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. 2026 Jul 15;11(29):44318–44325. doi: 10.1021/acsomega.6c04363

Manganese-Catalyzed Ortho-C–H Alkenylation of Aromatic Ketones

Xue Wang †, Xiaoxiao Huang ‡, Xianwen Zeng ‡, Yuehong Zou †, Qingqing Nie †, Jinquan Zhang ‡,*, Liping Chen §,*, Ziyan Meng †,*
PMCID: PMC13425307  PMID: 42540211

Abstract

Ortho-C–H alkenylation of aromatic ketones is a key transformation for bioactive molecules and functional materials, but all existing methods rely on scarce noble metals, hindering industrial applications. Herein, we report the first manganese-catalyzed ortho-C–H alkenylation of aromatic ketones with commercial acrylates. Using MnBr­(CO)5 as the precatalyst, the reaction proceeds under mild aqueous conditions with broad substrate scope, scalable to 10 mmol, and allows tunable mono/bis-alkenylation via acrylate stoichiometry. Mechanistic studies support an electrophilic C–H metalation pathway, and the products can be readily derivatized to isoquinoline frameworks. This work provides a sustainable alternative and enables manganese catalysis with weakly coordinating directing groups.

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Introduction

Aromatic ketones represent one of the most privileged structural motifs in materials science, pharmaceutical industry, and fine chemical manufacturing, serving as versatile building blocks for the construction of complex molecular architectures. Over the past three decades, transition metal-catalyzed C–H bond functionalization has emerged as a transformative synthetic paradigm, offering unprecedented atom- and step-economic alternatives to traditional cross-coupling strategies that rely on prefunctionalized substrates. In particular, directing group-assisted C–H activation has become the most powerful approach for achieving site-selective functionalization of aromatic compounds. Among various directing groups, the weakly coordinating ketone moiety holds exceptional synthetic value, as it obviates the need for additional installation and removal steps, enabling direct late-stage diversification of ketone-containing molecules.

Since Murai’s pioneering 1993 report on ruthenium-catalyzed ortho-C–H alkylation of aromatic ketones, ketone-directed C–H functionalization has attracted extensive research interest. Of particular importance is ortho-C–H alkenylation, which affords versatile intermediates for the synthesis of bioactive molecules and functional materials. Significant progress has been made using noble transition metals including ruthenium, rhodium, iridium, and palladium­(Scheme a). Jeganmohan and co-workers developed a ruthenium-catalyzed chelation-assisted alkenylation with acrylates, delivering Heck-type products in good to excellent yields with exclusive E-stereoselectivity, a while Prabhu et al. expanded the substrate scope using both rhodium and ruthenium catalysts. Despite these advances, all existing protocols rely exclusively on scarce and expensive noble metals, whose high cost, potential toxicity, and limited natural abundance severely hinder large-scale industrial applications. This has spurred intense efforts to develop catalytic systems based on earth-abundant first–row transition metals. Among these, manganese stands out as an exceptionally promising candidate owing to its high crustal abundance (∼1000-fold that of palladium), low cost, low toxicity, and rich redox chemistry. Recently, significant progress has been made in manganese-catalyzed C–H functionalizations mediated by weak directing groups such as ketone carbonyls. Previous elegant studies have successfully explored various manganese-catalyzed directed transformations of aromatic ketones, including ortho-C–H amidation, ortho-C–H allylation, α-alkenylation, C–H addition to imines, and redox-neutral olefination with unactivated alkenes.

1. (a, b) Case Studies on Aryl Ketone C–H Activation and Enylization Catalyzed by Transition Metals.

