Photoredox-catalyzed cascade [2 + 2 + 1] cyclization of 1,6-enynes with thiols

Abstract

Here, we report a visible-light-mediated [2 + 2 + 1] cascade cyclization of 1,6-enynes with thiols, providing a new synthetic protocol for the rapid construction of sulfur-containing polycyclic derivatives in moderate to good yields along with a broad substrate scope. Mechanistic investigations were also performed through control experiments and Stern–Volmer analysis as well as DFT calculations, suggesting that this cascade cyclization reaction stems from a sulfur radical addition to the alkynyl moiety of 1,6-enyne along with a cascade cyclization with the alkenyl unit. Then, the formation of sulfur-containing polycyclic molecules can be achieved by homolytic S_Hi-type substitution at the thioether unit, stripping away a sulfur atom. Further transformations of the obtained product have also been disclosed.

---

Introduction

Five- and six-membered heterocyclic rings are key fragments that can be found in numerous compounds of natural sources, presenting potent biological activities.¹ In particular, a number of sulfur-containing heterocyclic natural products, such as penicillin, neothiobinupharidine, and salacinol, have been applied as anticancer, antibacterial and antidiabetic drugs (Scheme 1a).^1b,2 However, obtaining sufficient amounts of sulfur-containing natural products from natural sources for biomedical studies remains a considerable challenge. Considering the above factors, the design and synthesis of sulfur-containing polycyclic compounds have attracted great interest in recent years.³

Scheme 1 Sulfur-containing cyclic compounds, previous work and this work.

The synthesis of complex polycyclic molecules has always been a momentous research subject in synthetic chemistry, especially the preparation of multiple cyclic systems in one step.⁴ One of the common synthetic strategies for constructing these structures is the [2 + 2 + m] annulation of 1,n-enynes (n = 6 or 7) with various m-atom units to form complex polycyclic compounds with high atom and step economy.⁵ Over the past decades, numerous [2 + 2 + 1] cascade annulations have been reported with transition-metal catalysis⁶ (Scheme 1b) or photoinduced catalysis⁷ (Scheme 1c). On the basis of transition-metal catalysis, 1,n-enynes (n = 6 or 7) can be used as feedstock materials to accept the addition of X-atom units, affording five- or six-membered ring fused polycyclic molecules. For example, the [2 + 2 + 1] cyclization reaction between 1,n-enynes and C-atom units can use CO as a C-atom reagent under transition metal catalysis (Paulson Handel type cyclization reaction), delivering the desired polycyclic products in good yields (Scheme 1b).^6b Other functional groups can also be utilized as C-atom units in [2 + 2 + 1] cyclization, such as alkanes,^6c arenes,^6d and imines.^6e However, it is more difficult for heteroatom units to undergo such [2 + 2 + 1] cyclization with 1,n-enynes than for C-atom units (Scheme 1b). Only three heteroatoms such as N,^6g S,^6h and Si^6k have been developed for the synthesis of heterocyclic compounds through [2 + 2 + 1] cyclization with 1,n-enynes under transition-metal catalysis with limited examples thus far (Scheme 1b). On the other hand, radical species can also be utilized to synthesize complex polycyclic molecules through [2 + 2 + 1] cyclization with 1,n-enynes. For instance, the cascade addition of carbon-centered radicals generated from fluoroalkanes^7d or other alkyl radical precursors⁷ upon photoredox catalysis to 1,6-enyne can afford polycyclic compounds under mild conditions (Scheme 1c). Nevertheless, the synthesis of sulfur-containing polycyclic compounds via visible-light mediated [2 + 2 + 1] heterocyclization with 1,n-enynes has never been reported before.

It has been well known that radical species allow the formation of cyclic structures via the cyclization of a radical species onto an unsaturated partner (e.g. alkene, alkyne, or arene).⁸ In addition, the formation of sulfur-containing heterocycles can be achieved by homolytic substitution at the sulfur atom.⁹ Inspired by these findings, we attempted to utilize tert-butylthiol 2a as a sulfur radical precursor for the reaction with 1,6-enynes 1 to realize a cascade [2 + 2 + 1] heterocyclization via photoredox catalysis under mild conditions (Scheme 1d).

