Electron donor–acceptor complex enabled photocascade strategy for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds via radical conjugate addition of pyridinium ylide

Abstract

A visible-light-induced photocascade strategy is disclosed for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds. The photocascade consists of electron donor–acceptor (EDA) complex enabled formation of arylidene coumarinone, followed by 1,4-radical conjugate addition (1,4-RCA) of an in situ generated pyridinium ylide radical (PyYR) towards diastereoselective formation of the trans-dihydrofuro[3,2-c]chromen-4-one scaffold in good to excellent yield. Thorough mechanistic investigations comprising photophysical, spectroscopic, electrochemical and DFT studies provide further insights into the reaction mechanism.

---

Visible light-based organic photochemistry is nowadays an indispensable synthetic tool for the synthesis of natural products, pharmaceuticals, and functional materials, because of its clean, green, and sustainable reaction profile.¹ In this domain, the electron donor–acceptor (EDA) complex outperforms traditional organic photochemistry utilizing costly and harmful photosensitizers to activate small organic molecules, mostly incapable of absorbing visible light directly.² Photo-irradiation on EDA complexes facilitates electron transfer between donor and acceptor molecules generating reactive radical species, crucial for various C–C and C–hetero atom bond formation reactions in organic synthesis.

Pyridinium ylides (PyY) are one of the widely explored intermediates in organic chemistry, traditionally known for their ionic nature in nucleophilic addition to C=X (X=C, O, S, etc.) bonds.³ But their radical nature was relatively unexplored, until Zhang et al. showed it in their seminal work followed by Kim et al. who utilized the same concept for C(sp²)–H alkylation.⁴ Reaction of photochemically generated pyridinium ylide radicals (PyYR) is even less explored.⁵ Hence, chemists are finding more interest in exploring the radical nature of PyY.

Photo cascade reactions are well known for their ability to form multiple bonds and/or rings in one vessel, producing structurally complex architectures from simple starting materials in a streamlined manner. Therefore, photocascade reactions are gaining huge popularity these days.⁶

Trans-dihydrofuro[3,2-c]chromen-4-one (DHFC) belongs to class of oxa-heterocycles having multifaceted biological activities, viz. COX-2 and 5-LOX inhibitors, anti-plasmodial, and anti-leishmanial activities, etc.⁷ Being inspired by its applications chemists have developed different synthetic techniques. Unfortunately, most of them rely on transition metal catalysis, Brønsted base catalysis, and photo-redox catalysis.⁸ The existing literature reports two photochemical approaches for the synthesis of DHFC scaffolds, one by Brahmachari et al. and another by Bagdi et al., both requiring external photocatalysts.⁹ In this context developing a photocatalyst-free visible light-mediated synthesis is highly desirable. We envisioned that it may be possible by 1,4-RCA of PyYR to the Michael acceptor arylidene coumarinone, formed via photo-irradiation of the EDA complex between 4-hydroxycoumarin and aryl aldehydes. To the best of our knowledge, no prior literature reports exist for visible light photocascade synthesis of DHFC scaffolds employing an EDA complex followed by 1,4-RCA of PyYR. As a part of our ongoing research on visible light-induced organic synthesis via an EDA complex,¹⁰ herein we report a convenient synthetic strategy for DHFC scaffolds culminating the potential of the EDA complex to form a Michael acceptor followed by base catalysed photo-induced in situ generation of PyYR and its 1,4-RCA for the successful synthesis of DHFC derivatives with exclusive diastereoselectivity (Scheme 1).

Scheme 1 (a) Previous approaches^{8a,c–e,9a,b} and (b) the present approach for dihydrofurocoumarin synthesis.

After screening different bases, their amounts, and solvents, we observed that the reaction was best conducted when a solution of 4-hydroxycoumarin (1a, 1 mmol), p-N,N-dimethylaminobenzaldehyde (2a, 1 mmol), p-bromophenacyl bromide (4a, 1 mmol) and pyridine (1 mmol) in ethanol was irradiated with blue LEDs under a nitrogen atmosphere in the presence of 25 mol% triethyl amine (TEA). Gratifyingly, under these conditions, 86% of the desired DHFC derivative 5a was obtained in 12 hours (entry 1, Table 1, for complete optimisation see Table S1 in the ESI†). On the other hand, a declined yield under green light irradiation accounts for the necessity of blue light for the success of the reaction (entry 2, Table 1). As expected, the reaction failed to produce the desired DHFC derivative 5a in the absence of either pyridine or TEA (entries 3 and 4, Table 1). The sharp declined yield of the reaction in the dark and in open air (entries 5 and 6, Table 1) strongly accounts for the synergistic role of base (cat.), pyridine, and blue light in an oxygen-free atmosphere for successful photocascade synthesis of DHFC derivatives.

