Chalcogen functionalized pyrimidine synthesis by three-component free radical chalcogenation and pyrimidine ring construction

Abstract

A rather facile transition metal-free protocol for the synthesis of chalcogen functionalized pyrimidines has been established via three-component reactions of enaminones, disulfides/diselenide, and amidines/guanidine. The reactions proceed efficiently in the presence of I₂/KOH and smoothly provide chalcogenated pyrimidines with a broad substrate scope. The reaction mechanism involves a key chalcogen (sulfur)-centered free radical, which has been verified by control experiments.

---

Introduction

The pyrimidine ring represents a fundamental heterocyclic moiety and is a key structural motif in a number of functional molecules, including pharmaceuticals, agrochemicals and natural products.¹ For example (Scheme 1A), vitamin B1 exhibits notable anti-fungal and anti-inflammatory activities.² Alamifovir, which features a sulfenylated pyrimidine backbone, is a clinical drug for the treatment of HBV.³ Recent research studies have also disclosed a wide range of additional bioactivities and functions of pyrimidine derivatives.⁴ Therefore, the synthesis of pyrimidines continues to attract extensive interest.⁵ For achieving the synthesis of pyrimidines from readily available materials, a plethora of methods have been investigated and established. Representative examples include the annulation of 1,3-dicarbonyl compounds⁶ or enals⁷ with amidines or related surrogates, the annulation of ketones with amines and C1 synthons,⁸ the annulation with organo cyanides,⁹ the Au-catalyzed annulation of alkynyl alcohols with 3-amino-benzo[d]isoxazoles,¹⁰ the annulation of amidines with alcohols¹¹ or alkene building blocks,¹² the transannulation reactions of chromones,¹³ and the cyclization of amidines with other less conventional partners,¹⁴ all of which have been demonstrated to be applicable tools for the synthesis of pyrimidines with diverse substructures.

Scheme 1 Typical backgrounds.

Despite the notable advances in pyrimidine synthesis, challenges remain in this area, including the reliance on noble metal catalysts and the need for harsh conditions and oxidants. In particular, the synthesis of functionalized pyrimidines by combining ring construction and functional group installation remains rather challenging. For instance, although enaminones have been proven to be valuable building blocks for pyrimidine synthesis,¹⁵ the synthesis of functionalized pyrimidines, such as sulfur-group functionalized pyrimidines, has not been successful via one-step reactions. Instead, pre-functionalization of enaminones to enable C–H thiolation is required before pyrimidine annulation in known methods (Scheme 1B).¹⁶ In this context, developing new methods that enable cascade functionalization and pyrimidine ring formation via a one-step operation is highly desirable, as it would expand the structural diversity and application scope of pyrimidine scaffolds.¹⁷ Herein, we present a one-step protocol for the synthesis of 5-chalcogenated pyrimidines via three-component reactions of enaminones, amidine/guanidine salts and disulfides/diselenide. In the presence of KOH and molecular iodine, the products were synthesized efficiently with a broad substrate scope via a free radical pathway without using any transition metal reagent,¹⁸ exhibiting both novelty and sustainability and providing a facile route to access these S/Se-functionalized pyrimidines (Scheme 1C).

Results and discussion

Initially, the reaction of enaminone 1a, disulfide 2a and guanidine salt 3a was performed under different conditions for optimization (Table 1). It was first found that the presence of molecular iodine and K₂CO₃ in DMSO enabled the formation of product 4a in 43% yield upon heating at 80 °C (entry 1). Subsequent screening of reaction media showed that DMSO was most favourable (entries 2–4). While a base was indispensable, KOH was found to be capable of promoting the formation of 4a, resulting in a much higher yield (entries 5–8). Afterwards, the reaction was also performed in the presence of different iodine reagents, which implied that electrophilic iodine reagents were also suitable (entries 9–12). A loading of 50 mol% of iodine gave a further improved yield (entries 13 and 14), and increasing the loading of the base was also beneficial (entries 15 and 16). Altering the temperature, on the other hand, did not give a better result (entries 17 and 18). A parallel experiment using thiophenol as the alternative substrate to 2a gave product 4a with 88% yield (entry 19).

