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Synlett 2025; 36(11): 1553-1558
DOI: 10.1055/a-2550-1878
letter
Hydrogen Atom Transfer Reactions

Visible-Light-Induced Hydrogen-Atom-Transfer Catalysis for the Regioselective Hydroacylation of N-Sulfonylimine Esters with Aldehydes

Zhiyong Chi‡
a   Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
,
Siyuan Huang‡
a   Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
,
Guo Tang
a   Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
b   State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources, College of Chemistry, Xinjiang University, Urumqi 830017 Xinjiang, P. R. of China
,
Qianyi Zhao
c   School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, P. R. of China
,
Lei Gong 
a   Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
› Author Affiliations

We thank the National Natural Science Foundation of China (grants nos. 22371237 and 22071209), the National Youth Talent Support Program, and the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University (No. 2024Y01).
› Further Information
 
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Abstract

The hydroacylation of unsaturated π-systems with aldehydes offers a direct and atom-economical route for introducing both a hydrogen atom and an acyl group into an organic molecule. Whereas hydroacylation reactions with alkanes and alkenes are well established, transformations involving imines have been much less successful. Existing approaches often favor C–C bond formation over C–N bond formation, due to the inherent properties of imines and acyl radicals. We present a photochemical approach that specifically targets N-sulfonylimine esters in combination with aldehydes. This reaction is facilitated by a decatungstate-salt-mediated double hydrogen-atom-transfer (HAT) activation that uniquely promotes the formation of C–N bonds under mild and simple conditions. Our method permits the efficient synthesis of a broad spectrum of distinctive N-sulfonyl N-carbonyl amide products with exclusive regioselectivity. We expect this streamlined method to expand the synthetic toolkit available for constructing complex nitrogen-containing compounds.


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Key words

visible light - photocatalysis - hydrogen atom transfer - hydroacylation - imines - regioselectivity

Hydroacylation, an atom-economical process that introduces both a hydrogen atom and an acyl group into a π-system, is widely recognized as an effective and versatile strategy for constructing structurally diverse carbonyl compounds.[1] Traditionally, this transformation has relied on transition-metal catalysis, often requiring harsh reaction conditions (Scheme [1]A). Such conditions can impose limitations on functional-group compatibility and can lead to less predictable regio- and chemoselectivity outcomes.[2] Furthermore, to overcome selectivity challenges, it is frequently necessary to incorporate specific directing groups into substrates.[3]

Recently, visible-light photocatalysis has emerged as a powerful tool in organic synthesis, with successful applications in the hydroacylation of various multiple bonds, including those found in alkenes,[4] alkynes,[5] and azo compounds.[6] However, despite its potential for selective hydroacylation of unsaturated substrates such as imines to synthesize nitrogen-containing carbonyl compounds, this area has seen limited development.[7] The challenges in achieving satisfactory reactivity and selectivity for imine hydroacylation arise from the lack of suitable reaction partners and effective activation strategies. Without these, it is difficult to establish reaction conditions that promote the desired transformations while maintaining high selectivity.

In this context, Zhang and Yu introduced a visible-light-driven radical acylation of imines using α-keto acids, mediated by an electron donor–acceptor (EDA) complex (Scheme [1]B).[8] The group of Liu and Feng reported an enantioselective method in which a chiral N,N′-dioxide–Sc(OTf)₃ complex acts as a chiral Lewis catalyst in conjunction with 9-fluorenone as an electron-shuttle catalyst.[9] Both approaches result in the addition of the carbonyl group to the carbon site of C=N double bonds, yielding amine products through C–C bond formation. To invert this inherent regioselectivity, Shu et al. developed a dual catalytic system that combined an iridium-based photoredox catalyst with an N-heterocyclic carbene (NHC) catalyst.[10] This protocol generates N-centered radicals from imines, forging C–N bonds rather than C–C bonds, thereby diversifying the synthetic outcomes.

