An electrochemical reductive allylation and alkylation of carbonyl groups in α,β-unsaturated aldehydes and ketones

Abstract

We report herein an electrochemical reductive allylation and alkylation of carbonyl groups in α,β-unsaturated aldehydes and ketones. This study provides a practical and efficient new method for synthesizing allyl alcohol, propargyl alcohol, and homoallylic alcohol.

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Allyl alcohol, propargyl alcohol, and homoallylic alcohol are not only abundant in natural products and pharmaceutical molecules but also serve as important synthetic intermediates with wide applications.¹ Therefore, numerous methods have been developed to synthesize these compounds in the past decades. Among them, the reductive alkylation and allylation of carbonyl groups in enones represents one of the most effective strategies. The classic synthetic methods are shown in Scheme 1A–C. Early strategies involved Barbier–Grignard type reactions (Scheme 1A).² Subsequently, Keck, Sakurai, and Roush et al. successfully achieved the allylation of carbonyl groups using allyl tin, silane, and boron (Scheme 1B).³ In addition, a wide range of metals such as Mg,⁴ Ti,⁵ Mn,⁶ Zn,⁷ In,⁸ Sn⁹ and Sb¹⁰ have been explored for the reductive allylation of aldehydes and ketones with allyl halides (Scheme 1C). These classic methods often require large quantities of metal, pre-prepared allyl reagents, and display low functional group tolerance.

Scheme 1 Strategies for allylation/alkylation of carbonyl compounds.

To overcome these limitations, several effective electrochemical approaches for the allylation of carbonyl groups using allyl halides have been developed (Scheme 1D). For example, Huang and co-workers reported two electrochemical allylation reactions of aldehydes and ketones in 2009–2010.¹¹ In recent years, Li's¹² group has also developed a reductive allylation of carbonyl compounds under electrochemical conditions. Very recently, Liu et al.¹³ achieved an electrochemical allylation of aldehydes and ketones with allylic alcohols. Despite these advances, the developed electrochemical allylation methods are largely limited to simple carbonyl substrates. The reductive functionalization of α,β-unsaturated aldehydes and ketones remains a considerable challenge due to the competing hydrogenation of the conjugated C=C bonds, which impedes chemoselective control. In continuation of our studies toward green synthetic methods via electrochemistry,¹⁴ we explored an electrochemical allylation/alkylation of carbonyl groups in α,β-unsaturated aldehydes and ketones. Fortunately, we accomplished reductive C–C bond formation through coupling reactions of alkyl and allyl halides with a series of α,β-unsaturated aldehydes and ketones under mild electrochemical conditions (Scheme 1E).

Our investigation of electrochemical allylation commenced with using 2-cyclohexen-1-one (1a) and allyl bromide (2a) as the model substrates to optimize the reaction conditions (Table 1). To our delight, the desired product 3a was obtained in a yield of 50% under the following conditions: zinc rod as the anode, graphite felt (GF) as the cathode, tetrabutylammonium tetrafluoroborate (Bu₄NBF₄) as the electrolyte, N,N-dimethylformamide (DMF) as the solvent, and a current density of 10 mA in an open flask for 3 hours (entry 1). When the amount of allyl bromide was adjusted to 3.0 equivalents, 3a was obtained in a yield of 74% (entry 3). Next, we examined various materials as electrodes and found that Zn/GF was more effective than the others (entries 4–6). Furthermore, increasing the current from 5 to 20 mA resulted in decreased yields of 3a (entries 8–10). Other electrolytes, such as Et₄NBF₄, TBAClO₄, Bu₄NPF₆, and LiClO₄, resulted in relatively lower yields (entries 11–14). In addition, DMF was more effective than other solvents (entries 15–17). Finally, the control experiment confirmed that electricity is necessary (entry 18).

