Catalyst-free, visible-light-induced [2<i>π</i> + 2<i>σ</i>] cycloaddition towards azabicyclohexanes

Catalyst-free, visible-light-induced [2π + 2σ] cycloaddition towards azabicyclohexanes

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Min Yan, Zihao Ye, Ping Lu^*

Chinese Chemical Letters | 2025, 36(6) : 110540

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Chinese Chemical Letters | 2025, 36(6): 110540

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Catalyst-free, visible-light-induced [2π + 2σ] cycloaddition towards azabicyclohexanes

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Min Yan, Zihao Ye, Ping Lu^*

Affiliations

Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, Shanghai 200433, China

Published: 2025-06-15 doi: 10.1016/j.cclet.2024.110540

Outline

Abstract

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2-Azabicyclo[2.1.1]hexanes (aza-BCHs) are constrained pyrrolidine analogues with improved physicochemical characteristics in drug design. Here, we report a direct visible light-mediated photocycloaddition of 4-aza-coumarins with mono- or disubstituted bicyclo[1.1.0]butanes for synthesizing aza-BCHs without an external catalyst. The introduction of the ester group on 4-azacoumarin is critical for direct imine excitation and versatile synthetic utility. Preliminary mechanistic studies indicated that the reaction took place primarily at the triplet hypersurface.

Key words

Bicyclo[1.1.0]butane / Bioisosteres / Imine / Photochemistry / Spectroscopy

Cite this Article

Min Yan, Zihao Ye, Ping Lu. Catalyst-free, visible-light-induced [2π + 2σ] cycloaddition towards azabicyclohexanes[J]. Chinese Chemical Letters, 2025 , 36 (6) : 110540 - . DOI: 10.1016/j.cclet.2024.110540

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Rigid Csp³-rich bicyclic hydrocarbon skeletons have been identified as valuable bioisosteres of phenyl ring in medicinal chemistry and agrochemistry since they often improve physicochemical and pharmacokinetic properties of drug candidates [1-4]. All-carbon ring systems, such as bicyclo[1.1.1]pentanes (BCPs), bicyclo[2.1.1]hexanes (BCHs), and bicyclo[3.1.1]heptanes (BCHeps), have gained rapidly growing attention as hydrocarbon bioisosteres for substituted arenes. Synthetic strategies, including the strain-release approach, have been developed to construct these highly rigid skeletons that mimic benzene derivatives with para-, meta-, and ortho-substituted patterns [5-26]. The heterocyclic variants, aza-BCHs as conformationally rigid pyrrolidine analogs, have shown improved water solubility, reduced lipophilicity, and retained bioactivity (Schemes 1a and b) [27-31]. The intramolecular cyclization approach was initially utilized to assemble the rigid aza-BCH scaffolds [32, 33]. Further lithiation-electrophilic substitution led to functionalized aza-BCHs. However, the development of a modular approach for accessing aza-BCHs with diverse chemical space is still in demand.

We envisioned that a [2π + 2σ] cycloaddition of imine derivatives with bicyclo[1.1.0]butanes (BCBs) would provide substituted aza-BCHs in a straightforward and modular fashion. Although an elegant Lewis acid-catalyzed cycloaddition of N-aryl imine and BCBs has been disclosed [34], a metal-free approach would avoid metal residue in the active pharmaceutical ingredient [35, 36]. Driven by inherent ring strain releasing, the cycloaddition of BCBs with π-bond substrates (such as C=C, N=N, N=O) has been explored in a thermal or photochemical way [37, 38]. On the other hand, the photocycloaddition of imine chromophores is a long-standing challenge, attributed to radiationless decay or oxidation of the excited state of imine. Recently, several approaches have been developed to overcome these challenges in aza Paternò-Büchi reaction [39-42]. Nevertheless, the current methods mostly rely on UV irradiation or triplet sensitizer to access the excited state species (Scheme 1c) [19, 43-53]. We wonder whether a rational design of imine substrate could enable a [2π + 2σ] photocycloaddition under visible-light irradiation in the absence of an external photocatalyst or photosensitizer.