Despite these significant advances, there remains a strong demand for simplified and convenient systems capable of achieving regioselective hydroacylations of imines. Specifically, there is a need for methods that can introduce carbonyl moieties onto specific nitrogen sites, thereby expanding the toolkit for synthesizing diverse and complex amide compounds.

Zoom Image
Scheme 1 Visible-light-induced regioselective hydroacylation of N-sulfonylimine esters with aldehydes

With these considerations in mind, and as part of our ongoing efforts to develop ecofriendly and sustainable photochemical syntheses,[11] we report an efficient approach for the hydroacylation of N-sulfonylimine esters with aldehydes (Scheme [1]C). This process is enabled by a decatungstate salt-mediated hydrogen-atom-transfer (HAT) activation of both substrates under mild and simplified conditions.[12] Our method produces a diverse array of N-sulfonyl N-carbonyl amide products with high efficiency and exceptional regioselectivity.

Table 1 Optimization of the Reaction Conditionsa

Entry

Photocatalyst

Additive (equiv)

Yieldb (%)

 1

TBADT

–

59

 2

Na4[W10O32]

–

52

 3

K4[W10O32]

–

50

 4c

TBADT

–

59

 5d

TBADT

–

60

 6e

TBADT

–

50

 7

TBADT

Na2CO3 (1.0)

87

 8

TBADT

Et3N (1.0)

trace

 9

TBADT

HCO2H (1.0)

46

10

TBADT

NaBr (2.0)

78

11

–

Na2CO3 (1.0)

NDf

12g

TBADT

Na2CO3 (1.0)

ND

a Reactions conditions: 1a (0.10 mmol), 2a (0.20 mmol), photocatalyst (0.0020 mmol), MeCN (1.0 mL), LED lamp (λmax = 410 nm), 25 °C, under argon, 24 h.

b Isolated yield.

c 2a (0.50 mmol).

d Irradiation for 36 h.

e 390 nm instead of 410 nm.

f ND = not detected.

g In darkness.

We began our study by investigating the hydroacylation of imines with aldehydes using tetrabutylammonium decatungstate (TBADT) as a HAT-type photocatalyst under visible-light irradiation (Table [1]). By employing the N-sulfonylimine ester 1a and benzaldehyde (2a) as model substrates, acetonitrile as the solvent, and a 50 W LED lamp with λmax = 410 nm as the light source, we obtained the desired N-sulfonyl-N-carbonyl amide product 3 in a yield of 59% with exclusive regioselectivity within 24 hours (Table [1], entry 1). Alternative decatungstate salts, such as sodium or potassium decatungstate, were also evaluated but resulted in slightly lower yields (entries 2 and 3). Increasing the amount of aldehyde to a large excess (5.0 equivalents), extending the reaction time to 36 hours, or using stronger light irradiation at λmax = 390 nm did not further improve the outcome (entries 4–6). Subsequently, we explored the impact of additives on this transformation. Notably, adding 1.0 equivalent of Na2CO3 significantly boosted the yield to 87% (entry 7). Conversely, other bases such as triethylamine suppressed the conversion (entry 8), whereas acidic additives such as formic acid led to a reduced yield of 46% (entry 9). Notably, the addition of NaBr as an additive significantly enhanced the yield to 78% (entry 10). This improvement can be attributed to the ability of the sodium cation to modulate the solubility and dispersion of the TBADT photocatalyst, thereby facilitating more-efficient photocatalytic activity and improving the overall reaction yield. Control experiments underscored the critical roles of both the photocatalyst and light irradiation. Without TBADT or in the absence of light, the reactions failed to yield the desired product 3 (entries 11 and 12).

