Difluoromethyl (CF₂H) is a marvelous and unique F- bearing functional group. It can serve as the more lipophilic hydrogen bond donors and bioisosteres of alcohols, thiols and amines,^[1] as well as dramatically changing physicochemical and biological properties of parent molecules like other F-containing compounds.^[1f,2] Thereby, incorporating CF₂H into biologically active molecules or natural products will endow their improved bioactivities, lipophilicity, membrane permeability, metabolic stability, bioavailability and so on, resulting in CF₂H-containing molecules widespread applications in pharmaceuticals,^[1a,2a,3] agrochemicals^[4] and materials.^[5] Consequently, plenty of research effort goes into the development of synthetic methods for difluoromethylated functional molecules over the past two decades, particularly various structurally diverse CF₂H- containing heterocycles due to their vital roles in pharmaceuticals and agrochemicals.^[6] On the other hand, coumarins, including broad range of natural products and enormous amount of artificially synthetic derivatives, represent a large class of quite important benzopyrones containing π-π conjugated system with rich electron and good charge- transport properties. Their rigid fused ring structure endues coumarin-based derivatives great potential applications in pharmaceuticals, materials and supramolecular chemistry. Specially, coumarins have attracted considerable attention in new drug innovation and discovery due to a wide variety of pharmacological activities, such as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antivirus, antiparasitic, antiinflammatory, antidiabetic and antidepressive actions etc.^[7]

Given the reasons aforementioned, collection of CF₂H- modified coumarin derivatives would great facilitate and accelerate finding of the lead compounds and new drug candidates. As a result, the synthesis of difluoromethylated coumarins is becoming of significant interest to synthetic chemistry and medicinal chemistry, and some examples were reported over the past few years. Recent years, difluoro- methyl radical chemistry has gained rapid advance, difluo- romethyl radical derived from various difluoromethyl sources via photoredox or electroredox strategies,^[8] then leading to further various difluoromethyl radical transformation reactions. Thereby, difluoromethylated coumarins are efficiently accessible by dint of difluoromethyl radical chemistry. One synthetic strategy is the direct radical di- fluoromethylation of coumarins.^[9-11] Deng, Wu, and Hu reported photoredox-catalyzed direct difluoromethylation of coumarins using CF₂HSO₂Na,^[8] PhI(OCOCF₂H)₂,^[10] and Ph₃P(CF₂H)₂^[11] as the difluoromethyl radical reagents via visible-light irradiation in the presence of appropriate photocatalyst, respectively (Scheme 1, a). Additionally, difluoro- methyl phenoxathiinium salt (PT- {\text{CF}}_{\text{2}}{\text{H}}^{＋}{\text{BF}}_{\text{4}}^{－}), a shelf- stable and versatile difluoromethylating reagent developed recently by our group, is also a suitable reagent for the direct difluoromethylation of coumarins.^[12] Notably, different of previous protocol, difluoromethyl phenoxathiinium salt facilitated this transformation in a manner of photocatalyst-free visible-light promotion (Scheme 1, b). Notably, radical triggered addition/cyclization cascade reaction of aryl alkynoates is an efficient pathway to access structurally-diverse 3-functionalized coumarins, and has been well documented over the past few years.^[13] Therefore, as an alternative strategy, the radical difluoromethylation/cycli- zation cascade reaction of alkynoates is considered as a useful method for the preparation of difluoromethylated coumarins (Scheme 1, c).^[14-15] In 2017, Fu and coworkers^[14] described the photoredox-catalyzed difluoromethylation of alkynoates to access 3-CF₂H-coumarins with ArSO₂CF₂H. Late on, Lu group^[15] also achieved visible-light- induced radical difluoromethylation of alkynoates using PhI(OCOCF₂H)₂ as difluoromethyl radical precursor. Despite a few protocols for radical difluoromethylation/cycli- zation cascade reaction of alkynoates were achieved previously, most of them required the photocatalysts, especially the costly Ir- or Ru-based photosensitizers. Therefore, developing more concise, greener, milder and general approach to conveniently access CF₂H-modified coumarin derivatives is still great desirable. Our difluoromethyl phenoxathiinium salt proved to be a good difluoromethyl radical reagent, which is capable of efficiently generating difluoromethyl radical under visible-light irradiation without externally adding photocatalyst, further resulting in various radical transformations. Herein, we report an elegant protocol for difluoromethylation of alkynoates with difluoromethyl phenoxa thiinium salt enabled by photocatalyst-free photo-mediation (Scheme 1, d).