1

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Nevertheless, manganese-catalyzed ketone-directed C–H activation remains largely underdeveloped, primarily due to the weak coordinating ability of the ketone carbonyl group and the inherently lower reactivity of first-row transition metals relative to their noble metal counterparts. − In particular, achieving oxidative ortho-C–H alkenylation of aromatic ketones with electron-deficient alkenes, such as acrylates, via manganese catalysis has remained a formidable challenge. Compared to the previously reported redox-neutral olefination using unactivated alkenes, utilizing acrylates necessitates an oxidative catalytic turnover. This oxidative process is inherently more difficult to control due to potential competing side reactions and the strict requirement for a compatible external oxidant that does not deactivate the highly reactive manganese catalyst. Herein, we report a highly efficient protocol for the manganese-catalyzed oxidative ortho-C–H alkenylation of aromatic ketones using commercially available acrylates as the alkenylating reagents (Scheme b). By employing the readily available manganese pentacarbonyl bromide [MnBr­(CO)5] as the precatalyst and leveraging the in situ generation of the highly reactive MnMe­(CO)5 species, we have developed a highly efficient and practical protocol that operates under mild aqueous conditions. This methodology exhibits several notable advantages over existing noble metal-based systems: (1) it utilizes an earth-abundant and inexpensive manganese catalyst; (2) all reagents are commercially available and air-stable; (3) it demonstrates excellent functional group tolerance and broad substrate scope; (4) it can be readily scaled up to gram quantities without significant loss of yield; and (5) it allows for tunable synthesis of both mono- and di-ortho-alkenylated products by simply adjusting the stoichiometry of the acrylate coupling partner. This work not only fills a long-standing gap in the field of ketone-directed C–H alkenylation but also provides a new strategic platform for the development of sustainable manganese-catalyzed C–H functionalization reactions with weakly coordinating directing groups.

Results and Discussion

We initiated our studies using acetophenone (1a) and methyl acrylate (2a) as model substrates to establish optimal conditions for the manganese-catalyzed ortho-C–H alkenylation of aromatic ketones. Initial solvent screening was conducted at 60 °C with Cu­(OAc)2 as the oxidant for 12 h (Table , entries 1–7). No desired product was detected in fluorinated solvents (HFIP and TFE, entries 1 and 2). Moderate yields were obtained in MeOH (13%, entry 3) and H2O (24%, entry 4), while 1,4-dioxane afforded product 3a in 56% yield (entry 5). Evaluation of mixed solvent systems showed that 1,4-dioxane/H2O (4:1) outperformed 1,4-dioxane/MeOH (4:1), delivering 3a in 68% yield (entries 6 and 7). Subsequent oxidant screening under the optimized solvent conditions confirmed Cu­(OAc)2 as the most effective oxidant (entry 7). AgOAc failed to promote the reaction, and CsOAc only provided 44% yield (entries 8 and 9). We then investigated the effect of reaction temperature (entries 10–12). Lowering the temperature to 40 °C resulted in no product formation, while increasing to 80 °C improved the yield to 72%. Further elevation to 100 °C led to a sharp drop in yield to 21%, presumably due to decomposition of starting materials or the alkenylated product.

1. Optimization of Conditions .

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entry solvent oxidant catalyst T (°C) x (h) yield (%)
1 HFIP Cu(OAc)2 MnBr(CO)5 60 12 N.R.
2 TFE Cu(OAc)2 MnBr(CO)5 60 12 N.R.
3 MeOH Cu(OAc)2 MnBr(CO)5 60 12 13
4 H2O Cu(OAc)2 MnBr(CO)5 60 12 24
5 1,4-dioxane Cu(OAc)2 MnBr(CO)5 60 12 56
6 1,4-dioxane:MeOH = 4:1 Cu(OAc)2 MnBr(CO)5 60 12 59
7 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 60 12 68
8 1,4-dioxane:H2O = 4:1 AgOAc MnBr(CO)5 60 12 N.R.
9 1,4-dioxane:H2O = 4:1 CsOAc MnBr(CO)5 60 12 44
10 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 40 12 N.R.
11 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 80 12 72
12 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 100 12 21
13 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 80 18 78
14 1,4-dioxane:H 2 O = 4:1 Cu(OAc) 2 MnBr(CO)5 80 24 93
15 1,4-dioxane:H2O = 4:1 Cu(OAc)2 MnBr(CO)5 80 30 90
16 1,4-dioxane:H2O = 4:1 Cu(OAc)2 Fe2(CO)9 80 24 N.R.
17 1,4-dioxane:H2O = 4:1 Cu(OAc)2 Co2(CO)8 80 24 N.R.
18 1,4-dioxane:H2O = 4:1 Cu(OAc)2 Mo(CO)6 80 24 N.R.
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a

Conditions: 1a (0.5 mmol), 2a (0.75 mmol), Catalyst (5.0 mol %), Me2Zn (1.0 mmol), and Oxidant (1.0 mmol) in the solvent (5.0 mL).