Table 1 Optimization of the reaction conditions^a

Entry	2a (eq.)	Electrode	Current (mA)	Electrolyte (0.1 M)	Solvent	Yield^b/%	Time/h
a Reaction conditions: undivided cell, zinc rod as anode, 1a (0.5 mmol, 1.0 equiv.), electrolyte (0.5 mmol, 1.0 equiv.), solvent (5.0 mL), constant current, room temperature, open to air. b Isolated yield. c ND = not detected.
1	1.0	Zn (+)|GF (−)	10	Bu4NBF4	DMF	50	3.0
2	2.0	Zn (+)|GF (−)	10	Bu4NBF4	DMF	66	3.0
3	3.0	Zn (+)|GF (−)	10	Bu4NBF4	DMF	80	3.0
4	3.0	GF (+)|GF (−)	10	Bu4NBF4	DMF	Trace	3.0
5	3.0	Ni (+)|GF (−)	10	Bu4NBF4	DMF	48	3.0
6	3.0	Mg (+)|GF (−)	10	Bu4NBF4	DMF	43	3.0
7	3.0	Sn (+)|GF (−)	10	Bu4NBF4	DMF	19	3.0
8	3.0	Zn (+)|GF (−)	5	Bu4NBF4	DMF	65	5.0
9	3.0	Zn (+)|GF (−)	15	Bu 4 NBF 4	DMF	85	2.0
10	3.0	Zn (+)|GF (−)	20	Bu4NBF4	DMF	70	2.0
11	3.0	Zn (+)|GF (−)	15	Et4NBF4	DMF	42	3.0
12	3.0	Zn (+)|GF (−)	15	TBAClO4	DMF	55	3.0
13	3.0	Zn (+)|GF (−)	15	Bu4NPF6	DMF	47	3.0
14	3.0	Zn (+)|GF (−)	15	LiClO4	DMF	35	3.0
15	3.0	Zn (+)|GF (−)	15	Bu4NBF4	DMSO	70	3.0
16	3.0	Zn (+)|GF (−)	15	Bu4NBF4	MeCN	60	2.0
17	3.0	Zn (+)|GF (−)	15	Bu4NBF4	THF	—	2.0
18	3.0	Zn (+)|GF (−)	—	Bu4NBF4	DMF	N.D.^c	2.0

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With the optimized conditions in hand, we next examined the substrate scope (Scheme 2). First, we evaluated six- and seven-membered enones, which afforded the corresponding products in good yields of over 80% (3a and 3b). Next, we investigated L-(−)-carvone and β-lononem, two unsaturated ketones derived from natural products, which also provided the target products in excellent yields (3c and 3d). We were pleased to find that the chain enone was also compatible with this system, affording 3e in nearly quantitative yield in only one hour. Similarly, aryl enones gave the corresponding allyl alcohol derivatives in excellent yields (3f–3h). Furthermore, phenyl- and ester-substituted enones also underwent selective 1,2-addition of the allyl halide to the carbonyl group, resulting in good yields (3i and 3j). Next, we also examined two unsaturated alkynones, which afforded the target products in moderate to good yields (57–70%) (3k and 3l). Finally, a series of natural steroids were also found to be effective substrates (3m–3p). To our surprise, reductive allylation occurred preferentially at the conjugated carbonyl groups, while the non-conjugated ones remained intact. This phenomenon assists in studying the mechanism of this reaction.

Scheme 2 Scope of α,β-unsaturated ketones. Reaction conditions: undivided cell, zinc rod as anode, 1 (0.5 mmol), 2 (1.5 mmol), Bu₄NBF₄ (0.5 mmol), DMF (5.0 mL), constant current = 15.0 mA, open to air, 2–6 h. Isolated yield.

Then we examined the substrate scope of α,β-unsaturated aldehydes. As shown in Scheme 3, both alkyl (5a–5d) and aryl (5e–5h) α,β-unsaturated aldehydes gave the desired products in 85–95% yields. Additionally, heteroarene-substituted α,β-unsaturated aldehydes, which are widely utilized as core structures in medicinal chemistry, were also suitable substrates (5i and 5j). Phenylpropiolaldehyde was also a suitable substrate (5k).

Scheme 3 Scope of α,β-unsaturated aldehydes. Reaction conditions: undivided cell, zinc rod as anode, 4 (0.5 mmol), 2 (1.5 mmol), Bu₄NBF₄ (0.5 mmol), DMF (5.0 mL), constant current = 15.0 mA, 2–6 h. Isolated yield.

