Visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization to construct α-chromone substituted α-amino acid derivatives

Abstract

Organophotocatalytic cascade cross-dehydrogenative-coupling/cyclization reaction of o-hydroxyarylenaminones with α-amino acid derivatives for the construction of α-chromone substituted α-amino acid derivatives was developed. Various N-arylglycine esters, amides and dipeptides underwent the cascade cyclization reaction well with o-hydroxyarylenaminones to afford the corresponding 3-aminoalkyl chromones in good to excellent yields. This approach consists of visible-light-promoted oxidation of α-amino acid derivatives, the Mannich reaction, and intramolecular nucleophilic cyclization under acidic conditions, and features a wide reaction scope, a simple operation and mild reaction conditions, which may have the potential to be used for the synthesis of bioactive molecules.

---

Chromones are common motifs abundant in many natural products, pharmaceuticals and materials.¹ Particularly, C3-substituted chromones have recently received considerable attention due to the diverse physiological and biological activities, including anti-inflammatory, anticancer, antioxidant, antimicrobial, anti-HIV, etc.² Moreover, 3-substituted chromones have been employed as useful building blocks in many research areas such as organic synthesis, biochemistry, and medicinal chemistry.³ Consequently, tremendous efforts have been devoted to constructing various C3-functionalized chromones.⁴ Conventional methods for 3-substituted chromones are mainly focused on the transition-metal-catalyzed cross-coupling reactions of halochromones as well as direct C–H functionalization of chromones.^4b,5 In recent years, cascade vinyl C–H functionalization and chromone annulation of o-hydroxyphenylenaminones has emerged as a powerful and reliable strategy to synthesize various C3-substituted chromones.⁶ Although significant achievements have been attained, cascade cross-dehydrogenative-coupling of o-hydroxyarylenaminones with various coupling partners and subsequent chromone annulation have scarcely been reported in the literature. In 2020, Wan's group reported transient halogenation-mediated chromone annulation for the synthesis of 3-vinyl chromones via the domino C–H alkenylation and cyclization of o-hydroxyarylenaminones.^5b

Cross-dehydrogenative-coupling reactions are a valuable synthetic route to forging new chemical bonds because this type of reaction avoids functional group interconversion and has the advantages of being atom economic and environmentally friendly.⁷ α-Amino acids are often seen as green reactants, which are more readily available and are widely used to construct complex organic molecules.⁸ Intensive interest and research have been aroused on direct cross-dehydrogenative-coupling of α-amino acid derivatives with a variety of nucleophiles to afford α-substituted α-amino acid derivatives in the past few years.⁹ Considering that the introduction of the chromone skeleton into α-amino acid derivatives is significant in the structural modification of drugs and the application of organic synthesis, and as our continuing research interest in photocatalytic C–H transformation,¹⁰ we herein report visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization of o-hydroxyarylenaminones with glycine derivatives for the synthesis of diverse α-chromone substituted α-amino acid derivatives.

At the outset, o-hydroxyarylenaminone 1a and N-4-methylphenylglycine ester 2a were selected as model substrates to test the feasibility of the designed process. The results are summarized in Table 1; after a systematic survey of various parameters, such as photosensitizers, solvents, and additives, the optimal conditions were determined as follows: 1a (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), Na₂-eosin Y (5 mol%), and citric acid·H₂O (2.0 equiv.) in EtOH (2 mL, 0.1 M) under the irradiation of 18 W blue LEDs (456 nm) in air at room temperature for 24 h (entry 1, Table 1). There was no improvement in the reaction yields when photosensitizers other than Na₂-eosin Y were used (entries 2–4, Table 1). Various solvents such as THF and DMSO were evaluated, and EtOH was found to be the best for the yield of 3aa (entries 5 and 6, Table 1). The structure of 3aa was unambiguously confirmed by X-ray (CCDC: 2237743†) as well as NMR analysis. Further screening of the reaction conditions revealed that the other additives and oxidants led to lower yields of 3aa (entries 7–9, Table 1). The experimental results indicated that visible-light, citric acid·H₂O and air were critical to the desired coupling cyclization (entries 10 and 11, Table 1). It was noteworthy that the desired cyclization product 3aa was formed in 38% yield only in the presence of citric acid·H₂O under the irradiation of visible-light (entry 12, Table 1). The ultraviolet-visible (UV-Vis) absorption spectrum of individual reaction partners and that of combined reaction components were recorded, which indicated the formation of an EDA complex (see Fig. S5 in the ESI†). A 63% yield of product 3aa was isolated under the illumination of green LEDs.