Table 1 Optimization of reaction conditions^a

Entry	Iodine source	Base	Solvent	Yield^b (%)
a Conditions: 1a (0.2 mmol), 2a (0.12 mmol), 3a (0.4 mmol), iodine source (0.2 mmol), base (0.4 mmol), solvent (2 mL), stirred at 80 °C for 14 h. b Isolated yield. c I2 (0.06 mmol). d I2 (0.1 mmol). e Base (0.6 mmol). f Base (0.8 mmol). g At 60 °C. h At 100 °C. i PhSH (0.24 mmol) was used as an alternative to 2a.
1	I2	K2CO3	DMSO	43
2	I2	K2CO3	Dioxane	12
3	I2	K2CO3	DMF	40
4	I2	K2CO3	MeOH	35
5	I2	—	DMSO	nr
6	I2	DABCO	DMSO	Trace
7	I2	KOH	DMSO	64
8	I2	^tBuOK	DMSO	26
9	—	KOH	DMSO	nr
10	KI	KOH	DMSO	nr
11	NIS	KOH	DMSO	12
12	PIDA	KOH	DMSO	nr
13^c	I2	KOH	DMSO	52
14^d	I2	KOH	DMSO	75
15^d^,^e	I2	KOH	DMSO	90
16^d^,^f	I2	KOH	DMSO	85
17^d^,^e^,^g	I2	KOH	DMSO	80
18^d^,^e^,^h	I2	KOH	DMSO	84
19^d^,^e^,^i	I2	KOH	DMSO	88

---

Following the results of the optimization experiments, the scope of the current method was examined. First, the scope of enaminones was investigated (Scheme 2). Enaminones with various functionalized benzoyl (4a–4l and 4v), heteroaroyl (4m–4o), and fused aroyl (4p and 4q) groups were all well tolerated. Substrates with strong electron-withdrawing groups on the aryl ring (4f, 4j and 4l) displayed lower reactivity, affording products in lower yields. Meanwhile, highly electron-rich arylated substrates also gave lower product yields, likely due to more number of side reactions (4m–4o and 4v). Notably, the extension of the method to the synthesis of 4-alkyl, 4-unsubstituted, and 4-vinyl pyrimidines could be efficiently achieved by using the corresponding enamine substrates. An even more significant fact was that the enaminones derived from functional molecules and natural products such as adamantine, α-ionone and pregnenolone were smoothly transformed into the pyrimidine derivatives 4w–4y. When an enaminone with a β-methyl group was used, the corresponding fully substituted pyrimidine 4z was obtained in 48% yield. The results in this section indicated the general application scope of enaminone substrates for the synthesis of the desired pyrimidines.

Scheme 2 Scope of enaminones (^a yield from a 5 mmol scale reaction).

Subsequently, the reactions of various disulfides and their chalcogen analogs, and the extension of the substrate scope from guanidine to amidines were investigated (Scheme 3). As expected, reactions using different diaryl disulfides afforded the corresponding products in good to excellent yields (4aa–4af). The pyridinylthiolated pyrimidine 4ag could be accessed in a moderate yield through the reaction with dipyridinyl disulfide. The electron-withdrawing nature of the aryl group in the disulfide reduced the efficiency of the corresponding product formation (4ag). Remarkably, the current method tolerated various dialkyl disulfides, affording the corresponding 5-alkylthiolated products 4ah–4aj in yields that were slightly lower than those obtained using equivalent thiophenols. A rather important point was that the 5-selenylated product 4ak could be synthesized via the reaction of diphenyl diselenide under the current conditions. Finally, amidines featuring alkyl or aryl groups at the C-site were proven to be practical substrates for the synthesis of 2-alkyl/aryl pyrimidines (4al and 4am). As an extended effort, reactions using an NH₂-based enaminone and dibenzyl diselenide as substrates were conducted under the standard conditions. However, neither of the two substrates was compatible for the synthesis of the desired compound (Scheme 3).

Scheme 3 Scope of disulfide/diselenide and amidine.

Furthermore, the synthetic applicability of the sulfenylated pyrimidines 4 was studied by carrying out different transformations on 4a (Scheme 4). Subjecting 4a to oxidation with mCPBA enabled the formation of the corresponding sulfinyl and sulfonyl pyrimidines 5 and 6 at room temperature via varying the oxidant loading and reaction time. In addition, treatment with NIS and NaNO₂ in DMF led to the synthesis of 2-iodopyrimidine 7via a formal substitution. Finally, the reaction of benzyl chloride with 4a led to dibenzoyl protected amino pyrimidine 8 under air conditions, promoted by triethyl amine (Scheme 4).