Subsequently, we examined the scope of allyl halides under the standard reaction conditions (Scheme 4). Methallyl bromide (6a) afforded the desired homoallylic alcohol (7a) in 88% yield. Interestingly, crotyl bromide (6b) and 3,3-dimethylallyl bromide (6c) gave products 7b and 7c in 81% and 89% yields, respectively. It is noteworthy that the C=C double bonds underwent migration. Cycloallylic halides were also effective substrates (7d). To our delight, a series of primary, secondary and tertiary haloalkanes were found to be compatible with this system (7e–7g). In addition, benzyl halides also produced the allyl alcohols 7h in moderate to high yields. In the case of 6d and 6h, different halides such as Cl, Br and I were evaluated to compare their reactivity. From these data, the following reactivity trend was established: (1) the reactivity follows the order RI > RBr > RCl; and (2) the reactivity trend of alkyl halides is 3° > 2° > 1°.

Scheme 4 Scope of allyl and alkyl halides. Reaction conditions: undivided cell, zinc rod as anode, 1f (0.5 mmol), 6 (1.5 mmol), Bu₄NBF₄ (0.5 mmol), DMF (5.0 mL), constant current = 15.0 mA, 2–6 h. Isolated yield.

To verify the scalability of this system, we conducted a scale-up experiment. As shown in Scheme 5a, under the optimal reaction conditions, 10 grams of 2-cyclohexen-1-one (1a) reacted with allyl bromide (2) and produced the target product 3a in an isolated yield of 87%. Finally, we performed a set of mechanistic investigations. First, we performed radical trapping experiments (Scheme 5b). 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO) completely suppressed the reductive allylation processes, and product 3a was not detected. Instead, two TEMPO-trapped products (8 and 10) were observed and identified by high-resolution mass spectrometry (HRMS). When cinnamyl bromide (9) was used as the allylation reagent, we successfully isolated the radical adduct 10 in 50% yield (Scheme 5c). Next, a radical clock experiment was carried out and the ring-opening product 12 was isolated in 62% yield (Scheme 5d). Based on the results obtained above, we proposed a possible mechanism for this reaction (Scheme 5e). The allyl halide is first reduced at the cathode surface to form the allyl radical (I), which is a transient radical. This radical readily undergoes resonance to form a more stable radical. At the same time, the enone is also reduced at the cathode to form the radical anion II, which is a persistent radical. Radical II does not readily undergo resonance because the lone pair electrons on the oxygen atom stabilize the adjacent carbon-centered radical more than the π electrons of the carbon–carbon double bond. Subsequently, cross coupling of these two radicals produces an anion (III), which undergoes protonation to afford the final product. The anodic half-reaction involves the oxidation of Zn to Zn²⁺.

Scheme 5 Scale-up experiments, mechanistic studies and the suggested mechanism.

In summary, we have developed a reductive allylation and alkylation of α,β-unsaturated aldehydes and ketones with allyl/alkyl halides in an undivided cell. This method features high reaction yields, a broad substrate scope, good functional group tolerance (with non-conjugated carbonyl groups remaining intact), scalability to gram-scale production and mild conditions.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01168j.

Acknowledgements

This project was supported by the National Natural Science Foundation of China (No. 22371129) and the Science Foundation of Jiangsu Province (No. BK 20220463).