Results and discussion

We first utilized substrate 1a as the model substrate for the initial investigation and subsequently optimized the reaction conditions. The results are shown in Table 1. After several initial experimental examinations, the optimal reaction conditions are identified as follows: 1,6-enyne 1a (0.1 mmol, 1.0 equiv.) is used as the substrate, tert-butylthiol 2a (0.2 mmol, 2.0 equiv.) is employed as a reagent, K₂CO₃ (0.2 mmol, 2.0 equiv.) is used as a base, p-toluenethiol is employed as an additive and Ir[(dFCF₃ppy)₂(dtbpy)]PF₆ is utilized as a photosensitizer in dichloroethane (DCE) (5.0 mL) and irradiated with a 30 W blue LED for 12 h, affording the desired product 3a in 97% NMR yield and 95% isolated yield (Table 1, entry 1). In addition, other photosensitizers such as fac-Ir(ppy)₃ and Ir(dtbpy)ppy₂ gave 3a in low and moderate yields of 15% and 50%, respectively (entries 2 and 3) (see Table S2 in the ESI† for more information). Moreover, attempting to improve the yield, we evaluated other bases including Cs₂CO₃, NEt₃, and Na₂CO₃, but none of them performed better than K₂CO₃ (entries 4–6) (see Table S4 in the ESI† for more information). We further examined solvent effects on this photochemical transformation and found that the use of other solvents, such as DCM and MeCN, afforded 3a in moderate yields ranging from 58% to 60%, demonstrating that the best solvent for the reaction was DCE (entries 7 and 8) (see Table S3 in the ESI† for more information). When the solvent volume was changed to 1.0 mL, the yield of 3a decreased to 59% (entry 9). Benzylthiol 2b, cyclohexylthiol 2c and mesna 2d could also be used as the sulfur radical precursor to react with 1a, affording the desired product in 43%, 66% and 10% yields, respectively (Table 1, entries 10–12). Furthermore, the control experiments revealed that base, p-toluenethiol, photosensitizer, and light were essential for this reaction (entries 13–15) (see Table S5 in the ESI† for more information).

Table 1 Optimization of the reaction conditions^a,b

Entry	Variation from the standard conditions	3a, yield^b [%]
a Reaction was carried out with 1a (0.1 mmol), 2a (2.0 equiv.), K2CO3 (2.0 equiv.), p-toluenethiol (0.2 equiv.), [Ir(dFCF3ppy)2(dtbpy)]PF6 (3.0 mol%) in DCE (5.0 mL) at ambient temperature under 30 W blue LED irradiation. b ^1H NMR yield using dimethyl terephthalate as an internal standard. c Isolated yield.
1	None	97 (95)^c
2	fac-lr(ppy)3 as PC	15
3	lr(dtbpy)ppy2 as PC	50
4	Cs2CO3 instead of K2CO3	72
5	NEt3 instead of K2CO3	0
6	Na2CO3 instead of K2CO3	77
7	DCM instead of OGE	58
8	MeCN instead of OGE	60
9	1.0 ml OGE instead of 5.0 ml OGE	59
10	2b instead of 2a	43
11	2c instead of 2a	66
12	2d instead of 2a	10
13	Without base	40
14	Without light or PC	0
15	Without p-toluenethiol	67

---

With the reaction conditions optimized, we explored the generality of this cascade annulation reaction, and the results are summarized in Scheme 2. It was found that most of the substrates successfully underwent these reactions smoothly, providing the desired products in moderate to good yields. Substrate 1b having a terminal alkyne unit (R¹ = H) was tolerated in this reaction, delivering the corresponding product 3b in 60% yields. Utilizing 1,6-enyne substrates 1c–1f (R¹ = alkyl group, R² = Ts, and R³ = Ph), the desired products 3c–3f were obtained in 80%–90% yields. It is worth noting that an increase of the steric hindrance of the alkyl group decreased the yield of the corresponding products 3. The structure of 3e was unambiguously determined by X-ray crystallographic analysis and its ORTEP drawing is shown in Scheme 2. In addition, substrate 1g having a protected hydroxy group, substrate 1h containing an imino group and substrate 1i with an ester group were all well compatible, giving the desired products 3g, 3h and 3i in 75%, 78% and 73% yields, respectively. Notably, in the case of substrate 1j containing a terminal alkenyl group, the thiophene product 3j was formed in 53% yield presumably due to the further oxidation in the reaction system. Next, we shifted our attention to examine the R³ group in 1,6-enynes 1 (R¹ = Me) and found that introducing an alkyl group, ester group and aryl substituent in the R³ group of 1,6-enynes 1k–1r afforded the desired products 3k–3r in 51%–96% yields. Moreover, the R² sulfonyl group was also exploited under the standard conditions and we identified that substrates 1s–1y with a variety of sulfonated groups in R² all provided the desired products in good yields. To our delight, upon changing the linker atom to an oxygen atom, the desired product 3z was obtained in 43% yield. However, when the (C(CO₂Et)₂)-linked substrate 1aa was utilized to carry out the reaction, the desired product 3aa was not obtained perhaps due to the steric effect. Further investigation revealed that this reaction also tolerated 1,6-enynes with several leaving groups (OMs, OTs, and OAc) such as substrates 1ab, 1ac and 1ad, giving the corresponding products 3ab, 3ac and 3ad in 85%, 90% and 83%, respectively, probably due to the mild reaction conditions.

Scheme 2 ^a  Standard conditions: substrate 1 (0.1 mmol, 1.0 equiv.), 2a (2.0 equiv.), K₂CO₃ (2.0 equiv.), p-toluenethiol (0.2 equiv.), [Ir(dFCF₃ppy)₂(dtbpy)]PF₆ (3.0 mol%) in DCE (5.0 mL) at ambient temperature under 30 W blue LED irradiation for 12 hours. ^b The desired product was obtained in a complex mixture.

