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DOI: 10.1039/D5GC02308D (Communication) Green Chem., 2025, Advance Article

Kinetic-control difunctionalization of olefins to α-hydroxycarbonyls under catalyst-free conditions

Hong-Yu Houab, Yuan-Yuan Chengab, Xin-Yu Zhangab, Ke Zhangab, Hui-Zhen Renab, Kaiyi Suab, Zhiyuan Huangab, Bin Chenab, Chen-Ho Tungab and Li-Zhu Wu*ab
aKey Laboratory of Photochemical Conversion and Optoelectronic Materials & CAS-HKU Joint Laboratory on New Materials, New Cornerstone Science Laboratory, Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100190, P. R. China. E-mail: lzwu@mail.ipc.ac.cn
bSchool of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, P. R. China

Received 9th May 2025 , Accepted 24th July 2025

First published on 1st August 2025

Abstract

Difunctionalization of olefins is effective in constructing diverse, valuable molecules. However, such a reaction always relies on catalysts to control activity and selectivity. Herein, a catalyst-free difunctionalization of olefins with sulfonyl or alkyl precursors and 1,2-dicarbonyls is reported to synthesize complex α-hydroxycarbonyls under visible light irradiation.


Green foundation

1. Valuable and complex α-hydroxycarbonyls, central motifs in many natural products and pharmaceuticals, are synthesized via a catalyst-free difunctionalization of olefins with sulfonyl or alkyl precursors and 1,2-dicarbonyls under mild conditions.

2. A new mechanism is established to control chemo- and regio-selectivity in the absence of a catalyst. The kinetic advantage of the single-electron transfer process between the excited-state 1,2-dicarbonyl substrates and sulfonyl or alkyl precursors, over the Paternò–Büchi reaction between 1,2-dicarbonyls and olefins, determines the chemo- and regio-selectivity of α-hydroxycarbonyls.

3. This reaction is directly driven by visible light without the need for any catalysts or additives, which is greener to achieve pharmaceuticals involving α-hydroxycarbonyl skeletons, beneficial for new drug development.


Difunctionalization of olefins is widely used to install two adjacent functional groups simultaneously to construct diverse, valuable structures from simple molecules.1–3 Over the past decades, transition metal catalysis,4–6 N-heterocyclic carbene catalysis7–9 and photocatalysis10,11 have been established to activate the substrate and control reaction selectivity. These catalysts activate radical precursors through single electron transfer (SET) or energy transfer (EnT) to generate radicals, which are then added to the β-position of alkenes to produce alkyl radicals.12–14 The alkyl radicals are then coupled with nucleophiles,15,16 electrophiles,17,18 persistent radicals19,20 or radical acceptors21,22 to afford difunctionalization products. In the absence of a catalyst, however, the difficulty in substrate activation23 and the self-coupling of radicals24 always result in negative effects, especially for a three-component reaction.

Herein, a catalyst-free difunctionalization of olefins with sulfonyl or alkyl precursors and 1,2-dicarbonyls is reported to construct complex α-hydroxycarbonyls, central motifs in many natural products and pharmaceuticals (Scheme 1).25–27 The key to success is that 1,2-dicarbonyls absorb light to reach spin-polarized diradical triplet states,28,29 and then interact with radical precursors and alkenes in a kinetic manner. The SET process from sulfonyl or alkyl precursors to the excited 1,2-dicarbonyls is kinetically favorable to generate sulfonyl or alkyl and ketyl radicals. Immediately, the sulfonyl or alkyl radicals are added to olefins, leading to benzyl radicals. By contrast, the Paternò–Büchi reaction between 1,2-dicarbonyls and olefins is too slow to generate oxetanes. Finally, the cross-coupling of the ketyl radicals and benzyl radicals provides α-hydroxycarbonyls. This protocol provides a route to control chemo- and regioselectivity resulting from the kinetic difference of interaction between the excited-state substrate and the ground-state substrate.


image file: d5gc02308d-s1.tif
Scheme 1 Catalyst-free difunctionalization of olefins to produce α-hydroxycarbonyls.

Initially, methyl benzoylformate 1a, sodium 4-methylbenzenesulfinate 2a and styrene 3a were allowed to react under 460 nm irradiation in DMF, and the targeted α-hydroxycarbonyl product 4a was obtained in 46% yield (Table 1, entry 1). LEDs with shorter wavelengths were screened, and 405 nm was determined as the best, giving a yield of 72% (Table 1, entries 2, 4 and 5). When DMF was substituted with a mixed solvent of MeCN and H2O, the yield was reduced to 56% (Table 1, entry 6). When the concentration of reactants was increased by reducing the volume of DMF, the yield improved to 80% (Table 1, entry 7). This result is equivalent to the yield obtained with a catalyst under blue light (Table 1, entry 3). In control experiments, irradiation and an argon atmosphere proved to be necessary, as no product was detected in the dark (even at high temperature) or in air (Table 1, entries 8 and 9).

