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. 2022 Dec 8;3(2):96–103. doi: 10.1021/acsorginorgau.2c00053

Photochemical [2 + 2] Cycloaddition of Alkenes with Maleimides: Highlighting the Differences between N-Alkyl vs N-Aryl Maleimides

Elpida Skolia 1, Christoforos G Kokotos 1,*
PMCID: PMC10080724  PMID: 37035280

Abstract

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Throughout the last 15 years, there has been increased research interest in the use of light promoting organic transformations. [2 + 2] Cycloadditions are usually performed photochemically; however, literature precedent on the reaction between olefins and maleimides is limited to a handful of literature examples, focusing mainly on N-aliphatic maleimides or using metal catalysts for visible-light driven reactions of N-aromatic maleimides. Herein, we identify the differences in reactivity between N-alkyl and N-aryl maleimides. For our optimized protocols, in the case of N-alkyl maleimides, the reaction with alkenes proceeds under 370 nm irradiation in the absence of an external photocatalyst, leading to products in high yields. In the case of N-aryl maleimides, the reaction with olefins requires thioxanthone as the photosensitizer under 440 nm irradiation.

Keywords: Photochemistry, Organocatalysis, [2 + 2]-Cycloadditions, Maleimides, Alkenes

Introduction

Throughout the history of organic synthesis, the identification of novel reaction methodologies that provide unreported activation modes played a focal role.1 In order to propose new reactivities, the reaction mechanism of the targeted reaction has to be elucidated.2 For more than a century, photochemistry, the use of light to promote organic reactions, has been known,3 but researchers did not exploit it, probably due to the harsh reaction conditions employed back then and the lack of understanding of the inherent reactivity of radicals. Since the reemergence of photochemistry in 2008 and the introduction of photoredox catalysis, researchers have gained valuable knowledge and comprehension on photochemical processes.4−28 Photochemical [2 + 2] cycloadditions are considered textbook chemistry today and have been known for over a century; however, research is still needed to provide alternative and improved protocols to access different scaffolds and widen the applicability of [2 + 2] cycloadditions. In this work, we report a detailed study on the photochemical reactivity of substituted maleimides, using their photophysical properties, in order to classify them and develop suitable protocols accordingly. In short, we provide a unified solution for the successful use of substituted maleimides in [2 + 2] reactions with alkenes and provide an explanation for the lack of literature precedent for N-aryl-maleimide family of compounds in such reactions.

[2 + 2] Photocycloadditions are a typical example of photochemical reactions, since the corresponding thermal reaction is forbidden. The outcome of such a cycloaddition is a cyclobutane core, which can be found in a number of biologically important natural products or pharmaceuticals (Figure 1).29−33

Figure 1.

Figure 1

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Pharmaceuticals or natural products having a cyclobutane core.

The [2 + 2] photocycloaddition of the alkene-double bond, intramolecularly or intermolecularly, has been well-studied, and numerous examples exist in the literature, like alkene-Michael acceptor, alkene-imine, Paterno-Buchi, aza- or thia-Paterno-Buchi, etc (Scheme 1A).34−45 At the same time, the [2 + 2] cycloaddition between maleimides and alkenes is far less studied. N-Alkyl substituted maleimides have been described to react with electron-poor olefins either under catalyst-free conditions using a Hannovia lamp46 or by using benzophenone as the photocatalyst at 366 nm (Scheme 1B).47,48 Only in the latter case, a single example using an N-aryl maleimide was disclosed, albeit in low yield.48 Moving from electron-poor alkenes to unactivated olefins, their [2 + 2] photochemical cycloaddition with N-H or N-alkyl maleimides has been described using mainly Hg lamps as the irradiation source; however, in all cases, a limited number of examples were showcased (Scheme 1C).49−54 In most cases involving N-alkyl maleimides, no photosensitizer is employed, since self-excitation of the maleimide under the harsh UV irradiation was enough to promote the reaction. As mentioned above, only a single example employing an aryl-substituted maleimide (e.g., N-Ph maleimide) was reported.48 In order for N-Ph maleimide to react and afford the desired product, its triplet state should be generated. Based on the photophysical studies by von Sonntag and co-workers55−57 [the triplet quantum yields (the ease of self-generation of triplet from singlet state upon irradiation) of differently substituted maleimides span from unity (N-H maleimide), 0.07 (N-ethyl maleimide), 0.03 (N-Me maleimide) to zero (N-Ph maleimide)56], it is obvious why the reaction with N-Ph maleimide does not generate the desired product. In the case of N-aryl maleimides, Sivaguru and co-workers have described both the intra- and intermolecular reaction with alkenes, utilizing a photosensitizer at 20 mol % (Scheme 1D).35,36 The focus of both studies was the ratio of atropoisomers obtained, while in the case of the intermolecular reaction, a high 10:1 ratio of reactants was employed.36 During the course of our investigation, He and Liu disclosed a systematic study where 405 nm LED irradiation was employed, in conjunction with an expensive iridium-based photocatalyst to promote these challenging [2 + 2] photocycloadditions (Scheme 1E).58 The authors mainly employed a number of electron-poor and electron-rich alkenes with both N-alkyl substituted maleimides and N-Ph maleimide that led to products from good to excellent yield and diastereoselectivities that varied from 1.6:1 to >20:1.58 Unfortunately, the differences on reactivity between these types of maleimides were not presented, since in all cases, the Ir-based photocatalyst was employed.58 Other N-substituted aromatic maleimides were not employed. Curiously, thioxanthone proved to be a very poor photocatalyst in their case.58