Finally, we optimized the reaction time at 80 °C (entries 13–15). Extending the reaction time from 12 to 18 and 24 h gradually increased the yield to 78% and 93%, respectively. Prolonging the reaction to 30 h caused a slight decrease in yield to 90%. To further demonstrate the unique advantages of manganese in this transformation, additional control experiments were conducted under the standard conditions (entries 16–18). Replacing MnBr­(CO)5 with other metal carbonyl catalysts, such as Fe2(CO)9, Co2(CO)8, and Mo­(CO)6, completely failed to promote the reaction, highlighting the indispensable role of the manganese catalyst. Thus, the optimal reaction conditions were identified as 1a (0.5 mmol), 2a (0.75 mmol), MnBr­(CO)5 (5.0 mol %), Me2Zn (1.0 mmol), Cu­(OAc)2 (1.0 mmol) in 1,4-dioxane/H2O (4:1, 5.0 mL) at 80 °C for 24 h.

With the optimal reaction conditions established, we next evaluated the generality of this manganese-catalyzed ortho-C–H alkenylation protocol (Scheme ). We first investigated para-substituted acetophenones. Electron-donating groups including methyl (3b), ethyl (3c), tert-butyl (3d), and methoxy (3e) were well tolerated, delivering the corresponding products in 88–96% yields. In contrast, electron-withdrawing substituents such as fluoro (3f), chloro (3g), and bromo (3h) afforded slightly lower yields (56–67%), consistent with an electrophilic C–H activation pathway where electron-deficient aromatic rings exhibit reduced reactivity. For meta-substituted acetophenones, the reaction proceeded with exclusive regioselectivity at the sterically less hindered ortho-C–H bond. Both electron-donating methyl (3i, 82%) and electron-withdrawing fluoro (3j, 63%) groups were compatible under the standard conditions. Notably, ortho-substituted acetophenones also reacted smoothly despite increased steric congestion. Methyl (3k, 89%), fluoro (3l, 72%), and bromo (3m, 70%) substituents at the ortho position were all tolerated, and the halogenated products provide versatile synthetic handles for subsequent derivatization.

2. Scope for Aryl Ketone 1 .

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a Conditions: 1 (0.5 mmol), 2a (0.75 mmol), MnBr­(CO) 5 (5.0 mol %), Me2Zn­(1.0 mmol), and Cu­(OAc)2 (1.0 mmol) in the mixed solvent (1,4-Dioxane:H2O = 4:1) (5.0 mL), stirred at 80 °C under oil bath for 24 h.

Furthermore, polysubstituted acetophenones including 3,4-dimethyl (3n, 86%), 2,4-difluoro (3o, 76%), 2,5-difluoro (3p, 70%), and 2,3-dimethoxy (3q, 64%) derivatives furnished the desired products in moderate to good yields, further demonstrating the broad functional group compatibility of this method. We then extended the scope to fused aromatic ketones. Tetralone-derived substrate (3r, 82%), α-acetonaphthone (3s, 77%), β-acetonaphthone (3t, 85%), and 6-methoxy-β-acetonaphthone (3u, 84%) all underwent efficient alkenylation. To further probe the steric effects and facilitate the formation of metallacycle intermediates, we investigated the sterically hindered benzophenone. Delightfully, it reacted smoothly to afford the desired ortho-alkenylated product (3v, 72%). However, heteroaromatic ketones such as 3-acetylpyridine (3w) and 3-acetylindole (3x) failed to yield the desired products, likely due to strong coordination of the heteroatoms to the manganese catalyst causing deactivation. Additionally, isopropyl phenyl ketone (3y) was unreactive under our conditions, indicating that α-branched alkyl aryl ketones are not suitable substrates for this transformation.