Zoom Image
Scheme 2 Reaction scope of the photochemical hydroacylation reaction between N-sulfonylimine esters and aryl aldehydes

Having established the optimal conditions, we proceeded to evaluate the substrate scope of the photochemical hydroacylation reaction of N-sulfonylimine esters with aldehydes (Scheme [2]). Initially, we examined a wide range of aryl aldehydes. Benzaldehydes containing electron-withdrawing groups such as bromo (products 4–6), fluoro (products 7 and 8), chloro (products 9 and 10), or cyano (product 11) were found to be compatible, yielding the corresponding products in yields ranging from 51 to 89%. Similarly, benzaldehydes featuring electron-donating groups such as methyl (products 12 and 13), ethyl (product 14), tert-butyl (product 15), methoxy (product 16), isobutoxy (product 17), phenoxy (product 18), acetoxy (product 19), benzoyloxy (product 20), trifluoromethoxy (products 21 and 22), or methylsulfanyl (product 23) also proved suitable, providing comparable yields in the range 51 to 95%. Furthermore, the reaction demonstrated versatility with aryl aldehydes containing polysubstituted benzyl rings (products 24–27), a fused naphthyl ring (product 28), or hetaryl rings (products 29–32). These substrates similarly afforded satisfactory yields (57–71%), confirming the robustness and broad applicability of this methodology. X-ray crystallographic analysis confirmed the structure of compound 33, in which the carbonyl group added to the nitrogen site of the C=N double bond.[13] Note that aliphatic aldehydes, such as cyclohexanecarbaldehyde or adamantane-1-carbaldehyde did not undergo this reaction, probably due to a mismatch in polarity between the corresponding radical intermediates generated by the two substrates. N-Sulfonylimine esters featuring a distinct ester group (products 33–36), electron-withdrawing substituents (products 37–39), electron-donating substituents within the benzenesulfonyl ring (products 40–42), or a fused naphthalenesulfonyl moiety (product 43) all gave the corresponding N-sulfonyl-N-carbonyl amide products in yields ranging from 48 to 77%.

Zoom Image
Scheme 3 Further investigations into the reaction process. (A) Reaction scale-up. (B–E) mechanistic studies. (F) Proposed mechanism.

To further investigate the reaction process, a series of experiments and spectroscopic analyses were designed and conducted (Scheme [3]). Initially, we performed a scaled-up reaction between the N-sulfonylimine ester 1b (225 mg) and benzaldehyde (2a; 212 mg), which gave the target product 33 in a 62% yield (205 mg) (Scheme [3]A). This yield was comparable to that from the small-scale syntheses, and demonstrated the scalability of this protocol.

Additionally, a byproduct resulting from the homocoupling of two molecules of 1a was detected by high-resolution mass spectrometry (HRMS). This finding suggests the involvement of N-sulfonylimine ester-based radical species in the photochemical reaction process (Scheme [3]B).

The addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the reaction of compounds 1a and 2a completely inhibited the formation of product 3. HRMS analysis revealed the presence of the TEMPO-coupled product 45, suggesting the involvement of benzoyl radicals in the photochemical reaction (Scheme [3]C).

Upon adding N-tert-butyl-1-phenylmethanimine oxide (PBN) to the standard reaction of 1a and 2a, distinctive signals (a H = 14.54 G, a N = 4.28 G) corresponding to benzoyl radical adducts were detected by electron paramagnetic resonance (EPR) spectroscopy (Scheme [3]D).[14] HRMS analysis also confirmed the generation of the PBN-adducts 46 and 47.

Moreover, the reaction progression from 1a and 2a to product 3 exhibited a clear light-dependent profile, demonstrating a pronounced response to light–dark cycles. This observation implied that light exposure is essential for the progress of the reaction (Scheme [3]E).

Based on these preliminary experiments and mechanistic studies, a plausible reaction pathway is proposed (Scheme [3]F). The process begins with the decatungstate salt TBADT (PC) absorbing photons from the LED irradiation, thereby becoming excited to its active state, PC*. This excited photocatalyst abstracts a hydrogen atom from benzaldehyde (2a) to give its hydrogenated form PC-H with generation of a benzoyl radical INT-I.[15] Subsequently, a second HAT event between PC-H and the N-sulfonylimine ester substrate 1a results in the formation of an N-centered radical intermediate INT-II and regeneration of the photocatalyst PC. Finally, coupling of intermediates INT-I and INT-II leads to the formation of the target product 3. In this mechanism, the polarity match between the N-sulfonylimine ester 1a and the hydrogenated photocatalyst PC-H plays a crucial role in ensuring an efficient second HAT process that generates the key N-centered radical INT-II for the subsequent C–N radical coupling process.

