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DOI: 10.1055/a-1938-9550
Visible-Light-Promoted Metal-Free 3-Arylation of 2-Aryl-2H-indazoles with Triarylsulfonium Salts
We acknowledge the financial support from the Hunan Provincial Natural Science Foundation of China (2021JJ40432), and the National Natural Science Foundation of China (21971224, 22171249).
Abstract
An efficient approach for the photosynthesis of various arylated 2-aryl-2H-indazoles (38 examples) in moderate to good yields (up to 87% yield) under mild conditions was developed by employing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an inexpensive photocatalyst. This protocol features wide substrate scope, good functional group tolerance, and operational simplicity. In addition, the strategy was successfully applied to the late-stage modification of drug molecules, and the meaningful introduction of complex drugs to the skeleton of 2H-Indazole was achieved for the first time.
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Key words
visible light - radical - metal-free - arylation - 2-aryl-2H-indazoles - triarylsulfonium saltsCurrently, N-containing heterocycles are privileged frameworks to possess meaningful applications in the fields of pharmaceuticals, agrochemicals, and materials science.[1] Among several N-heterocycles, indazoles are well recognized as bioisosteres of indoles, benzimidazoles, and purines, which has attracted massive attention for its numerous pharmacological and biological properties.[2] The indazole-based molecules are widespread in various marketed drugs and drug candidates, such as an estrogen receptor,[3] PARP inhibitor,[4] anti-angiogenic activity agent,[5] and liver X receptor agonists (Figure [1]).[6] Benefited from their therapeutic potential, multifarious methodologies have been developed for the direct C–H functionalization of 2H-indazoles over the past decade, such as acylation,[7] phosphonylation,[8] trifluoromethylation,[9] sulfonylation,[10] amination,[11] benzylation,[12] oxyalkylation,[13] and arylation.[14] Despite the great achievements that have been made, the development of novel synthetic methodologies for the construction of diversely functionalized 2H-indazoles is still highly desirable.
The classical strategies for C3-arylation of 2H-indazole were focused on transition-metal-catalyzed cross-coupling reactions, which usually required metal catalysts (Cu or Pd), expensive ligands, and inevitable additives (base, oxidant).[15] Photoredox catalysis, which employed low-cost and widely abundant light as the energy source, has become a versatile tool to achieve diverse organic synthesis under mild reaction conditions.[16] Recently, some elegant visible-light-mediated transformations have been developed into alternatives for the construction of C3-arylation of 2-aryl-2H-indazoles.[17] For instance, Kim’s group utilized aryl diazonium salts as radical precursors to obtain various arylated 2-aryl-2H-indazoles under visible-light irradiation in 2019 (Scheme [1a]).[18] The aryl precursors used in these reactions are mainly energy-intensive aryl diazonium salts or arylhydrazines, which are challenging to be site-selective prepared from corresponding arenes. Therefore, the development of a convenient strategy to access C3-arylated 2-aryl-2H-indazoles using more accessible candidates as aryl precursors is highly attractive.
Triarylsulfonium or alkylsulfonium salts, as promising precursors, offer a feasible transformative platform for arylation or alkylation reactions.[19] Especially, numerous complex drugs and biologically active molecules can be easily converted into the corresponding triarylsulfonium salts for the late-stage functionalization of complex scaffolds.[20] Herein, we disclose a visible-light-promoted metal-free method for the synthesis of various arylated 2-aryl-2H-indazoles in moderate to good yields under mild conditions by using 4CzIPN as a photocatalyst and triarylsulfonium salts as arylating reagents (Scheme [1b]). This protocol features wide substrate scope, good functional group tolerance, and operational simplicity. In addition, the strategy was successfully applied to the late-stage modification of drug molecules, and the meaningful introduction of complex drugs to the skeleton of 2H-indazole was achieved for the first time.