Next, we turned our attention to the scope of alkene coupling partners using acetophenone (1a) as the standard substrate (Scheme ). Ethyl acrylate reacted smoothly under the optimized conditions to afford product 4a in 88% yield, comparable to the performance of methyl acrylate (3a). We then evaluated a series of aryl acrylates to further expand the synthetic utility of this protocol. For para-substituted aryl acrylates, both electron-donating and electron-withdrawing substituents were compatible. Unsubstituted phenyl acrylate (4b) and its para-methyl (4c) and para-methoxy (4d) derivatives delivered the desired products in 71%, 75% and 78% yields, respectively. Aryl acrylates bearing electron-withdrawing fluoro (4e), chloro (4f) or bromo (4g) substituents showed slightly reduced reactivity, affording the corresponding products in 65–68% yields. Notably, the iodo-substituted derivative 4h gave a diminished yield of 43%, likely due to the larger steric bulk of iodine and potential competing side reactions involving the labile C–I bond. Meta-substituted aryl acrylates exhibited divergent reactivity. The methyl-substituted substrate 4i delivered the desired product in excellent yield (81%), while the meta-chloro derivative 4j failed to yield any detectable product, suggesting that the synergistic effect of electron-withdrawing character and steric hindrance at the meta position completely shuts down the catalytic cycle. Ortho-substituted aryl acrylates were also compatible, but their reactivity was more sensitive to steric constraints. The ortho-methyl derivative 4k afforded the product in 76% yield, whereas the ortho-chloro analog 4l only gave 32% yield, indicating that the steric hindrance imposed by the ortho-chloro group is significantly more pronounced than that of the ortho-methyl group.

3. Scope for Acrylates 2 .

3

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a Conditions: 1a (0.5 mmol), 2 (0.75 mmol), MnBr­(CO) 5 (5.0 mol %), Me2Zn­(1.0 mmol), and Cu­(OAc)2 (1.0 mmol) in the mixed solvent (1,4-Dioxane:H2O = 4:1) (5.0 mL), stirred at 80 °C under oil bath for 24 h.

Overall, these results demonstrate that our manganese-catalyzed system exhibits good functional group tolerance toward a broad range of acrylate derivatives, providing a flexible platform for the synthesis of structurally diverse ortho-alkenylated aryl ketones.

Having established the broad substrate generality of this manganese-catalyzed ortho-C–H alkenylation, we next evaluated its synthetic scalability, selectivity tunability and probed the underlying reaction mechanism (Scheme ). To assess the practical utility for large-scale synthesis, we scaled up the model reaction to 10 mmol. Gratifyingly, product 3a was isolated in 86% yield, which is comparable to the 0.5 mmol scale result, confirming the robustness of this protocol for preparative applications (Scheme a). Remarkably, the mono- versus bis-alkenylation selectivity could be quantitatively regulated by simply adjusting the stoichiometry of methyl acrylate. Using 1.5 equiv of 2a exclusively delivered the monoalkenylated product 3a in 93% yield, while increasing the loading to 5 equiv afforded the bis-alkenylated product 5 in 76% yield. This tunable selectivity provides a straightforward approach to access both mono- and disubstituted aryl ketones from identical starting materials (Scheme b). A competitive reaction between equimolar amounts of electron-rich 4-methoxyacetophenone (1e) and electron-deficient 4-fluoroacetophenone (1f) was conducted to probe the electronic effect on C–H activation. The reaction preferentially generated the alkenylated product from 1e, with a 3e:3f product ratio of 39:11. This observation indicates that electron-rich aromatic rings undergo faster C–H cleavage, consistent with an electrophilic C–H metalation pathway (Scheme c). We demonstrated the synthetic utility of the alkenylated products via downstream derivatization. Treatment of 3a with hydroxylamine hydrochloride converted the ketone moiety to the corresponding oxime. Subsequent rhodium-catalyzed intramolecular cyclization afforded the biologically important isoquinoline derivative 6 in 90% yield, highlighting the value of this method for the rapid construction of complex heterocyclic scaffolds (Scheme d).

4. (a−e) Larger Scale Synthesis and Mechanistic Study.

4

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Furthermore, to complete our mechanistic understanding, parallel kinetic isotope effect (KIE) experiments were conducted using acetophenone (1a) and pentadeuterated acetophenone (1a- d 5 ). The observed primary kinetic isotope effect clearly indicates that the ortho-C–H bond cleavage is involved in the rate-determining step (Scheme e).

On the basis of previous literature precedents and our experimental observations, − a plausible catalytic cycle for the manganese-catalyzed ortho–C–H alkenylation of aromatic ketones is depicted in Scheme . The catalytic cycle initiates with the transmetalation of the commercially available precatalyst manganese pentacarbonyl bromide [MnBr­(CO)5] with dimethylzinc (Me2Zn) or methylzinc bromide (BrZnMe) to generate the active catalytic species methylmanganese pentacarbonyl [MnMe­(CO)5]. Subsequent coordination of acetophenone 1a to the electrophilic manganese center of MnMe­(CO)5 forms the intermediate IN1. The key ortho-C–H bond activation step then proceeds via σ-bond metathesis, releasing one equivalent of methane (CH4) and furnishing the five-membered manganacycle intermediate IN2. This process is efficiently directed by the ketone carbonyl group, which chelates to the manganese center and brings the ortho-C–H bond into close proximity for selective activation. Reversible coordination of methyl acrylate 2a to the manganese center of IN2, combined with the activation of the alkene moiety by in situ generated Cu­(I) species (formed via the reduction of copper­(II) acetate [Cu­(OAc)2] by Me2Zn), gives rise to the intermediate IN3. Transmetalation of IN3 with Me2Zn then occurs to produce the intermediate IN4, with concomitant formation of methylzinc acetate (MeZnOAc).