Table 1 Optimization of the reaction conditions^a,b

Entry	Variations from standard conditions	Yield^a^,^b (%)
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), photosensitizer (5 mol%), solvent (2 mL, 0.1 M), additive (2.0 equiv.) at room temperature under the irradiation of 18 W light (456 nm) for 24 h in air. b Isolated yields.
1	None	75
2	Ru(bpy)3Cl2·6H2O instead of Na2-eosin Y	26
3	4CzPIN instead of Na2-eosin Y	9
4	Rose bengal instead of Na2-eosin Y	21
5	THF instead of EtOH	31
6	DMSO instead of EtOH	24
7	Na2HPO4 instead of citric acid·H2O	20
8	Acetic acid instead of citric acid·H2O	57
9	Under N2	0
10	In the dark	trace
11	No citric acid·H2O	15
12	No Na2-eosin Y	38
13	Green LEDs instead of blue LEDs	63

---

With the optimal reaction conditions established, a wide array of o-hydroxyarylenaminones 1 were prepared and subjected to reaction with N-4-methylphenylglycine ester 2a under the standard reaction conditions to explore the substrate scope. As shown in Table 2, various o-hydroxyphenyl enaminones 1b–f bearing different substituents R¹ (–Me, –OMe, –F, –Cl, and –Br) at the C5-position were engaged in this protocol efficiently to afford the corresponding products 3ab–af in 41–75% yields. Similarly, o-hydroxyarylenaminones 1 possessing different substituents R¹ (–OMe, –F, –Cl, and –Br) at the C4-position were examined, and the desired products 3ag–aj were isolated in good to high yields. The experimental results indicated that chromones bearing electron-withdrawing groups on the benzene rings were more favorable for the transformation than those bearing electron-donating groups. Furthermore, the disubstituted o-hydroxyarylenaminones 1k and 1l were also tolerated and gave the target products 3ak and 3al in 50% and 20% yields, respectively. As expected, fused aryl substrate 1m underwent the desired coupling cyclization smoothly to afford the desired product 3am with a satisfactory yield. Encouraged by the results presented above, we next investigated the reactions of o-hydroxyphenylenaminone 1a with various α-amino acid derivatives 2 under the current reaction conditions. As outlined in Table 3, a broad range of α-amino acid derivatives 2 underwent cyclization reactions readily with o-hydroxyphenylenaminone 1a, providing the corresponding products 3ba–ja in 47–70% yields. N-Arylglycine esters 2c–e bearing electron-rich (–Me, –OMe and 3,4-Me) substituents on the benzene ring reacted more efficiently than those bearing electron-deficient substituents 2f–j. Remarkably, several N-arylglycine esters, such as methyl, isopropyl, tert-butyl, and benzyl esters 2k–n, were also compatible with the reaction, producing the corresponding products 3ka–na in 40–67% yields. Interestingly, glycine amide 2o and dipeptide 2p were also suitable for this transformation, delivering the target products 3oa and 3pa in 43% and 48% yields, respectively. In addition, we also successfully realized the conversion of tertiary amine with 30% isolated yield by changing the reaction conditions appropriately.

Table 2 Reaction scope of o-hydroxyarylenaminones 1^a,b

a Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), Na₂-eosin Y (5 mol%), EtOH (2 mL, 0.1 M), citric acid·H₂O (2.0 equiv.) at room temperature under the irradiation of 18 W blue LEDs (456 nm) for 24 h in air. b Isolated yields based on 1.

---

Table 3 Reaction scope of α-amino acid derivatives 2^ab

a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 2.0 equiv.), Na₂-eosin Y (5 mol%), EtOH (2 mL, 0.1 M), citric acid·H₂O (2.0 equiv.) at room temperature under the irradiation of 18 W light (456 nm) for 24 h in air. b Isolated yields based on 1a. c 4CzPIN instead of Na₂-eosin Y.

---

To demonstrate the applicability of this protocol, a gram-scale synthesis was conducted under the standard conditions, giving the desired product 3aa in 63% yield (Scheme 1a). Furthermore, a set of control experiments were carried out to explore this photocatalytic reaction mechanism. Radical-trapping experiments indicated that the corresponding radical adducts and imine intermediate were detected by HRMS analysis. Thus, a free-radical pathway was probably involved in the process (Scheme 1b). Next, imine intermediate 6a was prepared and then reacted with o-hydroxyphenylenaminone 1a to obtain 3aa in 52% yield (Scheme 1c). Furthermore, the light on–off experiment results revealed that the photocatalytic cross-dehydrogenative-coupling/cyclization reaction required continuous visible-light irradiation (Scheme 1d). Moreover, fluorescence quenching experiments with the Na₂-eosin Y photocatalyst as well as cyclic voltammetry (CV) experiments to study the redox potential of substrates were also performed (see the ESI†), and the results suggested that N-arylglycine ethyl ester 2a was preferentially oxidized by Na₂-eosin Y in the excited state, and thus the reaction might proceed through a reductive quenching pathway.