To gain more insights into the reaction mechanism, we carried out several control experiments (Scheme 3). First, Stern–Volmer luminescence quenching analysis using 1a and 2a showed that 2a can more effectively quench the emission of Ir[(dFCF₃ppy)₂dtbpy]PF₆, suggesting that 2a is an effective quencher for the excited state of Ir[(dFCF₃ppy)₂dtbpy]PF₆ (Scheme 3A).¹⁰ To test whether the sulfur radical initiated a radical chain reaction, we analyzed the exclusive light-dependence of the reaction, in which the reaction basically stopped under dark conditions and continued when light was restored, indicating that visible light irradiation is a necessary condition for this reaction (Scheme 3B),¹¹ and the quantum yield was measured as Φ = 0.13 in this reaction (see page S15 in the ESI†), also suggesting that the intervention of a radical chain mechanism is unlikely. The addition of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a radical scavenger significantly inhibited the reaction. However, the TEMPO-trapped adduct cannot be characterized by HRMS spectrometry in our attempted experiment (Scheme 3C, also see page S16 in the ESI†).¹² Moreover, we utilized 1ae as a substrate which has large steric hindrance in the alkenyl moiety, giving the corresponding product 3ae instead of the [2 + 2 + 1] cyclization product (Scheme 3D). We subsequently embarked on DFT calculations to gain further insight into the reaction mechanism. All calculations have been performed at the SMD(dichloroethane)/B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level with the Gaussian 16 program.¹³ The solvation Gibbs free energy profile in dichloroethane (DCE) for the suggested reaction pathway is shown in Scheme 3E (see Table S6 in the ESI† for more information). We investigated the reaction pathway starting from a tert-butyl sulfur radical intermediate INT1 shown in Scheme 3E. First, the intermediate INT1 undergoes addition to the alkenyl moiety of 1kviaTS1 with an energy barrier of 13.5 kcal mol⁻¹ to generate a radical intermediate INT2. Subsequently, the intermediate INT2 produces another carbon-centered cyclized radical intermediate INT3 through an intramolecular cyclization with an energy barrier of 13.2 kcal mol⁻¹. Passing through transition state TS3, the radical intermediate INT3 undergoes the S_Hi process with an energy barrier of 6.5 kcal mol⁻¹ to afford the product complex INT4. According to the previous reports, the LUMO of INT3 is located at the S center which is more easily prone to intermolecular attack by the alkyl radical.¹⁴ Another possible reaction pathway was also investigated theoretically. Instead of starting from the terminal alkenyl moiety, INT1 undergoes addition to the alkynyl moiety of 1kviaTS1′ with an energy barrier of 21.4 kcal mol⁻¹ to produce a radical intermediate INT2′, which is higher than that of addition on the alkenyl moiety by 7.9 kcal mol⁻¹. The energy of intermediate INT2′ is higher than that of INT2 by 5.5 kcal mol⁻¹. Therefore, the addition of the alkenyl moiety is more favorable kinetically and thermodynamically. Next, the intermediate INT2′ similarly produces another carbon-centered cyclized radical intermediate INT3′ through an intramolecular cyclization with an energy barrier of 8.1 kcal mol⁻¹. The radical intermediate INT3′ also undergoes the S_Hi process through transition state TS3′, with an energy barrier of 12.1 kcal mol⁻¹ to afford the product complex INT4. In general, the reaction prefers to start from the addition of a tert-butyl sulfur radical to the alkenyl moiety of the substrate, and an intramolecular cyclization and an S_Hi process follow to generate the desired product. For special substrates having bulky substituents on the alkenyl moiety, the reaction may start from the alkynyl moiety since a side product 3ae was obtained when using 1ae as a substrate under the standard reaction conditions (see Scheme 3D).

Scheme 3 Mechanistic studies. (A) Luminescence quenching experiments (Stern–Volmer studies). (B) Light on/off experiment. (C) Radical trapping experiments. (D) Control experiment. (E) DFT calculations.

On the basis of control experiments and DFT calculations, we proposed a plausible mechanism to elucidate this visible light-induced photochemical reaction (Scheme 4). Upon irradiation with blue light, the ground state of the photosensitizer Ir[(dFCF₃tppy)₂dtbpy]PF₆ is converted into its excited state, which can further oxidize Me₃CS⁻ through a SET process to afford the tert-butyl sulfur radical, which reacts with the alkenyl moiety of 1,6-enyne viaTS1 with an energy barrier of 13.5 kcal mol⁻¹ to furnish a radical intermediate A.¹⁵ Based on the calculation result, the tert-butyl sulfur radical viaTS1′ with an energy barrier of 21.4 kcal mol⁻¹ forms an intermediate A′. Thus, we exclude Path A. Then, intramolecular cyclization takes place to afford radical intermediate B. Subsequently, intermediate B undergoes intramolecular cyclization via S_Hi-type substitution, which strips away a sulfur atom from the tert-butylthioether unit, affording the desired product 3a and a tert-butyl radical. The in situ generated Ir^II species reduces the tert-butyl radical to the corresponding tert-butyl anion, which is quenched by H⁺ in the reaction system. In this photochemical catalytic system, p-toluenethiol is utilized to increase the concentration of H⁺ in the reaction system, thereby improving the reaction efficiency.

Scheme 4 Proposed reaction mechanism.