In summary, we have developed an effective and regioselective hydroacylation reaction of N-sulfonylimine esters with aryl aldehydes, facilitated by decatungstate salt-mediated HAT catalysis.[16] This method permits the synthesis of a wide variety of unique N-sulfonyl N-carbonyl amide products with high efficiency and exceptional regioselectivity under mild and simple conditions. Systematic mechanistic studies, including byproduct identification, radical-probing experiments, EPR analysis, light on/off experiments, supporting a reaction pathway involving radical–radical coupling between benzoyl radicals and N-centered radicals derived from N-sulfonylimine esters. The continuous HAT events and polarity match effects are believed to play a crucial role in this transformation. This methodology expands the toolkit available for synthesizing complex nitrogen-containing compounds. Ongoing research in our laboratory is exploring its application in asymmetric synthesis, which promises to further enhance its utility in organic synthesis.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2550-1878.
  • Supporting Information
  • CIF File

  • References and Notes

    • 6a Koutoulogenis GS, Kokotou MG, Voutyritsa E, Limnios D, Kokotos CG. Org. Lett. 2017; 19: 1760
      Search in Google Scholar
    • 6b Stini NA, Poursaitidis ET, Nikitas NF, Kartsinis M, Spiliopoulou N, Ananida-Dasenaki P, Kokotos CG. Org. Biomol. Chem. 2023; 21: 1284
      Search in Google Scholar
    • 6c Liu L, Wang J, Feng X, Xu K, Liu W, Peng X, Du H, Tan J. Chin. J. Chem. 2024; 42: 1230
      Search in Google Scholar
    • 6d Li Q, Chen J, Luo Y, Xia Y. Org. Lett. 2024; 26: 1517
      Search in Google Scholar
  • 7 Mistry P, Das S, Patra R, Chatterjee I. Org. Chem. Front. 2024; 11: 6778
    Search in Google Scholar
  • 8 Zhang H.-H, Yu S. Org. Lett. 2019; 21: 3711
    Search in Google Scholar
  • 9 Zhong Z, Wu H, Chen X, Luo Y, Yang L, Feng X, Liu X. J. Am. Chem. Soc. 2024; 146: 20401
    Search in Google Scholar
  • 10 Liu M.-S, Shu W. ACS Catal. 2020; 10: 12960
    Search in Google Scholar
  • 13 CCDC 2412678 contains the supplementary crystallographic data for compound 33. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 14 Buettner GR. Free Radical Biol. Med. 1987; 3: 259
    Search in Google Scholar
  • 15 Dong J, Wang X, Wang Z, Song H, Liu Y, Wang Q. Chem. Sci. 2020; 11: 1026
    Search in Google Scholar
  • 16 Ethyl 2-Benzoyl-2,3-dihydro-1,2-benzisothiazole-3-carboxylate 1,1-Dioxide (3); Typical Procedure A dried Schlenk tube (10 mL) was charged with the N-sulfonylimine ester 1a (23.9 mg, 0.10 mmol), PhCHO (2a; 21.2 mg, 0.20 mmol), TBADT (6.6 mg, 0.0020 mmol), Na2CO3 (10.6 mg, 0.10 mmol), and MeCN (1.0 mL). The mixture was then degassed with argon through three freeze–pump–thaw cycles. The Schlenk tube was positioned approximately 4 cm from a 50 W lamp, and the mixture was stirred at 25 °C for 24 h. The resulting mixture was then purified by flash column chromatography [silica gel, PE–EtOAc (4:1)] to give a white solid; yield: 30.0 mg (0.087 mmol, 87%). 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.1 Hz, 2 H), 7.78–7.63 (m, 3 H), 7.56 (q, J = 7.5 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 2 H), 6.13 (s, 1 H), 4.32–4.14 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 168.32, 166.39, 134.32, 134.20, 133.59, 132.57, 130.76, 128.71, 128.41, 128.36, 125.38, 62.96, 59.86, 14.04. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO5S: 368.0563; found: 368.0567.