Scheme 1. Photochemical [2 + 2] Cycloadditions.

Scheme 1

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Since 2014, our group has been actively involved in photochemistry59 reporting various organic molecules as photomediators.60−69 For example, phenylglyoxylic acid was identified as a new photoinitiator,60−63 employing cheap household lamps as the irradiation source and water as the solvent, while very recently thioxanthone was studied for its photocatalytic properties.64,66 In the literature, most reports deal with the use of N-alkyl maleimides (either with the use of a photocatalyst or without), not paying attention to N-aryl maleimides or the reason why this class of substrates fails to lead to the desired products. Also, there is a single report on the successful use of both N-alkyl and N-aryl maleimides,58 using the same Ir catalyst, without stating whether these two classes exhibit any differences in reactivity. Herein, we present our detailed studies on the reactivity differences of N-alkyl to N-aryl maleimides, while offering a solution for the photochemical [2 + 2] cycloaddition of both N-alkyl or N-aryl maleimides to alkenes (Scheme 1F).

Results and Discussion

Based on previous knowledge obtained in our group regarding the [2 + 2] photocycloaddition between N-substituted maleimides and triple bonds70 and literature precedent,34−54,58 we embarked on investigating the feasibility and differences on reactivity (N-alkyl vs N-aryl maleimides) of a [2 + 2] cycloaddition between maleimides and olefins for the formation of cyclobutane scaffolds. Two different approaches were implemented based on the photophysical properties of maleimides depending on their N-substitution. Exploiting the fact that N-alkyl substituted have an adequate triplet quantum yield, we started by irradiating N-benzyl maleimide (1) with styrene (2) in CH2Cl2 under a UVA LED lamp (Kessil PR160L 370 nm), receiving successfully the corresponding product 3 with a diastereomeric ratio 65:35 (Table 1, entry 1). We proceeded to investigate this reaction using different irradiation wavelengths, as well as different solvents. The reaction proceeded smoothly at 370 nm, as well as 390 nm, but in the latter case in a lower yield (Table 1, entry 2). When the irradiation wavelength was increased, the reaction failed to take place (Table 1, entries 3, 4, 6–10), as was expected, and substrate polymerization was observed. Moreover, it is possible to perform the reaction under visible-light irradiation and thioxanthone sensitization, albeit at a lower yield (54%, entry 5). Choosing to continue with the best result at 370 nm, screening of different solvents showed that the best results considering yield and diastereomeric ratio are obtained using CH2Cl2.71 Unlike the previous protocol from our group, where triple bonds were employed, the use of HFIP did not assist the reaction but rather impeded it (Table 1, entry 11), probably via acceleration of the polymerization of the styrene. We then proceeded to study the [2 + 2] cycloaddition between N-aryl substituted maleimides, employing again styrene as the model substrate (Table 2). The reaction was not possible in the absence of a photocatalyst at any irradiation wavelength from 370 to 525 nm (Table 2, entries 1–6), which is in accordance with the inability of N-aryl maleimides to successfully undergo intersystem crossing to their triplet state.70 Our first attempts utilizing thioxanthone, a known and simple photosensitizer,59 at 20 mol % catalyst loading proved fruitful, affording the two desired diastereomers in 72% yield and 70:30 ratio after irradiation at 370 nm (Table 2, entry 7). We then moved on examining the optimum irradiation wavelength, ending up at blue LED irradiation at 440 nm (Kessil PR160L 440 nm), providing a 72% yield and 70:30 ratio of 5 (Table 2, entry 10 vs entries 