References

1. (a) Y. Yamamoto and N. Asao, Selective reactions using allylic metals, Chem. Rev., 1993, 93, 2207; (b) M. Rottlander, L. Boymond, L. Berillon, A. Lepre-tre, G. Varchi, S. Avolio, H. Laaziri, G. Queguiner, A. Ricci, G. Cahiez and P. Knochel, New Polyfunctional Magnesium Reagents for Organic Synthesis, Chem. – Eur. J., 2000, 6, 767; (c) Z.-J. Zhang, B.-S. Wan and H.-L. Chen, Progress of application of chiral binuclear complex catalyst to the asymmetric synthesis, Chin. J. Org. Chem., 2003, 23, 636; (d) J. W. J. Kennedy and D. G. Hall, Recent Advances in the Activation of Boron and Silicon Reagents for Stereocontrolled Allylation Reactions, Angew. Chem., Int. Ed., 2003, 42, 4732.
2. (a) H. P. C. R. Barbier, Sur quelques nouvelles méthodes de préparation des alcools, Seances Acad. Sci., 1899, 128, 110–111; (b) V. C. Grignard and C. R. Sur, quelques nouvelles combinaisons organométalliques du magnésium et leur application à des synthèses daalcools et d'hydrocarbures, C. R. Hebd. Seances Acad. Sci., 1900, 130, 1322–1324; (c) C.-J. Li, Aqueous Barbier-Grignard type reaction: Scope, mechanism, and synthetic applications, Tetrahedron, 1996, 52, 5643–5668.
3. (a) G. Keckand and L. Geraci, Catalytic asymmetric allylation (CAA) reactions. II. A new enantioselective allylation procedure, Tetrahedron Lett., 1993, 34, 7827–7828; (b) G. Keck, D. Krishnamurthy and M. C. Grier, Catalytic asymmetric allylation reactions. 3. Extension to methallylstannane, comparison of procedures, and observation of a nonlinear effect, J. Org. Chem., 1993, 58, 6543–6544; (c) G. Keck, K. Tarbet and L. Geraci, Catalytic asymmetric allylation of aldehydes, J. Am. Chem. Soc., 1993, 115, 8467–8468; (d) W. R. Roush, K. Ando, D. B. Powers, R. L. Halterman and A. D. Palkowitz, Enantioselective synthesis using diisopropyl tartrate modified (E)- and (Z)-crotylboronates: Reactions with achiral aldehydes, Tetrahedron Lett., 1988, 29, 5579–5582; (e) G. Dutheuil, N. Selander, K. J. Szabó and V. K. Aggarwal, Direct Synthesis of Functionalized Allylic Boronic Esters from Allylic Alcohols and Inexpensive Reagents and Catalysts, Synthesis, 2008, 2293–2297; (f) H. Sakurai, K. Sasaki and A. Hosomi, Regiospecific allylation of acetals with allylsilanes catalyzed by iodotrimethylsilane. Synthesis of homoallylethers, Tetrahedron Lett., 1981, 22, 745–748.
4. (a) C.-J. Li and W.-C. Zhang, Unexpected Barbier−Grignard Allylation of Aldehydes with Magnesium in Water, J. Am. Chem. Soc., 1998, 120, 9102–9103; (b) M. Wada, T. Fukuma, M. Morioka, T. Takahashi and N. Miyoshi, A Novel Aqueous Barbier-Grignard-Type Allylation of Aldehydes in a Mg/BiCl₃ Bimetal System, Tetrahedron Lett., 1997, 38, 8045–8048.
5. (a) R. E. Estévez, J. Justicia, B. Bazdi, N. Fuentes, M. Paradas, D. Choquesillo-Lazarte, J. M. García-Ruiz, R. Robles, A. Gansäuer, J. M. Cuerva and J. E. Oltra, Ti-Catalyzed Barbier-Type Allylations and Related Reactions, Chem. – Eur. J., 2009, 15, 2774–2791; (b) L. M. Fleury, A. D. Kosal, J. T. Masters and B. L. Ashfeld, Cooperative Titanocene and Phosphine Catalysis: Accelerated C–X Activation for the Generation of Reactive Organometallics, J. Org. Chem., 2013, 78, 253–269.
6. C.-J. Li, Y. Meng, X.-H. Yi, J. Ma and T.-H. Chan, Oxygenation Reaction of Organic Sulfides with Oxochromium(V) Ion, J. Org. Chem., 1998, 63, 21–26.
7. L. W. Bieber, M. F. da Silva, R. C. da Costa and L. O. S. Silva, Zinc barbier reaction of propargyl halides in water, Tetrahedron Lett., 1998, 39, 3655–3658.