Table 1 Optimization of the reaction conditions^a

Entry	Base (mol%)	Light source	Solvent	Yield^b (%)
a Reaction conditions: (a) 1a (1.0 mmol), 2a (1.0 mmol), and 4a (1.0 mmol), in different solvent with blue LEDs lamp (2 × 12 W) radiation at rt for 12 h under an N2 atmosphere. b NMR yield with 1,3,5-trimethoxybenzene as an internal standard. c Reaction performed without pyridine. d Reaction performed in the absence of light. e Reaction performed in an open vessel, nd: not detected, TEA: trimethylamine.
1	TEA (25)	Blue	EtOH	86
2	TEA (25)	Green	EtOH	71
3^c	TEA (25)	Blue	EtOH	nd
4	—	Blue	EtOH	nd
5^d	TEA (25)	—	EtOH	17
6^e	TEA (25)	Blue	EtOH	15

---

With the optimized conditions in hand, we screened the substrate scope for this photocascade reaction (Scheme 2). Initially, we explored the scope of various phenacyl bromides (4a–4c) bearing mild electron-withdrawing (e.g., p-Br, p-Cl) or electron-donating groups (e.g., p-Me) at the para-position of the phenyl residues along with 1a and 2a. Pleasingly, they underwent smooth transformation yielding the desired products (5a–5c) in good to excellent yields (84–90%). Electronically neutral phenacyl bromide (4d) also produced the desired product 5d in 88% yield along with 1a and 2a. Interestingly, replacing the p-NMe₂ group in aldehyde with an electron donating group (e.g., p-Me (2b), p-OMe (2c)) yielded the anticipated products 5e–5g, almost in similar yields (81–88%). Electronically neutral aldehyde (2d) was also a potent substrate, which combined with 1a and electronically poor (p-Cl, 4b), rich (p-OMe, 4e) as well as neutral (p-H, 4d) phenacyl bromides producing the desired DHFC derivatives (5h–i, 5q) in comparable yields (80–82%). Furthermore, electron-withdrawing substituents (e.g., F, Cl, NO₂, CF₃) at the ortho- and para-positions of the benzene ring enhanced the aldehyde reactivity yielding the corresponding DHFC derivatives (5j–k, 5m–n, 5p) in moderate to good yields (65–87%) with diverse phenacyl bromides (4a, 4c–e). However, the yield of the DHFC derivatives (5l and 5o) slightly diminished (60–65%) in the presence of ortho-substituents in aldehydes (2g and 2i) possibly due to steric hindrance. Whereas steric crowding at the meta- and para-positions of the benzene ring of the aldehyde do not have that much of a detrimental effect on the outcome of the reaction as evidenced from the reactivity of isovanillin (2k) yielding the corresponding DHFC derivative 5r in moderate yield (78%). We are pleased to report that our developed protocol is well applicable for heteroaromatic aldehydes. Furfuraldehyde (3a) and thiophene-2-carbaldehyde (3b) successfully combined with 1a and p-chlorophenacyl bromide (4b) yielding DHFC derivatives 6a and 6b in good yield (77–81%). Interestingly, the installation of a bromine atom at the C-5 position of thiophene-2-carbaldehyde (3c) showed an increase in yield of the desired DHFC derivative 6c with 85% yield. Expectedly, pyridine-2-carbaldehyde (6d) reacts with 1a and phenacyl bromide (4d) to yield DHFC derivative 6d in a slightly lower yield (70%), possibly due to competitive nucleophilic displacement of bromide from phenacyl bromide leading to the corresponding phenacyl pyridinium bromide (PyB).

Scheme 2 Substrate scope of photocatalytic DHFC synthesis.

To demonstrate the synthetic utility of the developed photocascade strategy, we performed the model reaction on a gram scale (10 mmol) and isolated 3.92 g (80%) of desired product 5a (see Section 4 in the ESI†). Various post synthetic transformations of DHFC derivative 5j to the corresponding thiophene (7a), furan (7b), tosyl hydrazone (7c) and alcohol (7d), all in high yield, highlighted the importance of the DHFC core in synthetic organic chemistry (Scheme 3, see Section 6 in the ESI†).

Scheme 3 Synthetic transformations of DHFC 5j.

