv.) in DMSO/DMF (0.2 M, 2 mL, 1 : 1) under a N₂ atmosphere and 10 mA constant current in an undivided cell at room temperature for 6 h. b 1.2 mmol scale. c Aryl iodides were used. Reported yields correspond to the isolated yields. For each compound, ee values were determined by SFC on a chiral stationary phase.

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A variety of functional groups, including phenyl (3e), electron-donating (3f and 3g), halogen (3h), and electron-withdrawing (3i and 3j) groups, were well tolerated, delivering the desired products in moderate to good yields (45–67%) with excellent enantiomeric excess (91–96% ee). Moreover, the method accommodated more sterically hindered substrates, such as 2-naphthyl-substituted ketone, which afforded product 3k in 70% yield with 96% ee. The method also proved effective for enones containing heteroaromatic groups, such as pyridinyl and furfuryl, yielding products 3l and 3m in high yields (79–90%) with excellent enantioselectivities (96% ee). In particular, the use of trans-crotonophenone gave 3n in an excellent yield of 92%, although with low enantiopurity (21% ee). The position of substituents on the phenyl ring α relative to the carbonyl moiety—whether ortho, meta, or para—had little impact on the outcome, resulting in products 3o–q with high yields and excellent enantioselectivities. A variety of aryl groups containing electron-donating and -withdrawing substituents, such as methoxy (3r) and fluoro (3s), as well as heteroaryl substituents like thiophen (3t) and 2-methoxypyridine (3u), were well accommodated. However, under the standard conditions, α,β-unsaturated carboxamides and esters did not yield the corresponding alkenylated products.

We then examined the scope of alkenyl bromides using this electrochemical protocol (Table 2(b)). Both β-bromostyrene and β-(trimethylsilyl)vinyl bromide afforded products 4a and 4b in good yields (66–72%), albeit with low enantioselectivities (21–23% ee). However, an alkenyl bromide bearing a β-substituent provided product 4c in moderate yield with excellent enantiopurity. Additionally, an α-substituted alkene reacted smoothly, yielding product 4d in 54% yield with 93% ee. Cyclohexenyl bromide gave product 4e in 89% yield with 83% ee, while 4-iodotoluene successfully yielded the arylated product 4f with excellent yield and enantioselectivity (93% yield and 96% ee). The reaction also accommodated both electron-donating and electron-withdrawing groups, yielding products 4g and 4h in good yields (83–84%) with moderate to excellent enantioselectivity (72–92% ee). Furthermore, N-heteroaryl iodides yielded product 4i in low yields but with good enantioselectivity. In contrast, the less sterically hindered product 4j was obtained with lower enantiopurity.

To gain further insight into the asymmetric nickel-catalysed electrochemical reductive conjugate addition, a series of control experiments were performed to verify the necessity of each reaction component (Fig. 1a). The process was completely suppressed in the absence of the nickel-ligand complex, ligand, or the electric current source, demonstrating that both the nickel-ligand catalyst and the electrical current were necessary for this transformation with no contribution from a competitive racemic background pathway. In addition, a low yield was obtained in the absence of alcohol and the deuterated product 3a was observed when using deuterated ⁱPrOD as the additive (Fig. 1b), suggesting that alcohol is crucial for hydrolysing nickel enolates and facilitating product formation after reductive elimination. Next, we conducted cyclic voltammetry experiments (Fig. 1c). The mixture of NiBr₂·DME and L1 in a ratio of 1 : 1 exhibits three reduction peaks (−1.13 V, −1.50 V and −1.72 V vs. Ag/Ag⁺), corresponding to the successive formation of Ni(I), Ni(0), and [Ni(0)-L1]˙⁻ species.²² Ni(0) can undergo oxidative addition with alkenyl bromide. The cyclic voltammetry of NiBr₂-L1 was carried out in the presence of 1.0 equiv. of 2-bromopropene 2a. New reductive peaks and the reduction of the oxidation peak (−0.68 V vs. Ag/Ag⁺) suggest that oxidative addition of alkenyl bromide to Ni(0) occurred readily.