To demonstrate the synthetic applicability of this protocol, a gram-scale reaction was conducted by employing 1.02 g (3.0 mmol) of 1a, delivering the desired product 3a in 90% yield (1.0 g) under the standard conditions (Scheme 5A). Epoxidation of 3a with m-CPBA as an oxidant furnished the product 4 in 93% yield (Scheme 5B). Moreover, hydrogenation of the obtained product 3a effectively afforded the corresponding product 5 in 70% yield (Scheme 5C).

Scheme 5 Synthetic transformations. (A) 1a (3.0 mmol, 1.0 equiv.), 2a (2.0 equiv.), K₂CO₃ (2.0 equiv.), p-toluenethiol (0.2 equiv.), [Ir(dFCF₃ppy)₂dtbpy]PF₆ (3.0 mol%) in DCE (30.0 mL) at ambient temperature under 30 W blue LED irradiation for 12 hours; (B) m-CPBA (3.0 equiv.), DCM; (C) Pd(OH)₂/C, MeOH, rt, H₂.

Conclusions

In summary, we have developed a novel and practical photoredox catalytic methodology for cascade [2 + 2 + 1] cyclization of 1,6-enynes with thiols, delivering sulfur-containing polycyclic derivatives in moderate to good yields with broad substrate scope and good functional group tolerance under mild conditions. Moreover, this S- and carbon-centered radical reaction could be achieved on a gram scale, and the products could be further functionalized to afford other novel polycyclic compounds. The reaction mechanistic paradigm has been proposed on the basis of control experiments and photophysical analysis as well as DFT calculations. Further exploration of this visible light photoinduced synthetic strategy for the synthesis of medicinally useful heteropolycyclic products is underway.

Data availability

Experimental and computational data have been made available in the ESI.†

Author contributions

Z. Meng contributed to the investigation. Z. Meng, Y. Wei and M. Shi contributed to the conceptualization and writing of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Key R & D Program of China (2022YFC2303100), the National Natural Science Foundation of China (21372250, 21121062, 21302203, 21772037, 21772226, 21861132014, 91956115 and 22171078) and the Fundamental Research Funds for the Central Universities 222201717003.