8. (a) C.-J. Li and T.-H. Chan, Organometallic reactions in aqueous media with indium, Tetrahedron Lett., 1991, 32, 7017–7020; (b) W. Chung, S. Higashiya, Y. Oba and J. T. Welch, Indium- and zinc-mediated allylation of difluoroacetyltrialkylsilanes in aqueous media, Tetrahedron, 2003, 59, 10031–10036; (c) T.-P. Loh, K.-T. Tan and Q.-Y. Hu, A new mechanistic proposal for the origin of α-homoallylic alcohols in indium-mediated allylation reactions in water, Tetrahedron Lett., 2001, 42, 8705–8708; (d) C. Reid, Y. Zhang and C.-J. Li, Fluorous tagging: an enabling isolation technique for indium-mediated allylation reactions in water, Org. Biomol. Chem., 2007, 5, 3589–3591.
9. (a) T.-H. Chan, Y. Yang and C.-J. Li, Organometallic Reactions in Aqueous Media. The Nature of the Organotin Intermediate in the Tin-Mediated Allylation of Carbonyl Compounds, J. Org. Chem., 1999, 64, 4452–4455; (b) X.-H. Tan, Y.-Q. Hou, B. Shen, L. Liu and Q.-X. Guo, SnCl2/PdCl2-mediated aldehyde allylation in fully aqueous media, Tetrahedron Lett., 2004, 45, 5525–5528.
10. (a) L.-H. Li and T. Chan, Organometallic reactions in aqueous media. Antimony-mediated allylation of carbonyl compounds with fluoride salts, Tetrahedron Lett., 2000, 41, 5009–5012; (b) X.-R. Li and T.-P. Loh, Indium trichloride-promoted tin-mediated carbonyl allylation in water: High simple diastereo- and diastereofacial selectivity, Tetrahedron: Asymmetry, 1996, 7, 1535–1538.
11. (a) J.-M. Huang and Y. Dong, Zn-mediated electrochemical allylation of aldehydes in aqueous ammonia, Chem. Commun., 2009, 26, 3943–3945; (b) J.-M. Huang and H.-R. Ren, Chem. Commun., 2010, 46, 2286–2288.
12. S. Zhang, Y. Liang, K. Liu, X. Zhan, W. Fan, M.-B. Li and M. Findlater, Electrochemically Generated Carbanions Enable Isomerizing Allylation and Allenylation of Aldehydes with Alkenes and Alkynes, J. Am. Chem. Soc., 2023, 145, 14143–14154.
13. J. Zhang, L. Zhang, W. Xie, M. Chen, C. Zhang, Y. Qin, J. Zhao, F. Wang and Z.-Q. Liu, Electrochemical allylation of aldehydes and ketones with allylic alcohols, Green Chem., 2024, 26, 7002–7006.
14. (a) Z. Qiu, X. Huang, J. Wu and Z.-Q. Liu, Electrochemical Hydroalkylation of Quinoxalin-2(1H)-ones with Alkyl Halides, Adv. Synth. Catal., 2023, 365, 318–322; (b) Z. Sun, R. Ji, J. Wu, J. Zhao, F. Fang, F. Wang, C. Jiang and Z.-Q. Liu, Electrochemical Deoxygenative Hydrogenation and Deuteration of Aldehydes/Ketones by Protic Acids in Water, Adv. Synth. Catal., 2023, 365, 476–481; (c) J. Zhao, C. Deng, L. Zhang, J. Zhang, Q. Rong, F. Wang and Z.-Q. Liu, NHPI-Catalyzed Electro-Oxidation of Alcohols to Aldehydes and Ketones, J. Org. Chem., 2024, 89, 15864–15876; (d) P. Fang, Q. Wang, X. Shen, J. Zhao, F. Wang and Z.-Q. Liu, Electrochemical Synthesis of Vinyl, Alkyl, and Allyl Sulfones from Sodium Sulfinates and Olefins, J. Org. Chem., 2024, 89, 12619–12627; (e) T. Shen, J. Zhao, X. Ren, Z.-Q. Liu and S. Liu, Metal-Free Electrochemical Allylic C–H Aerobic Oxidation, J. Org. Chem., 2025, 90, 1148–1158; (f) Q. Wang, P. Fang, J. Zhao, X. Huang, X. Shen, F. Wang and Z.-Q. Liu, Metal-Free Electrochemical C─H Chlorination of Terminal Alkanes, Angew. Chem., Int. Ed., 2025, 64, e202504478; (g) Q. Rong, Q. Wang, J. Zhao, Z. Zhang, X. Huang, F. Wang and Z.-Q. Liu, Site-selective 2° C-H chlorination of alkane by metal-free electrochemistry, Sci. China: Chem., 2025 DOI:10.1007/s11426-025-2830-6.

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