Scheme 1 Control experiments.

On the basis of the abovementioned experimental results and literature survey,^10a,b a plausible mechanism for the photocatalytic reaction is proposed in Scheme 2. Initially, upon irradiation, Na₂-eosin Y was excited to produce the excited-state Na₂-eosin Y*, which underwent single electron transfer (SET) with N-4-methylphenylglycine ester 2a to produce the radical cation A as well as Na₂-eosin Y˙⁻. At the same time, Na₂-eosin Y˙⁻ was oxidized by molecular oxygen to generate the ground-state Na₂-eosin Y and superoxide radical anion (O₂⁻˙). Then, the radical intermediate A resulted in the formation of aminoalkyl radical B by the superoxide radical (O₂⁻˙). In the presence of citric acid·H₂O, the intermediate B was then oxidized and protonated to afford the imine intermediate C, which interacted with o-hydroxyarylenaminone 1a to form the iminium intermediate D (path A). On the other hand, a ternary colored EDA complex was formed in the presence of 1a, 2a and citric acid·H₂O.¹¹ Upon irradiation, SET occurred between 1a and 2a under acidic conditions, followed by the formation of radical cation A and radical F, and they were further oxidized to the corresponding iminium/imine species, which then transformed into the key intermediate D (path B). Finally, intermediate D underwent intramolecular nucleophilic cyclization to deliver the desired product 3aa.

Scheme 2 Plausible mechanism.

In conclusion, we have developed a novel visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization of o-hydroxyarylenaminones with α-amino acid derivatives for the synthesis of structurally diverse α-chromone substituted α-amino acid derivatives. A plausible reaction mechanism has also been proposed on the basis of control experiments. This synthetic protocol features broad substrate scopes and good functional group tolerance under mild conditions, which provides a new and practical approach for the construction of various α-chromone substituted α-amino acid derivatives. Further investigations of reaction development and synthetic applications of this methodology are in progress in our laboratory.

Financial support from the National Natural Science Foundation of China (21966003), the Natural Science Foundation of Jiangxi Province (20232BAB203001), and the Open Fund of Jiangxi Province Key Laboratory of Synthetic Chemistry (JXSC202206) is gratefully acknowledged.