Herein, we report our work on visible light-induced photocycloaddition of azacoumarins with mono- and disubstituted BCBs to provide aza-BCHs in a divergent regioselective manner (Scheme 1d). Furthermore, the subsequent downstream functionalization of cycloadducts enables a programmable preparation of aza-BCHs with versatile substitution patterns.

We initiated our studies with the rational design of imine substrate. In 2020, Schindler disclosed that the cyclic imine, 2-isoxazoline-3-carboxylate (A) [48], could be excited by visible light to its triplet state via an energy transfer process (Fig. 1a). Subsequently, cyclic imines, such as quinoxalinone (B) [49] and N-sulfonylimine (C) [50], were employed as chromophores in the photosensitized cycloaddition to deliver azetidines. We envisioned that 4-azacoumarin (1a) would be a good candidate for direct visible light irradiation. First, the introduction of an ester group at position 3 could lower the excitation-state barrier due to lowering the energy of LUMO of imine. Second, the ester functional group could provide a useful synthetic handle, resulting in a programmable azetidine scaffold. Indeed, the UV–visible spectrum of 1a in CH₂Cl₂ reveals a strong absorption at 304 nm (ε = 10, 900 L mol⁻¹ cm⁻¹, Fig. 1b). A shoulder absorption at λ ≅ 360 nm (ε = 3700 L mol ⁻¹ cm⁻¹) is observed, and the band tails into the visible-light wavelength region. In contrast, 3-methyl-4-azacoumarin (D) exhibits no absorption beyond 370 nm. In addition, the spectrum of coumarin 4a reveals two absorptions at 292 nm (ε = 11000 L mol⁻¹ cm⁻¹) and 333 nm (ε = 6000 L mol⁻¹ cm⁻¹), respectively.

Guided by the observed photophysical properties, the cycloaddition of 4-azacoumarin 1a with methyl bicyclo[1.1.0]butane-1-carboxylate 2a under visible-light irradiation (450 nm) was examined (For the emission spectra, see Figs. S2 and S3 in Supporting information). After optimization (Table S1 in Supporting information), the expected 2, 4-methanoproline derivative 3a could be obtained in 94% yield as a single regioisomer when using CH₂Cl₂ as solvent (Scheme 2). In comparison, no photocycloadduct was observed when the reaction of D and 2a was conducted at 450 nm (Table S1).

The substrate scope of 4-azacoumarin 1 was then surveyed. The 4-azacoumarin 1b with fluoro group at position 5 provided cycloadduct 3b in 86% yield, while the aza-BCH 3c with methyl substituent was obtained in only 18% yield. In contrast, varying the position (6, 7, and 8) of the substituent on the phenyl ring of 4-azacoumarin 1 had little impact on yield. Both electron-rich and deficient substituents could be tolerated, giving the corresponding cycloadducts 3d-3k in 48%−92% yields. In addition, disubstituted cyclic imines were applicable, giving products 3l and 3m in 79%−80% yields. Replacement of ethyl ester to benzyl ester afforded product 3n in good yield as well.

The substrate scope of monosubstituted BCBs 2 was also investigated. The electron-withdrawing groups, including benzyloxycarbonyl, N‑methoxy-N-methylcarbamoyl, 2-naphthoyl, and phenylsulfonyl groups, were all tolerated, giving the single regioisomers 3o-3s in 48%−99% yields. Moreover, the cycloaddition of coumarins 4 was also studied. Switching the wavelength from 450 nm to 410 nm (Figs. S2 and S3), the photocycloaddition of coumarins 4 with BCB 2a provided the corresponding BCHs 5a-5b as single regioisomers in 85%−88% yields. The structures of 3a and 5b were determined by the single crystal X-ray diffraction analysis.

We next turned our attention to the photocycloaddition of 4-azacoumarin 1 with disubstituted BCBs 6. After optimization (Table S2 in Supporting information), the reaction of 6a and 1a provided cycloadduct 7a in 58% yield when irradiated at 450 nm in CH₂Cl₂. In contrast to cycloaddition with monosubstituted BCBs 2, the regioselectivity was reversed. We assumed this is attributed to the stability of radical intermediate (vide infra). Of note, the formal ene product 7a' (not shown, see Table S2) was also formed in 8% yield.