Fig. 1 Mechanistic proposal for asymmetric nickel-catalysed electrochemical reductive conjugate alkenylation. (a) Control experiments. (b) Deuterium labelling experiment. (c) Cyclic voltammetry studies of 2a, NiBr₂-L1, and the mixture of 2a and NiBr₂-L1. (d) Experimental ¹³C KIEs at natural abundance for the conjugate addition of trans-4-methylchalcone 1b with 2a from product analysis. Two experiments were carried out yielding up to 19 and 30% yields of the product 2b to determine the KIEs at dihydrochalcone and propenyl moieties. The numbers in parentheses represent the standard deviation of the last digit as determined from seven independent measurements.

Next, we investigated intramolecular ¹³C isotope effects by product analysis (Fig. 1d).²³ Determining KIEs can reveal major bonding changes in the rate-limiting step of a reaction.²⁴ We used high-precision NMR measurements of ¹³C KIEs at natural isotopic abundance, developed by Singleton.²⁵ We conducted two independent reactions of trans-4-methylchalcone 1b and 2a under optimised reaction conditions on a 5 mmol scale and stopped the reaction at low conversions to the product 3b (19 and 30%). The product 3b was isolated, and its ¹³C isotopic composition was compared to those of unreacted samples of 1b and 2a.

From changes in relative isotopic composition and fractional conversion, we determined ¹³C KIEs (see details in the ESI†). We observed a primary KIE of ∼2.7% at C_β of the dihydrochalcone moiety and ∼1.7% at C₂ of the propenyl moiety, suggesting that C_β and C₂ are involved in the rate-determining step in the catalytic process. In contrast, all other carbons in the molecule exhibited near-unity KIEs, indicating their lack of involvement in the rate-determining step. The observed KIEs on both carbons strongly support that the migration of the alkenyl group from organonickel species to the electrophilic site C_β of α,β-unsaturated ketones is the rate-determining step of the catalytic cycle.

Based on literature reports^9,10 and our studies, we suggest the plausible catalytic cycle (Scheme 2). Asymmetric electrochemical catalysis is initiated by the cathodic reduction of the L_nNi(II)X₂ precatalyst to form the active L_nNi(0) catalyst that subsequently undergoes oxidative addition with an alkenyl halide leading to L_nNi(II)RBr. The subsequent cathodic reduction produces L_nNi(I)R, which binds the α,β-unsaturated ketone. Migratory insertion leads to the formation of a nickel O-enolate, likely in the rate-determining step. Subsequent hydrolysis by alcohol releases the desired product and regenerates L_nNi(I) species. Finally, the cathodic reduction of L_nNi(I) (OR) or L_nNi(I)Br completes the catalytic cycle.

Scheme 2 Proposed reaction mechanism for the enantioselective nickel-catalysed electrochemical reductive conjugate addition.

Conclusions

In conclusion, we have developed asymmetric nickel-catalysed conjugate addition of alkenyl bromides and aryl iodides to α,β-unsaturated ketones in an undivided cell by merging electrochemistry and chiral nickel catalysis, affording a wide range of α,β-unsaturated ketones under mild reaction conditions. Additional investigations indicated that alkenyl halides get activated through oxidative addition to Ni(0) species and the rate-determining step of the transformation is likely reductive elimination that leads to the enolate product.

Data availability

Experimental and analytical data supporting this article are available in the ESI.†

Author contributions

Siriphong Somprasong designed the project, optimised the reaction conditions, investigated the substrate scope, analysed the data, performed the mechanistic experiments and wrote the draft of the manuscript. Bin Wan expanded the substrate scope and analysed the data. Syuzanna R. Harutyunyan supervised the project and edited the manuscript. All the authors contributed to and approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the European Research Council (S. R. H. grant no. 773264, LACOPAROM) and to the China Scholarship Council (CSC, to B. W.) are acknowledged. We thank P. van der Meulen and F. de Vries for help with structural elucidations using NMR spectroscopy and R. Sneep for help with the HRMS measurements.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4sc06891b

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