In our initial evaluation, 2-phenyl-2H-indazole (1a) and tolyl sulfonium salt 2a were selected as the model substrates to optimize reaction conditions. Satisfyingly, a 70% yield of the desired product 2-phenyl-3-(p-tolyl)-2H-indazole (3a) was obtained by employing Ir(ppy)3 as a photocatalyst and triethylenediamine (DABCO) as a base in MeCN for 12 h under the irradiation of blue LED at N2 atmosphere (Table [1], entry 1). Subsequently, the effect of other transition-metal-free photocatalysts, including methylene blue, 4CzIPN, fluorescein, eosin Y, Acr+-Mes·ClO4 –, rhodamine B, and rose bengal was investigated (entries 2–8). It was found that 4CzIPN was identified as the best photocatalyst for this reaction, giving product 3a in 74% yield. Afterward, various solvents, such as DMF, DMSO, DCM, DCE, 2-methyl tetrahydrofuran (2-Me-THF), acetone, MeOH, H2O, and dimethyl carbonate (DMC) were surveyed (entries 9–17). However, no better results were observed, and MeCN was still the best solvent. To further improve the reaction efficiency, bases including 1,1,3,3-tetramethylguanidine (TMG), Et3N, tetramethylethylenediamine (TMEDA), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), K2CO3, and Cs2CO3 were screened (entries 18–24). When DMAP was employed as a base, the desired product 3a could be obtained in 83% yield. When the loading of DMAP was decreased to 1 equivalent or increased to 3 equivalents, no positive results were observed (entries 25 and 26). The critical role of DMAP was confirmed by reaction in the absence of DMAP (entry 27). The control experiments performed without 4CzIPN or in dark did not give product 3a, suggesting that photocatalyst and light irradiation play important roles in this strategy (entries 28 and 29). Therefore, the optimal conditions were gained as follows: 1a (0.2 mmol), 2a (0.3 mmol), 4CzIPN (5 mol%), DMAP (2 equiv.), MeCN (2.0 mL) at N2 atmosphere for 12 h under blue LED illumination (λmax = 457 nm).
With the optimized reaction conditions in hand, we then explored the substrate scope of triarylsulfonium salts 2 (Scheme [2]).[21] As can be seen, this reaction could be compatible with a series of monosubstituted triarylsulfonium salts, affording desired products 3a–m in good to excellent isolated yields (53–85%). Then, a diverse set of multisubstituted aryl sulfonium were also proven to be suitable substrates to access targeted products 3n–q in moderate to good yields (72–87%). In these cases, various functional groups like Me, c Pr, t Bu, CH2CH2OAc, O i Pr, OPh, F, Cl, Br, I, CF3, CN could be tolerated, exhibiting a good functional group tolerance and broad reaction scope. Next, we further extended this transformation to complex bioactive molecules. Flurbiprofen and pyriproxyfen could be successfully introduced to the skeleton of 2H-indazole for the preparation of corresponding products 3r and 3s in moderate yields (63% and 71%, respectively).
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), PC (5 mol%), solvent (2 mL), base (2 equiv) under N2 for 12 h, room temperature, 10 W blue LED (460 nm), N.D. = not detected, PC = photocatalyst, DMC = dimethyl carbonate. Isolated yields are given.
b Base (1 equiv.).
c Base (3 equiv.).
d Experiment performed in the dark.
Subsequently, the reaction reactivities of different 2-aryl-2H-indazoles 1 were explored using tolyl sulfonium salt 2a as a coupling partner. As illustrated in Scheme [3, 2] H-indazoles bearing electron-donating substituents (4-Me, 4-OMe, 3-Me) or electron-withdrawing substituents (4-F, 4-Br, 4-CF3, 5-Br, 3-Cl) on the N-phenyl group (R3) are all compatible in this progress, leading to the corresponding arylating products 3t–aa in good yields (55–81%). Pleasingly, the 2H-indazoles containing the disubstituted N-phenyl group (R3) were also appropriate substrates in this approach, affording the products 3ab–ad in 73–83% yields. Moreover, the electron-donating substituents (–OMe) or electron-withdrawing group (–Br, –Cl) at the arene part of 2H-indazoles (R2) were also reacted smoothly to produce the corresponding products 3ae–ai in 71–85% yields in Scheme [3].
To clarify the practicality of this strategy, a natural sunlight-driven experiment was carried out (Scheme [4a]). To our delight, the desired product 3a was also obtained in a 61% yield. Furthermore, as illustrated in Scheme [4b], the gram-scale reaction produced the target product 3a in 68% yield (0.97 g) when the reaction was performed on 5 mmol scale under the irradiation of a 40 W blue LED.
To further demonstrate the utility of the reaction, this photochemical methodology is also applied to the synthesis of biologically active compounds. As shown in Scheme [5a,b], substrate 1aj reacted smoothly with 2aj and 2ak under standard conditions, affording the targeted liver X receptor (LXR) agonists 3aj and 3ak in 76% and 81% yields, respectively. These two inhibitors of LXR can be used to prevent and treat cardiovascular disease. Moreover, antimicrobial and anti-inflammatory agent 3al could also be prepared in a 78% yield by the reaction of 1a and 2al under standard conditions (Scheme [5c]), suggesting this methodology has promising potential in practical applications.