7–12). Solvent screening showed that CH2Cl2 as well as CHCl3 (Table 2, entries 10 and 17 vs 13–16) are the best solvents, albeit CH2Cl2 was chosen as it gave better diastereomeric ratio and a cleaner reaction.71 Again, the presence of HFIP did not prove to be of any assistance to the reaction (Table 2, entries 18–20). Other photosensitizers were also tested, but none of them outperformed thioxanthone.71 Having identified the optimum reaction conditions for N-alkyl, as well as N-aryl substituted maleimides, we proceeded to investigate the substrate scope for both protocols. We began by testing different olefins in their reaction with N-benzyl maleimide (1) (Scheme 2). Styrene and styrene derivatives were tested and afforded the corresponding products 3, 7, and 8 in good diastereomeric ratio good yield, except from 4-methylstyrene, which only gave a moderate yield. α-Methylstyrene failed to give a successful reaction with N-benzyl maleimide under UVA irradiation. Different aliphatic olefins reacted successfully with N-benzylmaleimide, affording the corresponding products in good yields. More specifically, products of the reaction with terminal aliphatic olefins, like 1-decene (9), vinyl (10), or allyl (11) systems, as well as a cyclic olefins, like cyclohexene (15), were obtained in high yields. The presence of a phenyl (12) or a bromine group (13), as well as an allylic TMS group (14), did not affect the cycloaddition. Moreover, the reaction of 1 with dihydropyran (16) led to 95% yield of the isolated products. Ethyl acrylate and methyl vinyl ketone were also tested as representative electron-deficient olefins, affording the corresponding products 17 and 18 in satisfactory yields, respectively. In the case of methyl vinyl ketone, 18a was isolated after column chromatography. The reaction mixture was quite complicated, and the minor diastereomer of 18 was not isolated by column chromatography, while in the crude reaction mixture its presence was in trace amounts, if any. In all cases, 1H NMR chemical shifts can be used to identify different diastereomers, with the all-cis-proton configuration on the cyclobutane being the minor diastereomer and the proton of the carbon bearing the substituent of the alkene resonating at higher ppm chemical shift vs the corresponding proton of the other diastereomer. The lack of adequate analysis on the stereochemistry of these particular products in the literature led us also to conduct two-dimensional NMR experiments (COSY and NOESY) to extract information about the relative stereochemistry of 3, 9, 15, and 16 and verify the stereochemistry of our products.71 In all instances, the proposed stereochemistry of our method is in agreement with literature (in the cases that compounds are known). Next, we sought to investigate the maleimide scope by testing different N-aliphatic maleimides in their reaction with styrene under UVA irradiation. The photocycloaddition was successful, leading to products deriving from 2-phenylethyl (19), methyl (20), primary (21 and 22), and secondary (23 and 24) N-substituted maleimides.

Table 1. Optimization of the Reaction Conditions for the Photochemical [2 + 2] Cycloaddition of Styrene to N-Alkyl Maleimides.

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entry lamp (nm) solvent yield (%)a dr (3a:3b)b
1 370 CH2Cl2 67 65:35
2 390 CH2Cl2 50 70:30
3 427 CH2Cl2 2  
4 440 CH2Cl2 0  
5 440/20 mol % THX CH2Cl2 54 65:35
6 525 CH2Cl2 0  
7 CFL CH2Cl2 0  
8 370 CHCl3 45 63:37
9 370 MeCN 53 58:42
10 370 EtOAc 52 70:30
11 370 CH2Cl2:HFIP (4:1) 39 49:51
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a

Yield was determined by 1H NMR using an internal standard.

b

Dr was determined by 1H NMR in the crude reaction mixture.

Table 2. Optimization of the Reaction Conditions for the Photochemical [2 + 2] Cycloaddition of Styrene to N-Aryl Maleimides.