Scheme 4 Transformation of compound 4a.

Control experiments aimed at exploring the reaction mechanism were conducted from two different perspectives. The first involved a reaction sequence test. The pre-synthesized sulfenyl enaminone 9 was reacted with guanidine 3a, and pyridine 10 was reacted with disulfide 2a, both the reactions were performed under the standard conditions. The former afforded 4a in an excellent yield, and the latter did not give 4a, confirming that sulfenylation took place before pyrimidine ring formation (Scheme 5A). Later, the model reaction was performed in the presence of typical free radical trappers (FRTs) such as 2,2,6,6-tetramethylpiperidoxyl (TEMPO), butylated hydroxytoluene (BHT) and 1,1-diphenylethylene (DPE). While all these entries show evident inhibition of product formation, the free radical adduct 11 resulting from the reaction between the sulfur-centered radial and DPE was detected via GC-MS, confirming that the generation of the sulfur-centered radical was a key step in the reaction. Additionally, when the reaction was conducted in the presence of DPE without adding iodine, neither product 4a nor adduct 11 was formed, indicating that molecular iodine was crucial for free radical generation (Scheme 5B).

Scheme 5 Control experiments.

Based on the insights from the control experiments, a possible reaction mechanism is proposed (Scheme 6). First, the typical reaction of disulfide with iodine takes place to afford phenyl hypoiodothioite A, which upon heating undergoes homolytic cleavage to afford the sulfur-centered free radical B and iodine radical. The addition of B to enaminone leads to intermediate C, which quickly couples with the iodine radical to provide intermediate D. The subsequent β-elimination of HI from D affords the sulfenyl enaminone 9. Meanwhile, the interaction of the base with the guanidine salt gives free guanidine E. Through a typical transamination between guanidine and the amino group in 9, intermediate G is formed, which undergoes intramolecular condensation to yield product 4via intermediate H.

Scheme 6 The plausible reaction mechanism.

In summary, by using simple starting materials of enaminones, disulfides/diselenide, and guanidine/amidines, we have developed a facile three-component method for the synthesis of 5-chalcogenated pyrimidines featuring diverse substitutions in the heterocycle. Without employing any transition metal reagent, the reactions proceed via a free radical pathway, enabling the synthesis of the desired product with a broad substrate scope and generally satisfactory yield. This method could be useful for the synthesis of sulfenyl/selenyl pyrimidines and their derivatives due to the simple starting materials and operation.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: general experimental information, synthetic procedures, characterization data and NMR spectra. See DOI: https://doi.org/10.1039/d5qo01206f.

CCDC 2473846 contains the supplementary crystallographic data for this paper.¹⁹

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22561026 and 22161022).