Afterward, the sensitivity experiment of this protocol towards the reaction conditions (concentration, water, temperature, oxygen, light intensity, and scale) was conducted (for details, see the Supporting Information).[22] The results are shown in the radar diagram in Figure [2], which revealed a vast sensitivity to oxygen (O2 balloon, yield 0%) and light intensity (0.6 W, yield 0%). The concentration, temperature, and water have a deceiving influence on the reaction efficiency.
Several control experiments were carried out to gain a deeper understanding of this photocatalyzed arylation reaction (Scheme [6]). When the radical scavenger 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the reaction under standard conditions, almost no target product 3a was detected, indicating that a radical pathway might be involved in this protocol. Moreover, adducts 4 and 5 were detected by high-resolution mass spectrometry (HRMS), suggesting the generation of aryl radicals in this reaction (for details, see the Supporting Information).
Moreover, a series of Stern–Volmer fluorescence quenching studies were carried out by mixing the photocatalyst 4CzIPN with 1a, 2a, and DMAP, respectively. As shown in Figure [3], DMAP showed an obvious fluorescence quenching effect on the photocatalyst (4CzIPN), whereas a slight luminescence quenching effect was observed when adding 1a or 2a to the photocatalyst solution. Furthermore, the linear relationship between I0/I and the concentration of DMAP demonstrated that a single-electron-transfer (SET) process between the photocatalyst 4CzIPN and DMAP might be involved in this system (for details, see the Supporting Information).
Additionally, the redox potential of the reactants was investigated by cyclic voltammetry (for details, see the Supporting Information). It was found that the oxidative potential of DMAP was E 1/2 ox = +1.2 V vs. SCE, and the oxidation potential of 1a was E 1/2 ox = 1.4 V vs. SCE,[23] indicating that the excited 4CzIPN (E 1/2(P*/P–) = +1.35 V vs. SCE)[24] can oxidize DMAP rather than 1a. On the other hand, the reduced potential of 2a was E 1/2 red = –1.3 V vs. SCE, which would be changed to E 1/2 red = –1.1 V vs. SCE by adding DMAP to the solution, which might be caused by the formation of unconsolidated complex intermediate (for details, see the Supporting Information). The DMAP in this protocol not only acted as a base for trapping protons but also effectively modulates the reduction potential of 2a to be reduced by the 4CzIPN– (E 1/2(P/P–) = –1.21 V vs. SCE).[25]
According to the above investigations and previous literature reports, a plausible reaction mechanism involving a radical pathway is proposed as illustrated in Scheme [7]. Initially, 4CzIPN is excited to 4CzIPN* under the irradiation of visible light. Then, 4CzIPN* is reductively quenched by DMAP to provide 4CzIPN•– and DMAP radical cation (DMAP•+). Subsequently, 4CzIPN•− reacts with 2a to regenerate the photocatalyst 4CzIPN along with the aryl radical 6 and thianthrene (TT) via a single-electron-transfer (SET) process. After that, the aryl radical 6 adds to the C-3 position of 1a to access the dearomatized radical intermediate 7. Finally, hydrogen atom transfer (HAT) from 7 to DMAP•+ generates DMAPH+ and the C3-arylated product 3a.
In summary, we have disclosed a visible-light-promoted direct arylation of 2-aryl-2H-indazoles by using 4CzIPN as a photocatalyst and aryl sulfonium salts as arylating reagents. Notable features of this method include wide substrate scope, good functional group tolerance, and an operationally simple procedure. Importantly, the strategy was successfully applied to the late-stage modification of drug molecules, and the meaningful introduction of complex drugs to the skeleton of 2H-indazole was achieved for the first time, further demonstrating the potential utilities in pharmaceutical and agrochemical research. Our preliminary mechanistic study showed that DMAP in this protocol not only acted as a base for trapping protons but also effectively modulates the reduction potential of triarylsulfonium salts. Further synthetic application of this methodology is ongoing in our laboratory.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1938-9550.