The formation of the EDA complex was confirmed by the appearance of a new peak around 504 nm for a mixture of 1a and 2a in UV-Vis analysis (see Fig. 1a and Fig. S1 in the ESI†). The spectrophotometric analysis of the EDA complex provided us with the 1 : 1 stoichiometry of 1a and 2a (Fig. 1b) and the association constant value of 18.0 M⁻¹ (Fig. 1c) and molar extinction coefficient of 158.8 L mol⁻¹ cm⁻¹ (see Fig. S2–S4 in the ESI†). Here, 1a acts as a donor and 2a as an acceptor was also supported by upfield shifting of the aldehyde proton of 2a in ¹H NMR titration (Fig. 1d) and cyclic voltammetric analysis (see Fig. S5–S8 and S9 in the ESI†). Formation of PyYR can be validated from the new peak at 430 nm in UV-Vis and cyclic voltammetric analysis (see Fig. S1 and S9 in the ESI†). In spite of successful inhibition of the model reaction in the presence of TEMPO and BHT, no HRMS-adduct was found. However, the radical pathway of the reaction was supported by the appearance of EPR signal 3274–3370 G for the reaction mixture (see Fig. 1e and Fig. S10 in the ESI†) in the presence of DMPO as a radical trapping agent,¹¹ and the appearance of an EPR signal at 1557 G along with 3251–3367 G for PyY accounts for the triplet diradical¹² nature of PyY (see Fig. S11 in the ESI†), further supported by ¹H NMR peak broadening during titration of PyB with TEA (see Fig. S12 in the ESI†). The necessity of blue light irradiation for successful occurrence of the reaction was evident from light on–off experiments (see Fig. 1f and Fig. S13 in the ESI†).

Fig. 1 Control experiments: (a) UV-Vis plot, (b) Job's plot, (c) Benesi–Hildebrand plot, (d) ¹H NMR titration between 1a and 2a, (e) EPR spectra of the reaction mixture, and (f) light “on–off” experiment.

The DFT analysis unequivocally revealed 1a as the donor and 2a as the acceptor for the EDA complex (see Fig. S14 in the ESI† for details). It was also found that intermediate IV is 0.35 kcal mol⁻¹ more stable than its counter E-isomer (see Section 7 and Table S4 in the ESI† for details). DFT studies also provide us with ³VIII, ³IX, and 5a having the highest thermodynamic stability among all other possibilities (see Tables S3 and S4 in the ESI†) and the potential energy surface provides us with the possible transition states (³TS1, ³TS2, and ¹TS3) for the reaction (see Fig. S15 in the ESI† for details).

Considering the experimental outcomes, DFT studies and corroborating literature, a plausible mechanistic pathway is proposed in Scheme 4. Initially, photoexcitation of the ground state EDA (GS-EDA) complex to the excited state EDA (ES-EDA) complex, followed by proton coupled electron transfer (PCET) results in the radical pair I and II. Subsequent radical–radical coupling followed by dehydration provides the active Michael acceptor IV. In tandem, base-induced photo irradiation of PyB (V) provides the triplet diradical ³VII, the active Michael donor. Interception of ³VII and IVvia 1,4-RCA leads to the intermediate ³VIII, which on the homolytic release of pyridine followed by intersystem crossing (ISC) and radical–radical coupling produced the desired DHFC derivative 5a. The molecular structure of compound (5a) was elucidated from the coupling constant value (J < 6 Hz, typical for trans-vicinal methine H atoms) in ¹H-NMR and finally from single-crystal X-ray diffraction (CCDC # 2366844 Fig. S16, ESI†).

Scheme 4 Proposed mechanism for photocascade synthesis of DHFC.

In summary, our research introduces a unique photocascade annulation for synthesizing trans-dihydrofuro[3,2-c]chromen-4-one scaffolds. This method utilises EDA complex formation followed by 1,4-RCA of PyYR, avoiding the use of external transition metals or photoredox catalysts and operates under mild conditions with readily available substrates. The developed strategy demonstrated wide substrate scope, successful scale up and post synthetic transformations, boosting the scaffold's synthetic importance. Comprehensive mechanistic investigations and DFT studies provide support for radical generation from the EDA complex and PyY via PCET and SET processes, respectively. Our ongoing effort aims to extend this technique to novel carbo- and heterocyclic syntheses utilising EDA complexes.