References

1. (a) A. K. Franz and S. O. Wilson, Organosilicon Molecules with Medicinal Applications, J. Med. Chem., 2013, 56, 388–405; (b) N. Z. Wang, P. Saidhareddy and X. F. Jiang, Construction of sulfur-containing moieties in the total synthesis of natural products, Nat. Prod. Rep., 2020, 37, 246–275; (c) A. A. Bhat, N. Tandon, I. Singh and R. Tandon, Structure-activity relationship (SAR) and antibacterial activity of pyrrolidine based hybrids: A review, J. Mol. Struct., 2023, 1283, 135175; (d) T. C. Adams, J. N. Payette, J. H. Cheah and M. Movassaghi, Concise total synthesis of (+)-luteoalbusins A and B, Org. Lett., 2015, 17, 4268–4271; (e) K. L. Rinehart, T. G. Holt, N. L. Fregeau, J. G. Stroh, P. A. Keifer, F. Sun, L. H. Li and D. G. Martin, Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the caribbean tunicate ecteinascidia turbinata, J. Org. Chem., 1990, 15, 4512–4515; (f) B. R. Beno, K. S. Yeung, M. D. Bartberger, L. D. Pennington and N. A. Meanwell, A survey of the role of noncovalent sulfur interactions in drug design, J. Med. Chem., 2015, 11, 4383–4438; (g) A. A. Bhat, N. Tandon and R. Tandon, Pyrrolidine derivatives as antibacterial agents, current status and future prospects: a patent review, Pharm. Pat. Anal., 2022, 11, 187; (h) A. A. Bhat, N. Tandon and R. Tandon, Pyrrolidine derivatives as anti-diabetic agents: current status and future prospects, ChemistrySelect, 2022, 7, e202103757.
2. (a) T. Morikawa, K. Ninomiya, G. Tanabe, H. Matsuda, M. Yoshikawa and O. Muraoka, A review of antidiabetic active thiosugar sulfoniums, salacinol and neokotalanol, from plants of the genus Salacia, J. Nat. Med., 2021, 75, 449–466.
3. (a) C. X. Li, R. J. Liu, K. Yin, L. R. Wen and M. Li, Synthesis of disulfides tethered pyrroles from β-ketothioamides via a bicyclization/ring-opening/oxidative coupling reaction, Org. Biomol. Chem., 2017, 15, 5820–5823; (b) Y. A. Zhang, Z. Ding, P. Liu, W. S. Guo, L. R. Wen and M. Li, Access to SCN-containing thiazolines via electrochemical regioselective thiocyanothiocyclization of N-allylthioamides, Org. Chem. Front., 2020, 7, 1321–1326; (c) B. B. Liu, H. W. Bai, H. Liu, S. Y. Wang and S. J. Ji, Cascade trisulfur radical anion (S₃₍^•–) addition/electron detosylation process for the synthesis of 1,2,3-thiadiazoles and isothiazoles, J. Org. Chem., 2018, 17, 10281–10288; (d) J. X. Feng, Y. Zhang, X. D. Wang, J. Liu, V. Benazzi, K. Lu, X. Zhao and S. Protti, Recent advances in visible-light-driven C−S bond formation, Adv. Synth. Catal., 2023, 365, 3413–3431; (e) Z. C. Shi, R. H. Li, W. Q. Lan, H. S. Wei, S. R. Sheng and J. M. Chen, Visible-light-induced intramolecular C-S bond formation for practical synthesis of 2,5-disubstituted 1,3,4-thiadiazoles, Synth. Commun., 2023, 53, 40–48; (f) W. K. Abdelbasset, M. Q. Sultan, A. F. Alkaim, T. A. Ashurov, U. S. Altimari, B. A. Hussein, Y. F. Mustafa and A. T. Hammid, Intramolecular cascade C-S bond formation: a safe and new strategy for the synthesis of riluzole analogues catalyzed by K₂S₂O₈, Polycyclic Aromat. Compd., 2023, 43, 7970–7978; (g) M. Z. Wu, C. X. Yan, D. J. Zhuang and R. L. Yan, Metal-free C-S bond formation in elemental sulfur and cyclobutanol derivatives: the synthesis of substituted thiophenes, Org. Lett., 2022, 24, 5309–5313.
4. (a) T. Nakata, Total synthesis of marine polycyclic ethers, Chem. Rev., 2005, 105, 4314–4347; (b) R. A. Craig and B. M. Stoltz, Polycyclic furanobutenolide-derived cembranoid and norcembranoid natural products: biosynthetic connections and synthetic efforts, Chem. Rev., 2017, 117, 7878–7909; (c) M. Hirai, N. Tanaka, M. Sakaiand and S. Yamaguchi, Structurally constrained boron-, nitrogen-, silicon-, and phosphorus-centered polycyclic π-conjugated systems, Chem. Rev., 2019, 119, 8291–8331; (d) G. Mehta and A. Srikrishna, Synthesis of polyquinane natural products: an update, Chem. Rev., 1997, 97, 671–720; (e) H. C. Guo and J. A. Ma, Catalytic asymmetric tandem transformations triggered by conjugate additions, Angew. Chem., Int. Ed., 2006, 45, 354–366; (f) Z. T. Li, Y. X. Gao, Z. D. Jiao, N. Wu, D. Z. Wang and Z. Yang, Diversity-oriented synthesis of fused pyran γ-lactones via an efficient Pd-thiourea-catalyzed alkoxycarbonylative annulation, Org. Lett., 2008, 10, 5163–5166; (g) X. M. Zhang, Y. Q. Tu, Y. J. Jiang, Y. Q. Zhang, C. A. Fana and F. M. Zhang, Tandem reactions of cis-2-acyl-1-alkynyl-1-aryl cyclopropanes tuned by gold(I) and silver(I) catalysts: efficient synthesis of pyran-fused indene cores and 2,4,6-trisubstituted phenols, Chem. Commun., 2009, 4726–4728; (h) T. Bach and J. P. Hehn, Photochemical reactions as key steps in natural product synthesis, Angew. Chem., Int. Ed., 2011, 50, 1000–1045.