References

1. (a) S. M. S. Rahman, G. Singh, M. S. Khan, A. K. Balasubramaniam and V. Monga, Recent developments of pyriminde appended HIV-1 non-nucleoside reverse transcriptase inhibitors, Bioorg. Chem., 2025, 157, 108273; (b) S. Cherukupalli, R. Karpoormath, B. Chandrasekaran, G. A. Hampannavar, N. Thapliyal and V. N. Palakollu, An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold, Eur. J. Med. Chem., 2017, 126, 298–352; (c) I. M. Lagoja, Pyrimidine as constituent of natural biologically active compounds, Chem. Biodiversity, 2005, 2, 1–50; (d) J. Zhuang and S. Ma, Recent development of pyrimidine-containing antimicrobial agents, ChemMedChem, 2020, 15, 1875–1886; (e) B. Nammalwar and R. A. Bunce, Recent advances in pyrimidine-based drugs, Pharmacetucals, 2024, 17, 104.
2. (a) J. T. B. Collie, R. F. Greaves, O. A. H. Jones, Q. Lam, G. M. Eastwood and R. Bellomo, Vitamin B1 in critically ill patients: needs and challenges, Clin. Chem. Lab. Med., 2017, 55, 1652–1658; (b) M. Mrowicka, J. Mrowicki, G. Dragan and I. Majsterek, The importance of thiamine (vitamin B1) in humans, Biosci. Rep., 2023, 43, 10; (c) J. A. Zastre, R. L. Sweet, B. S. Hanberry and S. Ye, Linking vitamin B1 with cancer cell metabolism, Cancer Metab., 2013, 1, 16.
3. (a) C. Chan, E. Abu-Raddad, G. Golor, H. Watanabe, A. Sasaki, K. P. Yeo, D. Soon, V. P. Sinha, S. D. Flanagan and M. X. M. He, Clinical pharmacokinetics of alamifovir and its metabolites, Antimicrob. Agents Chemother., 2005, 49, 1813–1822; (b) D. K. W. Soon, S. L. Lowe, C. H. Teng, K. P. Yeo, J. McGill and S. D. Wise, Safety and efficacy of alamifovir in patients with chronic hepatitis B virus infection, J. Hepatol., 2004, 41, 852–858.
4. (a) M. A. Marzouk, Pyrimidine derivatives as multifacected antidibetic agents: A comprehensive review of structure-activity relationships, memchanisms and clinical potential, Eur. J. Med. Chem., 2025, 296, 117859; (b) Y. Yan, Y. Chen, X. Hu and J. Wu, Synthesis and herbicidal activity of di-substituted pyrimidine-biphenyls and study of molecular mode of action, Chin. J. Org. Chem., 2025, 45, 358–366.
5. (a) V. M. Maikhuri, A. Chaudhary, R. Kumar, V. Parmar and B. K. Singh, Transition-metal catalyzed synthesis of pyrimidnes: Recent advances, mechanism, scope and future perspetives, Top. Curr. Chem., 2024, 382, 4; (b) S. Paul, T. Choudhuri, S. Das, P. Sikdar and A. K. Bagdi, Recent advances in the synthesis of functionalized pyrazolo[1,5-a]pyrimindes via C–H functionalization, Synlett, 2025, 1322–1337; (c) Y. Zhuang, X. Wang, B. Liu and L. Yao, Recent progress on the synthesis, biological actvity of fused pyrimindes from azole amines, Eur. J. Org. Chem., 2024, e202400446; (d) A. Kumar, A. Siwach and P. Verma, An overview of the synthetic route to the marketed formulations of pyrimidine: A review, Mini-Rev. Med. Chem., 2022, 22, 884–903; (e) M. Radi, S. Schenone and M. Botta, Recent highlights in the synthesis of highly functionalized pyrimidines, Org. Biomol. Chem., 2009, 7, 2841–2847.
6. (a) X.-Q. Chu, W.-B. Cao, X.-P. Xu and S.-J. Ji, Iron catalysis for modular pyrimidine synthesis through β-ammoniation/cyclization of saturated carbonyl compounds with amidines, J. Org. Chem., 2017, 82, 1145–1154; (b) M. Mahfoudh, R. Abderrahim, E. Leclerc and J.-M. Campagne, Recent approaches to the synthesis of pyrimidine derivatives, Eur. J. Org. Chem., 2017, 2856–2865; (c) M. Radi, S. Schenone and M. Botta, Recent highlights in the synthesis of highly functionalized pyrimidines, Org. Biomol. Chem., 2009, 7, 2841–2847; (d) A. R. White, L.-F. Wang and D. A. Nicewicz, Synthesis and characterization of acridinium dyes for photoredox catalysis, Synlett, 2019, 827–832.