Table 1 Optimization of the reaction conditionsa

image file: d5gc02308d-u1.tif
Entry Light source (nm) Solvent Yieldb (%)
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol) and 3a (0.6 mmol) in a solvent (2.0 mL) under LED irradiation for 12 h at room temperature under an Ar atmosphere.b 1H NMR yield with 2,2-diphenylacetonitrile as an internal standard.c 4CzIPN (2 mol%).d 3a (0.4 mmol), DMF (1.0 mL).e Room temperature or 80 °C.f In air.
1 460 DMF 46
2 440 DMF 68
3c 440 DMF 80
4 405 DMF 72
5 365 DMF 61
6 405 MeCN[thin space (1/6-em)]:[thin space (1/6-em)]H2O = 4[thin space (1/6-em)]:[thin space (1/6-em)]1 56
7d 405 DMF 80
8e — DMF 0
9f 460 DMF 0

UV–visible (UV–vis) absorption spectra excluded the formation of an electron donor–acceptor (EDA) complex, as neither a bathochromic shift nor a new absorption peak was observed in the reactant mixture (Scheme 2a). The Stern–Volmer plots revealed that the excited 1a* was quenched by 2a more efficiently than by 3a (Fig. S10 and S11). In time-resolved photoluminescence (TRPL) spectra (Fig. S12 and S13), the quenching rate constants of 1a* by 2a and 3a were determined as 5.9 × 109 M−1 s−1 and 4.0 × 108 M−1 s−1, respectively (Scheme 2b), indicating that 1a* was quenched by 2a roughly 15 times faster than by 3a. Based on UV–vis absorption spectra (Fig. S8), photoluminescence spectra and the redox potential of ground state 1a (E(1a/1a˙−) = −1.34 V vs. SCE in MeCN),30 the redox potential of the excited 1a* [E(1a*/1a˙−)] can be estimated as +1.64 V vs. SCE,31,32 enabling complete oxidation of 2a (E(2a˙+/2a) = +0.32 V vs. SCE in MeCN).33 Therefore, 75% of 1a* was intercepted by 2a (0.1 M) through the SET process and only 15% of 1a* was intercepted by 3a (0.3 M) through EnT. Consistent with the above results, 56% of 4a was obtained through the SET process between 1a* and 2a, and the following radical addition of the generated sulfonyl radical to 3a produced a benzyl radical, which finally underwent cross-coupling with a ketyl radical (Scheme 2c). By contrast, only 12% of oxetane 4a′ was obtained by the direct addition of 1a* to 3a and the subsequent intramolecular cyclization. In the absence of 2a, 4a′ was produced in 57% yield under the same conditions. These results mutually validated that the rate of the SET process between 1a* and 2a and the following radical addition and cross-coupling process is faster than that of the Paternò–Büchi reaction between 1a* and 3a. In a radical clock experiment, the cyclopropane moiety on (1-(2-phenylcyclopropyl)vinyl)benzene 3b opened to generate the sole linear product 4b in 53% isolated yield (Scheme 2d), suggesting that the reaction involved a benzyl radical. When 2 equiv. of 1,1-diphenylethylene (DE) or 2,6-di-tert-butyl-4-methylphenol (BHT) were added to the reaction system, the yield of 4a was obviously decreased (Scheme 2e). Adding 2 equiv. of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), the generation of 4a was completely inhibited, while the adducts of TEMPO with benzyl and ketyl radicals were detected by HRMS (Scheme 2f). These results supported a possible reaction pathway where sulfonyl radicals were added to alkenes to produce benzyl radicals, which then underwent radical cross-coupling with ketyl radicals to afford our desired α-hydroxycarbonyls.


image file: d5gc02308d-s2.tif
Scheme 2 Mechanism studies: (a) UV–vis absorption spectra of 1a (0.2 M), 2a (0.1 M), and 3a (0.2 M) in a mixed solvent of MeCN[thin space (1/6-em)]:[thin space (1/6-em)]H2O = 4[thin space (1/6-em)]:[thin space (1/6-em)]1. (b) Fitting results of TRPL of 1a (0.1 M) with different concentrations of 2a and 3a. (c–f) Competitive reactions and radical experiments. 1H NMR yield with 2,2-diphenylacetonitrile as an internal standard. a[thin space (1/6-em)]Isolated yield.