graphic file with name gg2c00053_0007.jpg

entry catalyst (mol %)/lamp (nm) solvent yield (%)a dr (5a:5b)b
1 –/370 CH2Cl2 7  
2 –/390 CH2Cl2 2  
3 –/427 CH2Cl2 0  
4 –/440 CH2Cl2 2  
5 –/456 CH2Cl2 0  
6 –/467 CH2Cl2 0  
7 THX (20)/ 370 CH2Cl2 72 (62) 70:30
8 THX (20)/390 CH2Cl2 42 70:30
9 THX (20)/427 CH2Cl2 (49) 75:25
10 THX (20)/440 CH2Cl2 75 (72) 75:25
11 THX (20)/456 CH2Cl2 59 (54) 50:50
12 THX (20)/467 CH2Cl2 49 50:50
13 THX (20)/440 EtOAc 69 (64) 60:40
14 THX (20)/440 MeCN 60 (55) 60:40
15 THX (20)/440 MeOH 65 (59) 50:50
16 THX (20)/440 Toluene 77 (70) 50:50
17 THX (20)/440 CHCl3 80 (74) 65:35
18 THX (20)/370 CH2Cl2:HFIP (4:1) 33 50:50
19 THX (20)/427 CH2Cl2:HFIP (4:1) 67 (50) 75:25
20 THX (20)/440 CH2Cl2:HFIP (4:1) 45 (35) 70:30
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a

Yield was determined by 1H NMR using internal standard. Yield of isolated product after column chromatography is presented in parentheses.

b

Dr was determined by 1H NMR in the crude reaction mixture.

Scheme 2. Substrate Scope of the Photochemical Reaction between Alkenes and N-Alkyl Maleimides.

Scheme 2

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Moving to N-aryl substituted maleimides (Scheme 3), we began by testing different substituted styrenes (5, 25–27) and obtained the desired products in good yields, with the exception of 4-methylstyrene (26). In this case, α-methylstyrene proved to be a good substrate. Different aliphatic olefins led to the desired cyclobutane scaffolds (28–34) in good yields and diastereomeric ratios after their reaction with N-phenylmaleimide in the presence of thioxanthone under blue LED irradiation reaching high yields similarly with the N-alkyl protocol. On the other hand, reaction with electron-deficient olefins is highly dependent on the substrate, since ethyl acrylate gave a good yield of 36, while methyl vinyl ketone and cyclohexenone were not suitable substrates. Once again, we carefully examined the stereochemistry of the products by two-dimensional NMR experiments, using 5, 28, 34, and 35 as models.71 This time, we faced a problem with the stereochemistry of 35. Based on our two-dimensional NMR spectra,71 combined with the lack of appropriate data for the stereochemistry of 35 in the literature (the stereochemistry in the literature is not based on two-dimensional NMR or X-ray for 35),58 we are led to believe that the relative stereochemistry presented in Scheme 3 is the correct one. Our next step was to investigate the cycloaddition of styrene with different N-aryl substituted maleimides, which led to satisfactory results (37–42). Unfortunately, the presence of a 4-NO2 group or a double −CF3 substitution at the meta-positions on the aromatic ring prevented the formation of the desired products.

Scheme 3. Substrate Scope of the Photochemical Reaction between Alkenes and N-Aryl Maleimides.

Scheme 3

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Comparing the two different protocols on the tolerability considering the alkene substrate, there are no significant differences. The only limitation that can be noted is that of electron-deficient olefins at 440 nm, probably due to polymerization. It should be also mentioned that, in almost all cases, the two diastereomers of each reaction were fully separable using flash column chromatography and were obtained pure individually, without the need of further processes. Moreover, our protocols proved to be suitable for scale-up, since we performed the reaction with styrene (2) and 1 g of N-benzyl maleimide (1) at the 1 g scale, leading to products 3a and 3b in 54% overall yield, while products 28a and 28b were obtained from 1 g of N-phenyl maleimide (4) and 1-decene at an impressive 84% overall yield with 73:27 diastereoselectivity.71

In 2015, Cismesia and Yoon employed the quantum yield measurement as a mechanistic tool.72 The quantum yield of the reaction between N-phenyl maleimide (4) and styrene (2) under blue LED irradiation and thioxanthone sensitization was found to be Φ = 0.56,71 revealing a closed catalytic cycle on the one hand, while indicating that the reaction is more efficient with double bonds, when compared with the corresponding reaction with triple bonds (Φ = 0.11).70 As expected, according to UV/vis spectroscopy mechanistic studies, there is no EDA complex formed between the reactants that absorbs irradiation.71

Several α,β-unsaturated carbonylic compounds have triplet energies that allow them to be excited upon irradiation and participate in [2 + 2] cycloadditions without further assistance. N-Alkyl maleimides fall in this case, and their excited triplet state quantum yield, measured at ∼0.03–0.07,55−57 is adequate to promote the reaction. Consequently, the proposed mechanism is illustrated in Scheme 4A and involves the maleimide’s I excitation, and after intersystem crossing it ends up in its triplet excited state III. It then reacts with an olefin molecule forming diradical V, which, after intersystem crossing and bond formation, affords bicyclic product VII.