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. (a) A. Gaspar, M. J. Matos, J. Garrido, E. Uriarte and F. Borges, Chem. Rev., 2014, 114, 4960; (b) B. M. Trost, E. Gnanamani, C. A. Kalnmals, C.-I. J. Hung and J. S. Tracy, J. Am. Chem. Soc., 2019, 141, 1489; (c) J. Cui, N. Kumagai, T. Watanabe and M. Shibasaki, Chem. Sci., 2020, 11, 7170; (d) A. Nazhand, A. Durazzo, M. Lucarini, R. Romano, M. A. Mobilia, A. A. Izzo and A. Santini, Nat. Prod. Res., 2020, 34, 137; (e) D. R. Joshi and I. Kim, J. Org. Chem., 2021, 86, 10235; (f) V. M. Patil, N. Masand, S. Verma and V. Masand, Chem. Biol. Drug Des., 2021, 98, 943.
2. (a) A. Danda, N. Kesava-Reddy, C. Golz, C. Strohmann and K. Kumar, Org. Lett., 2016, 18, 2632; (b) J. Lei, Y. Li, L.-J. He, Y.-F. Luo, D.-Y. Tang, W. Yan, H.-K. Lin, H.-Y. Li, Z.-Z. Chen and Z.-G. Xu, Org. Chem. Front., 2020, 7, 987; (c) C. Zhao, B. H. Shah, H. Li, X. Wu and Y. J. Zhang, Asian J. Org. Chem., 2021, 10, 545; (d) Y. Dai, W. Meng, X. Feng and H. Du, Chem. Commun., 2022, 58, 1558.
3. (a) L. Albrecht, A. Cruz Acosta, A. Fraile, A. Albrecht, J. Christensen and K. A. Jørgensen, Angew. Chem., Int. Ed., 2012, 51, 9088; (b) D. Jiang, J. Chen, N. Zan, C. Li, D. Hu and B. Song, J. Agric. Food Chem., 2021, 69, 12126; (c) L. Meng, X. Chang, Z. Lin and J. Wang, Org. Biomol. Chem., 2021, 19, 2663; (d) D.-G. Guo, H.-J. Wang, Y. Zhou and X.-L. Liu, Org. Biomol. Chem., 2022, 20, 4681.
4. (a) D. Kang, K. Ahn and S. Hong, Asian J. Org. Chem., 2018, 7, 1136; (b) S. Tian, T. Luo, Y. Zhu and J.-P. Wan, Chin. Chem. Lett., 2020, 31, 3073; (c) J. Duan, Z. Xiong, Y. Zhou, W. Yao, X. Li, M. Zhang and Z. Wang, Org. Lett., 2021, 23, 8007.
5. (a) L. Klier, T. Bresser, T. A. Nigst, K. Karaghiosoff and P. Knochel, J. Am. Chem. Soc., 2012, 134, 13584; (b) L. Fu, Z. Xu, J.-P. Wan and Y. Liu, Org. Lett., 2020, 22, 9518; (c) H. Choi, M. Min, Q. Peng, D. Kang, R. S. Paton and S. Hong, Chem. Sci., 2016, 7, 3900; (d) Y. Guo, Y. Xiang, L. Wei and J.-P. Wan, Org. Lett., 2018, 20, 3971.
6. (a) S. Mkrtchyan and V. O. Iaroshenko, Chem. Commun., 2020, 56, 2606; (b) S. Mkrtchyan and V. O. Iaroshenko, J. Org. Chem., 2021, 86, 4896; (c) H.-Y. Liu, J.-R. Zhang, G.-B. Huang, Y.-H. Zhou, Y.-Y. Chen and Y.-L. Xu, Adv. Synth. Catal., 2021, 363, 1656; (d) Z.-W. Wang, Y. Zheng, Y.-E. Qian, J.-P. Guan, W.-D. Lu, C.-P. Yuan, J.-A. Xiao, K. Chen, H.-Y. Xiang and H. Yang, J. Org. Chem., 2022, 87, 1477; (e) L. Lu, X. Zhao, W. Dessie, X. Xia, X. Duan, J. He, R. Wang, Y. Liu and C. Wu, Org. Biomol. Chem., 2022, 20, 1754.
7. (a) T. Tian, Z.-P. Li and C.-J. Li, Green Chem., 2021, 23, 6789; (b) H. Wang, X. Gao, Z. Lv, T. Abdelilah and A. Lei, Chem. Rev., 2019, 119, 6769.
8. (a) J. B. Hedges and K. S. Ryan, Chem. Rev., 2020, 120, 3161; (b) L. Xiao, Z. Zhu, Z. Xie and Z. Le, Chin. J. Org. Chem., 2019, 39, 2345.
9. (a) Z.-H. Wang, P.-S. Gao, X. Wang, J.-Q. Gao, X.-T. Xu, Z. He, C. Ma and T.-S. Mei, J. Am. Chem. Soc., 2021, 143, 15599; (b) Z.-H. Yuan, H. Xin, J.-Q. Tao, Y.-J. Ma, X.-H. Duan and L.-N. Guo, Org. Chem. Front., 2022, 9, 3546; (c) Y. Gao, J. Liu, C. Wei, Y. Li, K. Zhang, L. Song and L. Cai, Nat. Commun., 2022, 13, 7450; (d) L. Poletti, D. Ragno, O. Bortolini, F. Presini, F. Pesciaioli, S. Carli, S. Caramori, A. Molinari, A. Massi and G. Di Carmine, J. Org. Chem., 2022, 87, 7826 and references therein.
10. (a) Z.-Q. Zhu, D. Guo, J.-J. Ji, X. Zhu, J. Tang, Z.-B. Xie and Z.-G. Le, J. Org. Chem., 2020, 85, 15062; (b) Z.-Q. Zhu, S. Liu, Z.-Y. Hu, Z.-B. Xie, J. Tang and Z.-G. Le, Adv. Synth. Catal., 2021, 363, 2568; (c) Z.-Q. Zhu, J.-Y. Hu, Z.-B. Xie, J. Tang and Z.-G. Le, Adv. Synth. Catal., 2022, 364, 2169.
11. C. Wang, R. Qi, H. Xue, Y. Shen, M. Chang, Y. Chen, R. Wang and Z. Xu, Angew. Chem., Int. Ed., 2020, 59, 7461.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 2237743. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3cc04107g

---