The substrate scope of BCBs 6 investigated was summarized in Scheme 3. A variety of para- and meta-substituted phenyl BCBs 6 was tolerated under optimal conditions, affording the corresponding products 7b-7h in 43%−86% yields as single regioisomers. Both electron-rich and deficient substituents have a minor impact on the yield. However, the regioselectivity and yield dropped significantly when ortho-methyl phenyl BCB was used, and the product 7i was obtained in 20% yield and 2:1 rr. The formal ene product 7i' was obtained in 23% yield. Disubstituted phenyl and heteroaromatic BCBs were also applicable, giving the cycloadducts 7j-7k in 66%−77% yield. Replacing the aryl group with the alkyl group had a notable impact on the regioselectivity. When 3-methyl substituted BCB 6l was used, the product 7l was obtained in 76% yield and 2:1 rr. In sharp contrast, the reaction of Weinreb amide 6m gave a single isomer 7m in 51% yield. 1, 3-Dialkyl BCB 6n was also tolerated, resulting in the cycloadduct 7n in moderate yield.

We further examined 6-, 7- and 8-substituted 4-azacoumarins 1 with an array of 3-aryl substituted BCBs 6. Gladly, only single regioisomers were observed in all studied cases. The yields of 7o-7y were in the range of 53%−83%, except for 7u, which was isolated in 13% yield. The ene product 7u' (not shown, see Supporting information) was formed in 33% yield. Similar regioselectivity was observed when 3-alkyl substituted BCBs were applied, affording the products 7z, 7aa, and 7ab in good yields. In addition, the cycloaddition of coumarins 4 with BCB 6a furnished cycloadducts 8a-8b in 47%−57% yield. Of mention, the formal ene products 8′ were also observed. The structures of 7b, 7i', 7aa, 7ab, 8a', and 8b were elucidated by X-ray diffraction studies.

The quenching experiments were first conducted to elucidate the reaction mechanism of photocycloaddition (Scheme 4). In the presence of 1 equiv. of 1, 3-cyclohexadiene [54] or (E)−1, 3-pentadiene [55] no cycloadduct 3s was observed. Instead, the cycloaddition of 1a with diene occurred. We assumed that the rate of reaction of 1a with diene might be much faster than the triplet energy transfer process or the reaction might take place in the singlet manifold. As expected, the reaction was completely inhibited with a singlet and triplet quencher azulene [56]. The reaction was significantly suppressed when triplet quencher O₂ was introduced into the reaction. In addition, the thermal reaction of 1a and 2e gave no cycloadduct, indicating that light irradiation is critical for the success of the cycloaddition. Furthermore, the formation of a donor-acceptor complex between 1a and 2e could be excluded from the UV-visible absorption spectra studies (Fig. S9 in Supporting information) [57, 58].

β-Methylstyrene was employed to examine the [2π + 2π]-photocycloaddition of 4-azacoumarin. The photocyclization of 1a with trans-β-methylstyrene afforded cycloadducts 9 and epi‑9 in 75% yield and 2.1:1 dr. The structure of epi‑9 was elucidated by X-ray diffraction studies. Meanwhile, the corresponding reaction with cis-β-methylstyrene afforded cycloadducts 9 and epi‑9 in 73% yield and 1.2:1 dr. In addition, the reaction of 1a with both BCB 2e and trans-β-methylstyrene afforded cycloadducts 9 and epi‑9 in 2.1:1 dr. No cycloadduct 3s was observed. These results suggest that the photocycloaddition of 4-azacoumarin 1 likely takes place at the triplet hypersurface.

Based on control experiments and the photophysical properties of 1a, the reaction mechanism was postulated (Scheme 5). 4-Azacoumarin 1a was excited to the singlet state at visible-light irradiation, which then led to the formation of the triplet state via the intersystem crossing (ISC). The regioselectivity of radical addition was tuned by the stability of intermediates (M1 and M2) [22], and the corresponding cycloadducts 3 and 7 were obtained. The 1, 4-hydrogen abstraction took place in the case of 1, 3-disubsituted BCB, resulting in the side product cyclobutene 7a'.