5. Proposed Mechanism.

5

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Finally, ligand exchange between IN4 and a fresh molecule of substrate 1a releases the desired monosubstituted ortho-alkenylated aromatic ketone 3a, regenerates the intermediate IN1, and liberates the Cu­(I) species, thus completing the catalytic cycle. Notably, when an excess of methyl acrylate 2a is employed, the monosubstituted product 3a can re-enter the catalytic cycle to undergo a second round of ortho-C–H alkenylation, leading to the formation of the corresponding disubstituted product 5.

Experimental Section

General Procedure for the Manganese-Catalyzed ortho-C–H Alkenylation. Catalytic reactions were carried out in Schlenk tubes using oven-dried glassware. A Schlenk tube equipped with a magnetic stir bar was charged with aromatic ketone 1 (0.5 mmol), MnBr­(CO)5 (5.0 mol %, 0.025 mmol), and Cu­(OAc)2 (1.0 mmol). The tube was evacuated and backfilled with nitrogen three times. Under a strict nitrogen atmosphere, a mixed solvent of 1,4-dioxane/H2O (4:1, 5.0 mL), acrylate 2 (0.75 mmol), and Me2Zn (1.0 mmol) were added sequentially via gastight syringes. The reaction mixture was stirred at 80 °C in an oil bath for 24 h. Upon completion, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was purified by column chromatography on 200–300 mesh silica gel to afford the desired products. Detailed characterization data and copies of 1H, 13C, and 19F NMR spectra for all synthesized compounds are provided in the Supporting Information.

Conclusion

In conclusion, we have developed the first manganese-catalyzed ortho-C–H alkenylation of aromatic ketones using commercially available acrylates as alkenylating reagents, addressing a long-standing synthetic challenge that has previously been dominated exclusively by noble transition metal catalysts. By employing readily available MnBr­(CO)5 as the precatalyst and leveraging the in situ generation of highly reactive MnMe­(CO)5 species, the reaction proceeds efficiently under mild aqueous conditions. The methodology exhibits excellent functional group tolerance and broad substrate scope, accommodating a wide range of substituted acetophenones, fused aromatic ketones, and structurally diverse acrylate derivatives. Notably, the reaction can be readily scaled up to 10 mmol without significant erosion of yield, and the mono- versus bis-alkenylation selectivity can be precisely tuned by simply adjusting the stoichiometry of the acrylate coupling partner. Mechanistic investigations, including competitive experiments between electron-rich and electron-deficient aryl ketones, support an electrophilic C–H metalation pathway. The synthetic utility of this transformation is further demonstrated by the facile downstream derivatization of the alkenylated products to access biologically important isoquinoline frameworks. This work not only expands the repertoire of manganese-catalyzed C–H activation reactions but also provides a sustainable and cost-effective alternative to existing noble metal-based protocols for the synthesis of ortho-alkenylated aryl ketones. Given the ubiquity of ketone moieties in organic molecules and the inherent advantages of manganese catalysis, we anticipate that this strategy will find broad applications in the synthesis of pharmaceuticals, agrochemicals, and functional materials. Future efforts will focus on extending this catalytic system to other types of C–H functionalization reactions and developing enantioselective variants for the construction of chiral molecules.

Supplementary Material

ao6c04363_si_001.pdf (9.1MB, pdf)

Acknowledgments

This work was supported by the Youth Fund Project of Natural Science Foundation of Jiangxi Province 20242BAB21036 and 20232BAB216135.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c04363.

  • 1H and 13C NMR spectra of all newly synthesized compounds (PDF)

∥.

X.W. and X.H. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

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Supplementary Materials

ao6c04363_si_001.pdf (9.1MB, pdf)

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