MFH acknowledges SERB, India [SUR/2022/000342] and SD acknowledges CSIR, India [09/0285(11414)/2021/EMR-I] for financial support.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. (a) N. Hoffmann, Chem. Rev., 2008, 108, 1052; (b) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527; (c) M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem., 2016, 81, 6898; (d) N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075; (e) M. Parasram and V. Gevorgyan, Chem. Soc. Rev., 2017, 46, 6227.
2. (a) C. G. Lima, T. de, M. Lima, M. Duarte, I. D. Jurberg and M. W. Paixao, ACS Catal., 2016, 6, 1389; (b) G. E. M. Crisenza, D. Mazzarella and P. Melchiorre, J. Am. Chem. Soc., 2020, 142, 5461; (c) J. Y. Kim, Y. S. Lee, Y. Choi and D. H. Ryu, ACS Catal., 2020, 10, 10585; (d) T. Tasnim, M. J. Ayodele and S. P. Pitre, J. Org. Chem., 2022, 87, 10555; (e) N. Singh, A. Sharma, J. Singh, A. P. Pandey and A. Sharma, Org. Lett., 2024, 26, 6471.
3. (a) S. D. Allgäuer, P. Mayer and H. Mayr, J. Am. Chem. Soc., 2013, 135, 15216; (b) D. L. Funt, S. M. Novikov and F. A. Khlebnikov, Tetrahedron, 2020, 76, 131415; (c) A. Kumari, D. J. Patanvadiya, A. Jain, R. Patra, M. Paranjothy and N. K. Rana, J. Org. Chem., 2024, 89, 8230.
4. (a) F. Liao, W. Huang, B. Chen, Z. Ding, X. Li, H. Su, T. Wang, Y. Wang, H. Miao, X. Zhang, Y. Luo, J. Yang and G. Zhang, Chem. Commun., 2020, 56, 11287; (b) P. Ghosh, Y. Byun, Y. N. Kwon, Y. J. Kang, K. N. Mishra, S. J. Park and S. I. Kim, Cell Rep. Phys. Sci., 2022, 3, 100819.
5. (a) Y. Moon, W. Lee and S. Hong, J. Am. Chem. Soc., 2020, 142, 12420; (b) W. Lee, Y. Koo, H. Jung, S. Chang and S. Hong, Nat. Chem., 2023, 15, 1091.
6. (a) J. R. Chen, D. M. Yan, Q. Wei and W. J. Xiao, ChemPhotoChem, 2017, 1, 148; (b) B. Sun, X. Shi, X. Zhuang, P. Huang, R. Shi, R. Zhu and C. Jin, Org. Lett., 2021, 23, 1862; (c) Y. Lu, C. Z. Fang, Q. Liu, B. L. Li, Z. X. Wang and X. Y. Chen, Org. Lett., 2021, 23, 5425; (d) D. L. Zhang, Z. G. Le, Q. Li, Z. B. Xie, W. W. Yang and Z. Q. Zhu, Chem. Commun., 2024, 60, 2958; (e) D. Liang, Q. Q. Zhou and J. Xuan, Org. Biomol. Chem., 2024, 22, 2156.
7. (a) H. A. Oketch-Rabah, E. Lemmich, S. F. Dossaji, T. G. Theander, C. E. Olsen, C. Cornett, A. Kharazmi and S. B. Christensen, J. Nat. Prod., 1997, 60, 458; (b) K. P. Barot, S. V. Jain, L. Kremer, S. Singh and M. D. Ghate, Med. Chem. Res., 2015, 24, 2771.
8. (a) E. Altieri, M. Cordaro, G. Grassi, F. Risitano and A. Scala, Tetrahedron, 2010, 66, 9493; (b) A. T. Khan, M. Lal and R. S. Basha, Synthesis, 2013, 0406; (c) C. B. Miao, R. Liu, Y. F. Sun, X. Q. Sun and H. T. Yang, Tetrahedron Lett., 2017, 58, 541; (d) G. Mali, S. Maji, K. A. Chavan, M. Shukla, M. Kumar, S. Bhattacharyya and R. D. Erande, ACS Omega, 2022, 7, 36028; (e) S. H. Banitaba, Org. Lett., 2023, 25, 215.
9. (a) M. Mandal and G. Brahmachari, J. Org. Chem., 2022, 87, 4777; (b) S. Das, S. Paul, T. Choudhuri, P. Sikdar and A. K. Bagdi, Synthesis, 2023, 2027.
10. S. Dey, A. Das, R. N. Yadav, P. J. Boruah, P. Bakli, T. Baishya, K. Sarkar, A. Barman, R. Sahu, B. Maji, A. K. Paul and M. F. Hossain, Org. Biomol. Chem., 2023, 21, 1771.
11. B. Pal, A. Mathuri, A. Manna and P. Mal, Org. Lett., 2023, 25, 4075.
12. (a) M. Abe, Chem. Rev., 2013, 113, 7011; (b) M. N. Gallagher, J. J. Bauer, M. Pink, S. Rajca and A. Rajca, J. Am. Chem. Soc., 2016, 138, 9377.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 2366843 and 2366844. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4cc04720f

---