5. (a) C. Aubert, O. Buisine and M. Malacria, The Behavior of 1,n-enynes in the presence of transition metals, Chem. Rev., 2002, 102, 813–834; (b) S. T. Diver and A. J. Giessert, Enyne metathesis (enyne bond reorganization), Chem. Rev., 2004, 104, 1317–1382; (c) P. A. Inglesbya and P. A. Evans, Stereoselective transition metal-catalysed higher-order carbocyclisation reactions, Chem. Soc. Rev., 2010, 39, 2791–2805; (d) C. Raviola, S. Protti, D. Ravelli and M. Fagnoni, (Hetero)aromatics from dienynes, enediynes and enyne-allenes, Chem. Soc. Rev., 2016, 45, 4364–4390; (e) J. Xuan and A. Studer, Radical cascade cyclization of 1,n-enynes and diynes for the synthesis of carbocycles and heterocycles, Chem. Soc. Rev., 2017, 46, 4329–4346; (f) M. H. Huang, W. J. Hao and B. Jiang, Recent advances in radical-enabled bicyclization and annulation/1,n-bifunctionalization reactions, Chem. – Asian J., 2018, 13, 2958–2977; (g) X. F. Tong, M. Beller and M. K. Tse, A palladium-catalyzed cyclization-oxidation sequence: synthesis of bicyclo[3.1.0]hexanes and evidence for SN2 C-O bond formation, J. Am. Chem. Soc., 2007, 129, 4906–4907; (h) Y. Liu, J. L. Zhang, R. J. Song, P. C. Qian and J. H. Li, Cascade nitration/cyclization of 1,7-enynes with ^tBuONO and H₂O: one-pot self-assembly of pyrrolo[4,3,2-de]quinolinones, Angew. Chem., Int. Ed., 2014, 53, 9017–9020; (i) Y. Li, G. H. Pan, M. Hu, Ba. Liu, R. J. Song and J. H. Li, Intermolecular oxidative decarbonylative [2 + 2 + 2] carbocyclization of N,-(2-ethynylaryl)acrylamides with tertiary and secondary alkyl aldehydes involving C(sp₃)-H functionalization, Chem. Sci., 2016, 7, 7050–7054.
6. (a) K. Matsui, M. Shibuya and Y. Yamamoto, Catalytic [2 + 2 + 1] synthesis of fused thiophenes using thiocarbonyls as sulfur donors, Angew. Chem., Int. Ed., 2016, 55, 15397–15400; (b) Y. Park, S. Ahn, D. Kang and M. H. Baik, Mechanism of rh-catalyzed oxidative cyclizations: closed versus open shell pathways, Acc. Chem. Res., 2016, 49, 1263–1270; (c) J. K. Qiu, B. Jiang, Y. L. Zhu, W. J. Hao, D. C. Wang, J. Sun, P. Wei, S. J. Tu and G. G. Li, Catalytic dual 1,1-H-abstraction/insertion for domino spirocyclizations, J. Am. Chem. Soc., 2015, 137, 8928–8931; (d) Y. F. Qiu, X. Y. Zhu, Y. X. Li, Y. T. He, F. Yang, J. Wang, H. L. Hua, L. Zheng, L. C. Wang, X. Y. Liu and Y. M. Liang, AgSCF₃-mediated trifluoromethylthiolation/radical cascade cyclization of 1,6-enynes, Org. Lett., 2015, 17(15), 3694–3697; (e) J. X. Yu, F. Teng, J. N. Xiang, W. Deng and J. H. Li, One-carbon incorporation using cyclobutanone oxime ester enabled [2 + 2 + 1] carboannulation of 1,7-enynes by C-C/N-O bond cleavage and C-H functionalization, Org. Lett., 2019, 21, 9434–9437; (f) S. Suzuki, S. Nishigaki, Y. Shibata and K. Tanaka, Rhodium-catalyzed enantioselective [2 + 2 + 1] cycloaddition of 1,6-enynes with cyclopropylideneacetamides, Org. Lett., 2018, 20, 7461–7465; (g) Y. Y. Zhao, Y. C. Hu, H. L. Wang, X. C. Li and B. S. Wan, Transition-metal controlled diastereodivergent radical cyclization/azidation cascade of 1,7-enynes, J. Org. Chem., 2016, 81, 4412–4420; (h) Y. Liu, J. L. Zhang, R. J. Song and J. H. Li, Sulfur incorporation: copper-catalyzed cascade cyclization of 1,7-enynes with metal sulfides toward thieno[3,4-c]quinolin-4(5H)-ones, Org. Lett., 2014, 16, 5838–5841; (i) T. Ohmura, I. Sasaki and M. Suginome, Catalytic generation of rhodium silylenoid for alkene-alkyne-silylene [2 + 2 + 1] cycloaddition, Org. Lett., 2019, 21, 1649–1653; (j) M. Hu, R. J. Song, X. H. Ouyang, F. L. Tan, W. T. Weia and J. H. Li, Copper-catalyzed oxidative [2 + 2 + 1] annulation of 1,n-enynes with α-carbonyl alkyl bromides through C-Br/C-H functionalization, Chem. Commun., 2016, 52, 3328–3331; (k) M. Hu, H. X. Zou, R. J. Song, J. N. Xiang and J. H. Li, Copper-catalyzed C-H oxidative radical functionalization and annulation of aniline-linked 1,7-enynes: evidence for a 1,5-hydride shift mechanism, Org. Lett., 2016, 18, 6460–6463; (l) M. Hu, M. Li, F. L. Tan, R. J. Song, Y. X. Xie and J. H. Li, Oxidative divergent bicyclizations of 1,n-enynes through α-C(sp₃)-H functionalization of alkyl nitriles, Adv. Synth. Catal., 2017, 359, 120–129; (m) Y. Liu, R. J. Song and J. H. Li, Palladium-catalyzed dearomatizative [2 + 2 + 1] carboannulation of 1,7-enynes with aryl diazonium salts and H₂O: facile synthesis of spirocyclohexadienone-fused cyclopenta[c]quinolin-4(5H)-ones, Chem. Commun., 2017, 53, 8600–8603.