Corresponding Author

Lei Gong
Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University
Xiamen, Fujian 361005
P. R. of China   

Publication History

Received: 11 February 2025

Accepted after revision: 03 March 2025

Accepted Manuscript online:
03 March 2025

Article published online:
10 April 2025

© 2025. Thieme. All rights reserved

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  • References and Notes

    • 6a Koutoulogenis GS, Kokotou MG, Voutyritsa E, Limnios D, Kokotos CG. Org. Lett. 2017; 19: 1760
      Search in Google Scholar
    • 6b Stini NA, Poursaitidis ET, Nikitas NF, Kartsinis M, Spiliopoulou N, Ananida-Dasenaki P, Kokotos CG. Org. Biomol. Chem. 2023; 21: 1284
      Search in Google Scholar
    • 6c Liu L, Wang J, Feng X, Xu K, Liu W, Peng X, Du H, Tan J. Chin. J. Chem. 2024; 42: 1230
      Search in Google Scholar
    • 6d Li Q, Chen J, Luo Y, Xia Y. Org. Lett. 2024; 26: 1517
      Search in Google Scholar
  • 7 Mistry P, Das S, Patra R, Chatterjee I. Org. Chem. Front. 2024; 11: 6778
    Search in Google Scholar
  • 8 Zhang H.-H, Yu S. Org. Lett. 2019; 21: 3711
    Search in Google Scholar
  • 9 Zhong Z, Wu H, Chen X, Luo Y, Yang L, Feng X, Liu X. J. Am. Chem. Soc. 2024; 146: 20401
    Search in Google Scholar
  • 10 Liu M.-S, Shu W. ACS Catal. 2020; 10: 12960
    Search in Google Scholar
  • 13 CCDC 2412678 contains the supplementary crystallographic data for compound 33. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 14 Buettner GR. Free Radical Biol. Med. 1987; 3: 259
    Search in Google Scholar
  • 15 Dong J, Wang X, Wang Z, Song H, Liu Y, Wang Q. Chem. Sci. 2020; 11: 1026
    Search in Google Scholar
  • 16 Ethyl 2-Benzoyl-2,3-dihydro-1,2-benzisothiazole-3-carboxylate 1,1-Dioxide (3); Typical Procedure A dried Schlenk tube (10 mL) was charged with the N-sulfonylimine ester 1a (23.9 mg, 0.10 mmol), PhCHO (2a; 21.2 mg, 0.20 mmol), TBADT (6.6 mg, 0.0020 mmol), Na2CO3 (10.6 mg, 0.10 mmol), and MeCN (1.0 mL). The mixture was then degassed with argon through three freeze–pump–thaw cycles. The Schlenk tube was positioned approximately 4 cm from a 50 W lamp, and the mixture was stirred at 25 °C for 24 h. The resulting mixture was then purified by flash column chromatography [silica gel, PE–EtOAc (4:1)] to give a white solid; yield: 30.0 mg (0.087 mmol, 87%). 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.1 Hz, 2 H), 7.78–7.63 (m, 3 H), 7.56 (q, J = 7.5 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 2 H), 6.13 (s, 1 H), 4.32–4.14 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 168.32, 166.39, 134.32, 134.20, 133.59, 132.57, 130.76, 128.71, 128.41, 128.36, 125.38, 62.96, 59.86, 14.04. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO5S: 368.0563; found: 368.0567.

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Zoom Image
Scheme 1 Visible-light-induced regioselective hydroacylation of N-sulfonylimine esters with aldehydes
Zoom Image
Scheme 2 Reaction scope of the photochemical hydroacylation reaction between N-sulfonylimine esters and aryl aldehydes
Zoom Image
Scheme 3 Further investigations into the reaction process. (A) Reaction scale-up. (B–E) mechanistic studies. (F) Proposed mechanism.