Scheme 4. Proposed Reaction Mechanism for (A) N-Alkyl Maleimides and (B) N-Aryl Maleimides.

Scheme 4

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In the case of N-aryl maleimides, their triplet energy is approximately zero,55−57 so a sensitizer with a high triplet energy is essential. Thioxanthone (THX) is a known sensitizer with a triplet energy ET = 65.5 kcal/mol, capable of transferring triplet energy to maleimides.70 A photoredox mechanism can be excluded, since the reduction and oxidation potential of triplet thioxanthone [E*red = +1.18 V, E*ox = −1.11 V vs saturated calomel electrode (SCE), respectively]6,59 and that of N-phenylmaleimide [E*ox = >1.75 V, E*red = −1.01 V vs saturated calomel electrode (SCE), respectively].41 Fluorescence quenching studies verify the interaction between thioxanthone and N-phenyl maleimide, while no significant interaction between the catalyst and styrene was detected.71 Taking this information into consideration, the proposed mechanism is illustrated in Scheme 4B. Thioxanthone is excited in its triplet excited state, an energy transfer process from the sensitizer to the maleimide takes place leading to B. Then, upon reaction with a nonexcited olefin C, D is formed, and after intersystem crossing and bond formation, the final product F is yielded.

Conclusion

In conclusion, a mild, sustainable and easy-to-perform photochemical protocol for the synthesis of cyclobutane bicyclic scaffolds was developed. Taking into consideration the different photophysical properties of N-alkyl and N-aryl maleimides, two different approaches were utilized for the [2 + 2] cycloaddition of N-substituted maleimides with double bonds. In the case of N-alkyl maleimides, their triplet energy allows for the development of a catalyst-free method, using UVA LED irradiation (370 nm), leading to good to high yields and good stereoselectivity. On the other hand, for N-aryl maleimides, due to their approximately zero triplet energy, an organic, simple yet efficient sensitizer, thioxanthone, was chosen to facilitate the photochemical process under visible light (blue LED, 440 nm).

Experimental Section

Chromatographic purification of products was accomplished using forced-flow chromatography on Merck Kieselgel 60 70–230 mesh. Structural assignments were made utilizing additional information from gCOSY and gNOESY experiments. Kessil lamps PR160L were used as the irradiation source. For all experiments, the intensity of the Kessil lamps was controlled in the maximum level with power consumption: 370 nm (max 43W), 390 nm (max 52W), 427 nm (max 45W), 440 nm (max 45W), 456 nm (max 50W), 467 nm (max 44W), and 525 nm (max 44W).

General Procedure for the Photochemical [2 + 2] Cycloaddition of Alkenes with N-Alkyl Maleimides

In a glass vial containing the alkene (2.0 equiv., 0.40 mmol), maleimide (1.0 equiv., 0.20 mmol) and CH2Cl2 (2.0 mL) were added. The vial was sealed with a rubber cup and purged with argon, and the reaction mixture was left stirring under UVA LED (Kessil PR 160L, 370 nm) irradiation under argon atmosphere for 16–70 h. The desired products were purified by column chromatography (pet. ether/EtOAc: 8:2 or 7:3).

General Procedure for the Photochemical [2 + 2] Cycloaddition of Alkenes with N-Aryl Maleimides

In a glass vial containing the alkene (2.0 equiv., 0.40 mmol), maleimide (1.0 equiv., 0.20 mmol), thioxanthone (20 mol %, 0.04 mmol, 9 mg), and CH2Cl2 (2 mL) were added. The vial was sealed with a cup or a rubber cup and purged with argon, and the reaction mixture was left stirring under blue LED (Kessil PR 160L, 440 nm) irradiation for 16 h. The desired products were purified by column chromatography (pet. ether/EtOAc: 8:2 or 7:3).

Acknowledgments

The authors gratefully acknowledge the Hellenic Foundation for Research and Innovation (HFRI) for financial support through a grant, which is financed by 1st Call for H.F.R.I. Research Projects to Support Faculty Members & Researchers and the procurement of high-cost research equipment grant (grant number 655).

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.2c00053.

  • Reaction optimization, photochemical setup, products’ characterization and NMR traces, as well as mechanistic studies (PDF)

Author Contributions

The manuscript was written through contributions of all authors.

The authors declare no competing financial interest.

Supplementary Material

gg2c00053_si_001.pdf (7MB, pdf)

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Supplementary Materials

gg2c00053_si_001.pdf (7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

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