7. (a) R. Wang, W. Guan, Z.-B. Han, F. Liang, T. Suga, X. Bi and H. Nishide, Ambient-light-promoted three-component annulation: Synthesis of perfluoroalkylated pyrimindes, Org. Lett., 2017, 19, 2358–2361; (b) L. Li, X. He, L. Zhou, H. Qu, C. Feng and K. Xu, NH₄SCN-promoted formal [3 + 3] annulation for the synthesis of 5-arylated pyrazolo[1,5-a]pyrimidines, Chin. J. Org. Chem., 2024, 44, 2832–2840; (c) Y.-J. Zhu and C. Czekelius, One-pot synthesis of fluorinated pyrimidine derivatives from aldehydes by photocatalytic α-perfluoroalkenylation, Eur. J. Org. Chem., 2025, e202500047; (d) J. Liu, J. Zhuo, M. Zhou, L. Ma and M. Zhang, A metal-free synthesis of pyrimidines from amidines with α,β-unsaturated ketones via tandem [3 + 3] annulation and visible-light-enabled photo-oxidation, Org. Biomol. Chem., 2023, 21, 3411–3416.
8. (a) F. Fang, J. Xia, S. Quan, S. Chen and G.-J. Deng, Metal- and solvent-free synthesis of substituted pyrimidines via an NH₄I-promoted three-component tandem reaction, J. Org. Chem., 2023, 88, 14697–14707; (b) J. Singh, P. Singh and M. Nath, Cascade amination and aza-6π-annulation–aromatization strategy for the synthesis of β-pyrimidine-fused porphyrines, J. Org. Chem., 2023, 88, 7302–7310; (c) S. D. Jadhav and A. Singh, Oxidative annulations involving DMSO and formamides: K₂S₂O₈ mediated syntheses of quinolines and pyrimidines, Org. Lett., 2017, 19, 5673–5676; (d) Y. Ding, R. Ma, R. C. Hider and Y. Ma, Acid-catalyzed pseudo five-component annulation for a general one-pot synthesis of 2,4,6-triaryl pyrimidines, Chem. – Asian J., 2020, 9, 242–246.
9. (a) M.-Y. Chang, C.-Y. Lin and S.-M. Chen, Synthesis of 1-aryl isoquinolinones or o-diaryl pyrimidines via bismuth triflate-mediated intermolecular annulation of arylacetic acids with nitroarylaldehydes or trimethoxybenzene in the presence of acetonitrile, Adv. Synth. Catal., 2022, 364, 2629–2641; (b) G. Yao, C. Zhu, T. Qin, M. Wang, Z. Sun, R.-Y. Tang, C. Zhao, H. Jiang and H. Xu, Oxidative annulation of aldehydes, 5-aminopyrazoles, and nitriles: Synthesis and application of pyrazolo[3,4-d]pyrimidines, Adv. Synth. Catal., 2023, 365, 1191–1204; (c) X. Wang, H. Yan, C. Jia, Z. Fang, J. Duan and K. Guo, Synthesis of 2,4,6-trisubstituted pyrimidines through copper-catalyzed [4 + 2] annulation of α,β-unsaturated ketoximes with activated nitriles, J. Org. Chem., 2023, 88, 12236–12243.
10. A. Wang, M. Lu, X. Xie and Y. Liu, Org. Lett., 2022, 24, 2944–2949.
11. (a) N. Deibl, K. Ament and R. Kempe, A sustainable multicomponent pyrimidine synthesis, J. Am. Chem. Soc., 2015, 137, 12804–12807; (b) B. Zhang, T. Guo, Z. Li, F. E. Kühn, M. Lei, Z. K. Zhao, J. Xiao, J. Zhang, D. Xu, T. Zhang and C. Li, Transition-metal-free synthesis of pyrimidines from lignin β-O-4 segments via a one-pot multi-component reaction, Nat. Commun., 2022, 13, 3365; (c) N. Deibl and R. Kempe, Manganese-catalyzed multicomponent synthesis of pyrimidines from alcohols and amidines, Angew. Chem., Int. Ed., 2017, 56, 1663–1666; (d) P. K. Sekar, A. Pennamuthiriyan and R. Rengan, Sustainable synthesis of pyrimidines by [NNO]-pincer-supported nickel(II) complexes via dehydrogenative annulation of alcohols, J. Org. Chem., 2025, 90, 9845–9858.