Our investigation commenced with radical difluoromethylation/cyclization of alkynoate 1a. As shown in Table 1, difluoromethyl phenoxathiinium salt 2 (2.5 equiv.) smoothly generated difluoromethyl radical species under 40 W 395 nm light irradiation in the absence of photosensitizer at ambient temperature, facilitating radical difluoromethylation/cyclization of alkynoate 1a (1.0 equiv.) with KH₂PO₄ (2.5 equiv.) as base to afford the desired 3-CF₂H-coumarin 3a in 47% isolated yield (Table 1, Entry 1). Inspired by this result, various bases were further screened. Strong base LiOH gave the similar comparable yield of 45% (Table 1, Entry 2), but desired transformation was thoroughly inhibited using stronger t-BuOLi (Table 1, Entry 3). Delightedly, weaker base Li₂CO₃ significantly improved this transformation to increase yield to 78% (Table 1, Entry 4). Next, the effect of solvent was examined. Use of dichloromethane (DCM) and dichloroethane (DCE) also achieved good yields of 67% and 70%, respectively (Table 1, Entries 5, 6). However, EtOAc was less efficient resulting in decreased 43% yield (Table 1, Entry 7). The yield was further improved to 84% when 3.0 equiv. of reagent 2 was used (Table 1, Entry 8), while decreasing base to 2.0 equiv. resulted in less effective affording a lower yield of 60% (Table 1, Entry 9). Finally, the reaction time was surveyed, neither prolonging nor shortening time worked well (Table 1, Entries 10, 11). Longer time irradiation may cause decomposition of desired product, thus resulting in lower yield (Table 1, Entry 10).

To demonstrate the generality and potential applications of this approach, the reaction scope of alkynoates with difluoromethylating reagent 2 was explored under the optimized reaction conditions obtained above (Table, Entry 8). As shown in Table 2, a broad range of alkynoates smoothly underwent difluoromethylation/cyclization reaction to give their corresponding 3-CF₂H-coumarin in moderate to good yields. Firstly, the influences of substituents on Ar¹ were investigated. para- and meta-substituted phenyl 3-phenyl- propiolates were suitable substrates for this transformation to deliver desired difluoromethylated coumarins in moderate to good yields, regardless of the position or electronic properties of substituents (3a~3n), whereas these substrates bearing ortho-substituent did not work or showed extremely low reactive (3u~3v). It should be noted that meta-F and Br-phenyl alkynoates 1i and 1j gave a mixture of ortho- and para-substituted coumarins 3i (o∶p=1∶3) and 3j (o∶p=1∶2), respectively. Particularly, synthetically useful halogens including fluorine, bromine, chlorine and iodine were compatible with this protocol to provide desired coumarins in moderate to good yields (3b~3e, 3i, 3j, 3p, 3q). Electron-donating group alkyl and alkoxy- substituted substrates were well tolerated to achieve good yields (3f~3h, 3k and 3m~3o). Moreover, di-substituted phenyl alkynoates also worked well to afford 3o, 3p and 3q in 37%, 59% and 60% yields, respectively. Longer reaction time of 12 h is necessary to obtain better results for cases 3b, 3f and 3g, while 3r and 3t accomplished higher yields within 5 h, which may be due to the decomposition under a long period of light irradiation. Notably, the properties of functional groups on Ar² have almost no influence to the reaction, and desired difluoromethylation/cyclization pro-ceed with high reactivities regardless of whether electron- withdrawing and electron-donating groups were included, affording 3r, 3s and 3t in 61.9%, 68% and 89% yields, respectively.

To gain detailed insight into the reaction mechanism, the radical trapping experiment was conducted. As shown in Scheme 2a, when radical scavenger 2,2,6,6-tetramethyl-1- piperidinyloxyl (TEMPO, 3.0 equiv.) was added to the standard reaction of mixture of 1t and 2, the desired transformation was completely depressed, and no desired product 3t was formed along with 45% 1-(difluoromethoxy)- 2,2,6,6-tetramethylpiperidine (4) generated from the trap of •CF₂H radical with TEMPO. This result indicated that the reaction involved in •CF₂H pathway. Based on the result of radical trapping experiment, previous literatures^[14-15] and our own report,^[12] a plausible difluoromethyl radical addition/5-exo radical cyclization cascade process is proposed in Scheme 2b. Initially, difluoromethylating reagent 2 happened homolysis under 395 nm light irradiation to deliver difluoromethyl radical (•CF₂H) and radical cation A, followed by •CF₂H adding to alkynoate 1 resulting in formation of intermediate radical B. Then B occurred intramolecular 5-exo cyclization to give spirocyclic radical intermediate C. Subsequently, single electron redox of C and radical cation A created spirocyclic cation species D along with generation of phenoxathiin. Finally, 1,2-ester migration of D formed cation E, followed by rearomatization by deprotonation to furnish desired difluoromethylated coumarin 3.

In conclusion, a photocatalyst-free photo-induced radical difluoromethylation of alkynoates by PT-$\mathrm{CF}_{2} \mathrm{H}^{+} \mathrm{BF}_{4}^{-}$ to facilitate ready synthesis of 3-CF₂H-coumarins is reported. The reaction smoothly proceeded under mild photosensitizer-free conditions, and a broad scope of alkynoates were converted to desired 3-CF₂H-coumarins in moderate to good yields with good functional groups tolerance. Additional, the rational difluoromethyl radical addition/spiro- cyclization/ester migration cascade process was proposed based on our previous research and related literature reports. Notably, this protocol also further extends the synthetic applications of the PT-$\mathrm{CF}_{2} \mathrm{H}^{+} \mathrm{BF}_{4}^{-}$ as a powerful and versatile difluoromethylating reagent.