The further synthetic utility of cycloadducts was explored to demonstrate programmable preparation of aza-BCHs with versatile substitution patterns (Scheme 6). Radical chlorination by photolysis of N-chlorosuccinimide (NCS) at 450 nm irradiation occurred selectively on arene moiety in 3a [59], giving product 3g in 92% yield. Selective opening of lactone motif was then pursued. Basic hydrolysis of 3s using EtONa led to aza-BCH 10 in 88% yield [60], while the reduction of lactone with NaBH₄ provided diol 11 in 81% yield [61]. Further elaboration of cycloadducts with retaining lactone structural unit was also investigated. Reduction of the benzyloxycarbonyl group in 3n afforded alcohol 12 via sequential debenzylation and reduction of mixed anhydride [62]. Deprotection of silyl group in 7n furnished diol 13 in good yield. Similarly, diol 14 with different substitution positions was obtained from 7z through a three-step manipulation. Interestingly, lactone 15 was concurrently formed when the benzyloxycarbonyl group in 7z-rr was transformed into mixed anhydride. The structures of 14 and 15 were elucidated by X-ray diffraction studies.

3-Dimensionality (3D) of aza-BCHs was then evaluated by the principal moment of inertia (PMI) analysis [63, 64]. A survey reveals that the 3D scores (I₁/I₃ + I₂/I₃) of selected products range from 1.21 to 1.59, representing quite broad topological characteristics (Fig. 2). The cycloadducts 3a, 7a, and 7m possess close 3D scores, in the range of 1.25–1.34. The diol derivatives 11 and 13 have much higher scores (1.50–1.59) than 14 (1.25), highlighting the importance of selective functionalization of cycloadducts.

In conclusion, we report here a visible-light-induced cycloaddition of 4-azacoumarins with BCBs, delivering a range of aza-BCHs derivatives. The reaction mechanism was proposed by combining control experiments and the photophysical properties of the imine chromophore. Selective functionalization of cycloadducts was also pursued, delivering aza-BCHs molecules with a diverse chemical space.

Declaration of competing interest

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

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Min Yan: Methodology, Investigation. Zihao Ye: Investigation. Ping Lu: Writing – review & editing, Writing – original draft, Conceptualization.

Acknowledgments

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This work was supported by the National Key R & D Program of China (No. 2022YFA1503200) and the National Natural Science Foundation of China (Nos. 22071028, 21921003).

Supplementary materials

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Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110540.

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Year 2025 volume 36 Issue 6

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doi: 10.1016/j.cclet.2024.110540

Receive Date：2024-05-31
Online Date：2025-10-29
Published：2025-06-15

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Received：2024-05-31
Revised：2024-09-20
Accepted：2024-10-09

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Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, Shanghai 200433, China

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Scheme 1 Saturated bioisosteres. (a) The substituted saturated bioisosteres aza-BCHs. (b) Selected bioactive molecules containing aza-BCH motifs. (c) The retrosynthetic analysis and synthetic challenges. (d) The photocycloaddition and divergent structural elaboration.

Fig. 1 (a) Studied imine chromophores. (b) Normalization absorption spectra of compounds 1a, D, and 4a (c = 0.05 mmol/L in CH₂Cl₂).

Scheme 2 The substrate scope of azacoumarin 1 and BCBs 2. Conditions: 1 or 4 (0.1 mmol), 2 (2.0 equiv.), and CH₂Cl₂, hν (450 nm), r.t. ^a Irradiation at 410 nm.

Scheme 3 The substrate scope of 1 and BCBs 6. Conditions: 1 (0.1 mmol), 6 (2.0 equiv.), CH₂Cl₂, hν (450 nm), r.t. ^a 1 (0.2 mmol), 6n (3.0 equiv.), PhCH₃. ^b 1m (0.25 mmol), 6 (3.0 equiv.). ^c 4a (0.1 mmol), CH₂Cl₂, hν (410 nm). ^d 4b (0.1 mmol), MeCN, hν (410 nm).

Scheme 4 Preliminary mechanistic studies of photocycloaddition.

Scheme 5 Proposed reaction mechanism.

Scheme 6 Further transformation of cycloadducts 3 and 7.

Fig. 2 PMI analysis of 3-dimensionality.

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