7. (a) J. J. Luo, G. H. Zeng, X. H. Cao and B. L. Yin, Visible-light-induced [2 + 2 + 1] dearomative cascade cyclization of indole/furan alkynes to synthesize sulfonyl polycycles, Adv. Synth. Catal., 2022, 364, 2197–2204; (b) Y. Li, B. Liu, R. J. Song, Q. A. Wang and J. H. Li, Visible light-initiated C(sp₃)-Br/C(sp₃)-H functionalization of α-carbonyl alkyl bromides through hydride radical shift, Adv. Synth. Catal., 2016, 358, 1219–1228; (c) M. J. Jiao, D. Liu, X. Q. Hu and P. F. Xu, Photocatalytic decarboxylative [2 + 2 + 1] nnulation of 1,6-enynes with N-hydroxyphthalimide esters for the synthesis of indene-containing polycyclic compounds, Org. Chem. Front., 2019, 6, 3834–3838; (d) Y. Qu, W. T. Xu, J. J. Zhang, Y. X. Liu, Y. Q. Li, H. J. Song and Q. M. Wang, Visible-light-mediated [2 + 2 + 1] carbocyclization reactions of 1,7-enynes with bromofluoroacetate to form fused monofluorinated cyclopenta[c]quinolin-4-ones, J. Org. Chem., 2020, 85, 5379–5389; (e) J. X. Yu, F. Teng, J. N. Xiang, W. Deng and J. H. Li, One-carbon incorporation using cyclobutanone oxime ester enabled [2 + 2 + 1] carboannulation of 1,7-enynes by C-C/N-O bond cleavage and C-H functionalization, Org. Lett., 2019, 21, 9434–9437; (f) F. Gao, C. Yang, N. Ma, G. L. Gao, D. Z. Li and W. J. Xia, Visible-light-mediated 1,7-enyne bicyclizations for synthesis of cyclopenta[c]quinolines and benzo[j]phenanthridines, Org. Lett., 2016, 18, 600–603; (g) X. H. Ouyang, R. J. Song, Y. Liu, M. Hu and J. H. Li, Copper-catalyzed radical [2 + 2 + 1] annulation of benzene-Linked 1,n-enynes with azide: fused pyrroline compounds, Org. Lett., 2015, 17, 6038–6041; (h) G. B. Deng, R. L. Zhong, J. X. Song, P. Y. Choy and F. Y. Kwong, Assembly of furazan-fused quinolines via an expeditious metal-free [2 + 2 + 1] radical tandem cyclization process, Org. Lett., 2021, 23, 6520–6524; (i) Y. Liu, R. J. Song, S. L. Luo and J. H. Li, Visible-light-promoted tandem annulation of N-(o-ethynylaryl)acrylamides with CH₂Cl₂, Org. Lett., 2018, 20, 212–215.
8. (a) H. Jiang and A. Studer, Intermolecular radical carboamination of alkenes, Chem. Soc. Rev., 2020, 49, 1790–1811; (b) H. W. Xiao, H. G. Shen, L. Zhu and C. Z. Li, Copper-catalyzed radical aminotrifluoromethylation of alkenes, J. Am. Chem. Soc., 2019, 141, 11440–11445; (c) X. W. Lan, N. X. Wang and Y. L. Xing, Recent advances in radical difunctionalization of simple alkenes, Eur. J. Org. Chem., 2017, 5821–5851; (d) B. Zhang, T. T. Li, Z. C. Mao, M. Jiang, Z. H. Zhang, K. Zhao, W. Y. Qu, W. J. Xiao and J. R. Chen, Enantioselective cyanofunctionalization of aromatic alkenes via radical anions, J. Am. Chem. Soc., 2024, 146, 1410–1422; (e) J. Wang, X. X. Wu, Z. Cao, X. Zhang, X. X. Wang, J. Li and C. Zhu, E-selective radical difunctionalization of unactivated alkynes: preparation of functionalized allyl alcohols from aliphatic alkynes, Adv. Sci., 2024, 2309022; (f) P. Wang, H. H. Zhang, M. Q. Zhao, S. S. Ji, L. Lin, N. Yang, X. L. Nie, J. S. Song and S. H. Liao, Radical hydro-fluorosulfonylation of unactivated alkenes and alkynes, Angew. Chem., Int. Ed., 2022, 61, e202207684; (g) E. R. Lopat'eva, L. B. Krylov, S. A. Paveliev, D. A. Emtsov, V. A. Kostyagina, A. A. Korlyukov and A. O. Terent'ev, Free Radicals in the Queue: Selective Successive Addition of Azide and N-Oxyl Radicals to Alkenes, J. Org. Chem., 2023, 88, 13225–13235; (h) M. H. Huang, W. J. Hao, G. G. Li, S. J. Tu and B. Jiang, Recent advances in radical transformations of internal alkynes, Chem. Commun., 2018, 54, 10791–10811; (i) C. W. Hu, J. Mena and I. V. Alabugin, Design principles of the use of alkynes in radical cascades, Nat. Rev. Chem., 2023, 7, 405–423; (j) W. Q. Su, P. Xu, R. Petzold, J. Y. Yan and T. Ritter, Ligand-to-copper charge-transfer-enabled C-H sulfoximination of arenes, Org. Lett., 2023, 25, 1025–1029; (k) W. Z. Fu, N. M. Neris, Y. Fu, Y. L. Zhao, B. K. Hansen, P. Liu and Y. Yan, Enzyme-controlled stereoselective radical cyclization to arenes enabled by metalloredox biocatalysis, Nat. Catal., 2023, 6, 628–636.