12. (a) W. Guo, J. Liao, D. Liu, J. Li, F. Ji and W. Wu, A four-component reaction strategy for pyrimidine carboxamide synthesis, Angew. Chem., Int. Ed., 2017, 56, 1289–1293; (b) J. Li, J. Li, R. He, J. Liu, Y. Liu, L. Chen, Y. Huang and Y. Li, Selective synthesis of substituted pyridines and pyrimidines through cascade annulation of isopropene derivatives, Org. Lett., 2022, 24, 1620–1625; (c) X.-Q. Chu, B.-Q. Cheng, Y.-W. Zhang, D. Ge, Z.-L. Shen and T.-P. Loh, Copper-catalyzed three-component cyclization of amidines, styrenes, and fluoroalkyl halides for the synthesis of modular fluoroalkylated pyrimidines, Chem. Commun., 2018, 54, 2615–2618.
13. (a) T. Zhang, W. J. Yao and J. P. Wan, tBuOK/TMSOK-mediated “alkyl halide to alkyl free radical” transformation for transition-metal-free benzoin α-C–H alkylation, Chin. J. Chem., 2024, 42, 3041–3046; (b) Q. Yu, Y. Liu and J.-P. Wan, Transition metal-free synthesis of 3-trifluoromethyl chromones via tandem C–H trifluoromethylation and chromone annulation of enaminones, Org. Chem. Front., 2020, 7, 2770–2775; (c) M. Liu, Z. Zhang, Y. Xu, X. Wang, Y. Wang, M. Peng, M. Zhang, Y. Wang and F. Yu, AgNO₃-catalyzed regio-selective bis-heteroannulation of o-hydroxyphenyl enaminones and yne-enones: A facile synthesis of functionalized 3-(furan-3-ylmethyl) chromones, Adv. Synth. Catal., 2025, 367, e202500172; (d) Z.-W. Wang, Y. Zheng, Y.-E. Qin, J.-P. Guan, W.-D. Lu, C.-P. Yuan, J.-A. Xiao, K. Chen, H.-Y. Xiang and H. Yang, Photoredox-catalyzed cascade of o-hydroxyarylenaminones to access 3-aminated chromones, J. Org. Chem., 2022, 87, 1477–1484.
14. (a) S. Wang, N. Luo, Y. Li and C. Wang, DBU-mediated cyclization of acylcyclopropanecarboxylates with amidines: Access to polysubstituted pyrimidines, Org. Lett., 2019, 21, 4544–4548; (b) J.-L. Zhan, M.-W. Wu, F. Chen and B. Han, Cu-catalyzed [3 + 3] annulation for the synthesis of pyrimidines via β-C(sp³)–H functionalization of saturated ketones, J. Org. Chem., 2016, 81, 11994–12000; (c) C. Xu, S.-F. Jiang, X.-H. Wen, Q. Zhang, Z.-W. Zhou, Y.-D. Wu, F.-C. Jia and A.-X. Wu, Dimethyl sulfoxide serves as a dual synthon: Construction of 5-methyl pyrimidine derivatives via four-component oxidative annulation, Adv. Synth. Catal., 2018, 360, 2267–2271; (d) Q. Gao, M. Wu, K. Zhang, N. Yang, M. Liu, J. Li, L. Fang, S. Bai and Y. Xu, I₂-catalyzed aerobic α,β-dehydrogenation and deamination of tertiary alkylamines: Highly selective synthesis of polysubstituted pyrimidines via hidden acyclic enamines, Org. Lett., 2020, 22, 5645–5649; (e) F. Zhang, J. Liu, W. Luo, Y. Zhu, Y. Xiao, S. Ma, F. Luo and Z. Chen, Annulation of α-bromocinnamaldehydes to access 3-formyl-imidazo[1,2-α]pyridines and pyrimidines under transition metal-free conditions, Org. Biomol. Chem., 2023, 21, 4766–4769.
15. (a) W. Zuo, Z. Zhu, Y. Cheng, L. Zuo, X. Geng, Z. Li and L. Wang, Switchable multicomponent cyclization reactions to access fluoroalkylated dihydropyrimidines and pyrimidines under solvent-free conditions, Chin. J. Chem., 2024, 42, 1394–1398; (b) D. Lou, Y. Ding, Z. Jin, W. Huang, Y. Shi, C. Zhang and Y. Xie, One-pot multicomponent selective synthesis of 5-trifluoromethyl pyrimidine derivatives, Adv. Synth. Catal., 2024, 366, 2715–2720; (c) J.-Y. Liu, S.-Y. Zhuang, Y.-X. Tang, X.-L. Chen, Y. Zhou, Y.-D. Wu, K.-L. Zheng and A.-X. Wu, J. Org. Chem., 2023, 88, 12000–12012; (d) H. Jalani, W. Cai and H. Lu, Copper-catalyzed one-pot synthesis of pyrimidines from amides, N,N′-dimethylformamideacetal, and enamines, Adv. Synth. Catal., 2017, 359, 2509–2513; (e) E. Gayon, M. Szymczyk, H. Gérard, E. Vrancken and J.-M. Campagne, Stereoselective and catalytic access to β-enaminones: An entry to pyrimidines, J. Org. Chem., 2012, 77, 9205–9220.