A range of alkenes, aromatic 1,2-dicarbonyls, sulfinates and bis(catecholato)silicates were used to examine the generality of this protocol (Scheme 3). The different electronic effects and steric effects showed good tolerance when alkenes were tested with 1a and 2a as reaction partners. Electron-withdrawing groups including F, Cl, p-Br, m-Br, o-Br and CF3, and electron-donating groups including MeO, p-Me, m-Me and 2,5-dimethyl all worked smoothly to provide their products in 39%–89% yields (4c–4l). Br substitution at different sites showed an obvious steric hindrance effect (4e–4g). Styrenes with larger steric hindrance, such as α-,β-methyl styrenes, 1,2-dihydronaphthalene and vinylnaphthalene, gave 32%–64% yields (4m–4p). The addition of a sulfonyl radical to 4p produced an α-naphthalene carbon radical intermediate with a larger electron delocalization range. The smaller difference between the self-coupling reaction rate constant of the α-naphthalene carbon radical and that of the ketyl radical led to lower selectivity for their cross-coupling.24 2-Vinylpyridine (4q) gave low yields, due to the detrimental electron-withdrawing effect. Alkyl butadiene afforded a distal sulfonylation product (4r) in high yield. The α-ketoesters with different alkyl groups on ester moieties and different electronic effects on arenes were all compatible (4s–4x, 58%–79%). 1,2-Diketones with different electronic effects were transformed with yields up to 94% (4y–4ab). Both aromatic and aliphatic sulfinates were successfully converted to the corresponding products in 49%–78% yields (4ac–4ag). Bis(catecholato)silicates were chosen as alkyl precursors,34 using styrene and benzil as reaction partners. Unstabilized primary and secondary alkyl radicals were converted to target products in 50%–72% yields (4ah–4al). Styrenes with strong electron-donating MeO and electron-withdrawing CF3 groups, as well as benzyls with MeO and F groups, were all suitable (4am–4ap, 51%–85%). An α-ketoester offered a low yield (4aq, 27%), and methyl mandelate was obtained as a by-product in 28% yield based on 1a. 4-Iodotoluene and DABSO (1,4-diazabicyclo [2.2.2] octane-sulfur dioxide) were used instead of 2a in a four-component coupling reaction with phenanthrene-9,10-dione and 3a in the presence of DIPEA (N,N-diisopropylethylamine) (Scheme 3). The β-sulfonylated four-component coupling product 4ar, the β-arylated three-component coupling product 4as, and the two-component coupling product 4as′ were obtained in 12%, 10% and 8% yields, respectively. This reaction may proceed via a halogen atom transfer (XAT) process promoted by in situ-generated α-aminoalkyl radicals to afford aryl radicals,35 which then underwent three different processes including (i) sulfur dioxide insertion36–39 to form sulfonyl radicals, finally leading to 4ar, (ii) radical relay with 3a, finally producing 4as, and (iii) direct cross-coupling with ketyl radicals, generating 4as′. This reaction was complicated by the competitive trapping of the aryl radical intermediate by DABSO and 3a. A gram-scale experiment (3 mmol) afforded 4l in 71% yield, implying the potential of this light-driven difunctionalization of alkene for scaled-up production of complex α-hydroxycarbonyls.


image file: d5gc02308d-s3.tif
Scheme 3 Substrate scope. Standard reaction conditions (Table 1, entry 7). dr = 1[thin space (1/6-em)]:[thin space (1/6-em)]1. a[thin space (1/6-em)]A gram-scale experiment of 2a (3 mmol, 1 equiv.) for 18 h. b[thin space (1/6-em)]3 (3 eq.) under 460 nm LED irradiation in EtOH (2 mL). c[thin space (1/6-em)]1 (2.5 eq.) and 3 (4 eq.) in DMF (2 mL) under 460 nm LED irradiation for 9 h. d[thin space (1/6-em)]1 (2.5 eq.), 2 (0.1 mmol), and 3 (4 eq.) under 460 nm LED irradiation for 9 h. e[thin space (1/6-em)]3 (3 eq.). f[thin space (1/6-em)]phenanthrene-9,10-dione (2 eq.), 4-Iodotoluene (2 eq.), DABSO (2 eq.) and 3a (0.2 mmol) with DIPEA (3 eq.) additive in dry MeCN (2 mL) under 460 nm LED irradiation. g[thin space (1/6-em)]based on 4-Iodotoluene.

Conclusions

In summary, we constructed complex α-hydroxycarbonyls via catalyst-free difunctionalization of olefins under visible light irradiation. Different from the well-studied Paternò–Büchi reaction of 1,2-dicarbonyls with olefins, the SET process from sulfonyl or alkyl precursors to excited 1,2-dicarbonyls is kinetically favorable, generating sulfonyl or alkyl radicals and ketyl radicals. The sulfonyl or alkyl radicals are immediately added to olefins to offer benzyl radicals. Then, the cross-coupling process between benzyl radicals and the ketyl radicals affords α-hydroxycarbonyls. This study achieves an ideal catalyst-free difunctionalization of alkenes based on the kinetic difference of interaction between the excited-state substrate and the ground-state substrate, showing good chemo- and regioselectivity, a broad substrate scope and potential large-scale synthesis.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

The data underlying this study are available in the manuscript and its SI: materials, methods, experimental details, additional data, and NMR spectra for all compounds. See DOI: https://doi.org/10.1039/d5gc02308d.

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2023YFA1507200, 2021YFA1500100, and 2022YFA1503200), the National Natural Science Foundation of China (22193013, 22471281 and 22088102), the Beijing Natural Science Foundation (2242023), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0960000), the CAS Project for Young Scientists in Basic Research (YSBR-094), and the New Cornerstone Science Foundation.

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