9. (a) D. Crich, Homolytic substitution at the sulfur atom as a tool for organic synthesis, Helv. Chim. Acta, 2006, 89, 2167–2182; (b) F. Dénès, Heteroatom-centred radicals for the synthesis of heterocyclic compounds, Top. Heterocycl. Chem., 2018, 54, 151–230; (c) A. L. J. Beckwith and D. R. Boate, Stereochemistry of intramolecular homolytic substitution at the sulphur atom of a chiral sulphoxide, J. Chem. Soc., Chem. Commun., 1986, 189–190; (d) D. C. Harrowven, J. C. Hannam, M. C. Lucas, N. A. Newman and P. D. Howes, A thiyl radical mediated cascade sequence for the co-cyclisation of 1,6-hexadienes with sulfur atom transfer, Tetrahedron Lett., 2000, 41, 9345–9349; (e) P. James, K. Schenk and Y. Landais, Radical-mediated 5-exo-trig cyclizations of 3-silylhepta-1,6-dienes, J. Org. Chem., 2006, 71, 3630–3633; (f) J. A. F. Salas, M. M. R. Fernández, M. C. Maestro and J. L. G. Ruano, Stereochemical aspects and the synthetic scope of the SHi at the sulfur atom. Preparation of enantiopure 3-substituted 2,3-dihydro-1,2-benzoisothiazole 1-oxides and 1,1-dioxides, Chem. Commun., 2014, 50, 6046–6048; (g) J. A. Kampmeier and T. R. Evans, Radical reactions of organic sulfides. II. behavior of the 2-(2′-methylthio)biphenylyl radical, J. Am. Chem. Soc., 1966, 88, 4096–4097; (h) A. L. J. Beckwith and D. R. Boate, formation of fused tricyclic azetidinones and pyrrolidinones by intramolecular SH2 processes, J. Org. Chem., 1988, 53, 4339–4348; (i) L. Benati, G. Calestani, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo and S. Strazzari, Generation and intramolecular reactivity of acyl radicals from alkynylthiol esters under reducing tin-free conditions, Org. Lett., 2003, 5, 1313–1316; (j) P. Carta, N. Puljic, C. Robert, A. L. Dhimane, L. Fensterbank, E. Lacote and M. Malacria, Generation of phosphorus-centered radicals via homolytic substitution at sulfur, Org. Lett., 2007, 9, 1061–1063; (k) S. H. Kyne, H. M. Aitken, C. H. Schiesser, E. Lacote, M. Malacria, C. Ollivierc and L. Fensterbank, Intramolecular homolytic substitution of sulfinates and sulfinamides-a computational study, Org. Biomol. Chem., 2011, 9, 3331–3337.
10. (a) Q. Z. Li, X. T. Gu, Y. Wei and M. Shi, Visible-light-induced indole synthesis via intramolecular C-N bond formation: desulfonylative C(sp²)-H functionalization, Chem. Sci., 2022, 13, 11623–11632; (b) Z. Liu, Y. Wei and M. Shi, Visible-light-mediated regioselective ring-opening hydrogenolysis of donor-acceptor cyclopropanes with DIPEA and H₂O, Org. Chem. Front., 2022, 9, 1960–1966.
11. (a) J. Yan, Z. Q. Yu, H. Z. Wei, M. Shi and Y. Wei, Visible light-mediated hydrogen atom transfer and proton transfer for the conversion of (2-vinylaryl) methanol derivatives to aryl aldehydes or aryl ketones, Org. Chem. Front., 2023, 10, 5876; (b) Z. Meng, X. Y. Zhang and M. Shi, Visible-light mediated cascade cyclization of ene-vinylidenecyclopropanes: access to fluorinated heterocyclic compounds, Org. Chem. Front., 2021, 8, 3796–3801.
12. X. Y. Zhang, X. Y. Wu, B. Zhang, Y. Wei and M. Shi, Silyl Radical-mediated carbocyclization of acrylamide-/vinyl sulfonamide-attached alkylidenecyclopropanes via photoredox catalysis with a catalytic amount of silane reagent, ACS Catal., 2021, 11, 4372–4380.
13. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman and D. J. Fox, Gaussian 16, Revision A.03, Gaussian, Inc., Wallingford CT, 2016.
14. (a) Y. S. Chen, X. X. Wu, S. Yang and C. Zhu, Asymmetric radical cyclization of alkenes by stereospecific homolytic substitution of sulfinamides, Angew. Chem., Int. Ed., 2022, 61, e202201027.
15. (a) A. Luridiana, A. Frongia, M. A. Scorciapino, G. Malloci, B. Manconi, S. Serrao, P. C. Ricci and F. Secci, Z-selective synthesis of α-sulfanyl carbonyl compounds from internal alkynes and thiols via photoredox catalysis, Adv. Synth. Catal., 2022, 364, 124–131; (b) S. S. Zalesskiy, N. S. Shlapakova and V. P. Ananikov, Visible light mediated metal-free thiol-yne click reaction, Chem. Sci., 2016, 7, 6740–6745; (c) L. Benati, L. Capella, P. C. Montevecchi and P. Spagnolo, Free-radical addition of alkanethiols to alkynes. rearrangements of the intermediate .beta.-(vinylthio) radicals, J. Org. Chem., 1994, 59, 2818–2823; (d) M. H. Huang, W. J. Hao, G. G. Li, S. J. Tu and B. Jiang, Recent advances in radical transformations of internal alkynes, Chem. Commun., 2018, 54, 10791–10811; (e) X. F. Xia, G. W. Zhang and S. L. Zhu, Visible-light-induced synthesis of benzothiophenes and benzoselenophenes via the annulation of thiophenols or 1,2-diphenyldiselane with alkynes, Tetrahedron, 2017, 73, 2727–2730.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data of new compounds. CCDC 2222581. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo00460d

---