16. (a) J. Ye, Y. Liu, J. Luo and J.-P. Wan, “Alkene-to-alkene” difunctionalization of enaminones for the synthesis of polyfunctionalized alkenes by transition-metal-free C–H and C–N bond transformation, Org. Lett., 2023, 25, 8451–8456; (b) Q. Yu, Y. Y. Liu and J. P. Wan, Metal-free C(sp²)–H perfluoroalkylsulfonylation and configuration inversion: stereoselective synthesis of α-perfluoroalkylsulfonyl E-enaminones, Chin. Chem. Lett., 2021, 32, 3514–3517; (c) J. Ying, T. Zhou, Y. Liu, L. Zhou and J.-P. Wan, Transition-metal-free C–H trifluoromethylthiolation of N,N-disubstituted enaminones to access CF₃S-functionalized enaminones and their application in the synthesis of CF₃S-heteroaryls, J. Org. Chem., 2024, 89, 9078–9085; (d) T. Zhou, J. Zhou, Y. Liu, J.-P. Wan and F.-E. Chen, Transition-metal-free tunable synthesis of 3-(trifluoromethylthio) and 3-trifluoromethyl sulfinyl chromones via dimino C–H functionalization and chromone annulation of enaminones, Chin. Chem. Lett., 2024, 35, 109683.
17. During the preparation of our manuscript, Guo and Zheng et al. reported the synthesis of 5-sulfenylated/selenylated pyrimidines by enaminone-based three-component reactions employing thio/seleno-benzenesulfonates as the sulfenyl/selenyl source via a fully ionic cascade transformation: Z. Zhang, Y. Wang, X. Hua, C. Zheng, P. Chen, Y. Lin, X. Zhu, L. Zheng and W. Guo, One-pot three-component cascade strategy for the site-selective synthesis of 5-sulfenylated/selenylated 2,4-disubstituted pyrimidines, Org. Lett., 2025, 27, 7247–7252.
18. For selected recent works, see: (a) Z. Wang, L. Gan, Z. Song, Y. Liu and J.-P. Wan, tBuOK/TMSOK-mediated “alkyl halide to alkyl free radical” transformation for transition-metal-free benzoin α-C–H alkylation, Chin. J. Chem., 2024, 42, 3041–3046; (b) C. Wang, Y. Liu and J.-P. Wan, Construction of fused oxacyclic compounds via dual α- and β-C–H functionalization and ring decomposition of cyclic ethers, Org. Lett., 2025, 27, 3983–3987; (c) W.-T. Ouyang, J. Jiang, Y.-F. Jiang, T. Li, Y.-Y. Liu, H.-T. Ji, L.-J. Ou and W.-M. He, Sono-photocatalytic amination of quinoxalin-2(1H)-ones with aliphatic amines, Chin. Chem. Lett., 2024, 35, 110038; (d) J.-Z. Li, L. Mei, X.-E. Cai, C.-C. Zhang, T.-T. Cao, X.-J. Huang, Y.-L. Liu and W.-T. Wei, Transition-metal-free radical cyclization of 2-arylbenzoimidazoles with unactivated alkanes via C(sp³)–H functionalizations in aqueous media, Adv. Synth. Catal., 2022, 364, 2080–2085; (e) P. Xiang, K. Sun, S. Wang, X. Chen, L. Qu and B. Yu, Direct benzylation reactions from benzyl halides enabled by transition-metal-free photocatalysis, Chin. Chem. Lett., 2022, 33, 5074–5079; (f) X. Wang, S. Guo, Y. Zhang, Z. Zhang, G. Zhang, Y. Ye and K. Sun, Metal-free organoselenium-enabled radical relay azidation-carbocyclization, Adv. Synth. Catal., 2021, 363, 3290–3296; (g) G. Guo, X. Li, J. Ma, Y. Shi, J. Lv and D. Yang, Chin. Chem. Lett., 2024, 35, 110024; (h) Y. Lv, J. Hao, J. Huang, L. Song, H. Yue, W. Wei and D. Yi, Metal-free visible-light-mediated aerobic nitrooxylation for the synthesis of nitrate esters with t-BuONO, Chem. Commun., 2024, 60, 9801–9804; (i) H. Guo, Y. Liu and J.-P. Wan, Electrochemical cascade pyrazole annulation and C–H halogenation for the synthesis of 4-halopyrazoles, Green Synth. Catal., 2025, 6, 206–210; (j) M. Cabrera-Afonso, A. Jaafar, C. Cristóbal, J. Adrio and M. Ribagorda, Visible-light-promoted synthesis of 1,6-imino alcohols by metal-free 1,2-carboimination of alkenes, Org. Lett., 2025, 27, 2346–2351.
19. CCDC 2473846: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2p17hh.

---