- Supporting Information
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References and Notes
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- 21 General Experimental Procedures for the Desired Product 3 The mixture of 2-aryl-2H-indazole (0.2 mmol), aryl sulfonium salt (0.3 mmol, 1.5 equiv.), DMAP (0.4 mmol, 2.0 equiv.), 4CzIPN (5 mol%), and MeCN (2.0 mL) were sequentially added in a 25 mL reaction vessel. Then the reaction vessel was exposed to 10 W blue LED irradiation at room temperature under N2 atmosphere for 12 h. After reaction, the solvent was evaporated under vacuum, and all the crude products were purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as eluting solvent to give the desired products. Methyl 2-[2-Fluoro-4′-(2-phenyl-2H-indazol-3-yl)-(1,1′-biphenyl)-4-yl]propanoate (3r) White solid (56.7 mg, 63%); mp 142.5–143.2 °C. 1H NMR (400 MHz, chloroform-d): δ = 7.83 (dd, J = 16.3, 8.6 Hz, 2 H), 7.65–7.57 (m, 2 H), 7.55–7.49 (m, 2 H), 7.49–7.33 (m, 7 H), 7.23–7.13 (m, 3 H), 3.80 (q, J = 7.2 Hz, 1 H), 3.73 (s, 3 H), 1.57 (d, J = 7.2 Hz, 3 H). 13C NMR (101 MHz, chloroform-d): δ = 174.4, 161.0, 149.1, 142.3 (d, J = 7.7 Hz), 140.2, 135.4, 135.0, 130.6 (d, J = 3.8 Hz), 129.7, 129.2 (d, J = 3.3 Hz), 129.1, 128.4, 127.1, 127.0, 126.8, 126.1, 123.7 (d, J = 3.4 Hz), 122.7, 121.8, 120.5, 117.8, 115.4 (d, J = 23.7 Hz), 52.3, 44.9, 18.4. 19F NMR (376 MHz, chloroform-d): δ = –117.19. HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H24N2O2: 451.1816; found: 451.1821. 2-Phenyl-3-(4-{4-[2-(pyridin-2-yloxy)propoxy]phenoxy}phenyl)-2H-indazole (3s)White solid (72.9 mg, 71%); mp 171.1–172.3 °C. 1H NMR (400 MHz, chloroform-d): δ = 8.21–8.16 (m, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.62–7.57 (m, 1 H), 7.53–7.22 (m, 8 H), 7.16 (ddd, J = 8.4, 6.6, 0.7 Hz, 1 H), 7.08–7.02 (m, 2 H), 7.01–6.93 (m, 4 H), 6.91–6.86 (m, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 5.65–5.58 (m, 1 H), 4.23 (dd, J = 9.9, 5.3 Hz, 1 H), 4.11 (dd, J = 9.8, 4.8 Hz, 1 H), 1.52 (d, J = 6.4 Hz, 3 H). 13C NMR (101 MHz, chloroform-d): δ = 163.1, 158.9, 155.7, 149.2, 149.0, 146.8, 140.3, 138.7, 135.1, 131.0, 129.0, 128.3, 127.0, 126.0, 123.7, 122.4, 121.6, 121.4, 120.5, 117.7, 117.3, 116.8, 115.9, 111.7, 71.0, 69.2, 17.0. HRMS (ESI-TOF): m/z [M + H]+ calcd for C33H28N3O3: 514.2125; found: 514.2136.
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Corresponding Authors
Publication History
Received: 09 August 2022
Accepted after revision: 08 September 2022
Accepted Manuscript online:
08 September 2022
Article published online:
17 October 2022
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References and Notes
- 1a Kusama H, Orita H, Sugihara H. Sol. Energy Mater. Sol. Cells 2008; 92: 84
- 1b Sokolova AS, Yarovaya OI, Bormotov NI, Shishkina LN, Salakhutdinov NF. Chem. Biodiversity 2018; 15: e1800153
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- 21 General Experimental Procedures for the Desired Product 3 The mixture of 2-aryl-2H-indazole (0.2 mmol), aryl sulfonium salt (0.3 mmol, 1.5 equiv.), DMAP (0.4 mmol, 2.0 equiv.), 4CzIPN (5 mol%), and MeCN (2.0 mL) were sequentially added in a 25 mL reaction vessel. Then the reaction vessel was exposed to 10 W blue LED irradiation at room temperature under N2 atmosphere for 12 h. After reaction, the solvent was evaporated under vacuum, and all the crude products were purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as eluting solvent to give the desired products. Methyl 2-[2-Fluoro-4′-(2-phenyl-2H-indazol-3-yl)-(1,1′-biphenyl)-4-yl]propanoate (3r) White solid (56.7 mg, 63%); mp 142.5–143.2 °C. 1H NMR (400 MHz, chloroform-d): δ = 7.83 (dd, J = 16.3, 8.6 Hz, 2 H), 7.65–7.57 (m, 2 H), 7.55–7.49 (m, 2 H), 7.49–7.33 (m, 7 H), 7.23–7.13 (m, 3 H), 3.80 (q, J = 7.2 Hz, 1 H), 3.73 (s, 3 H), 1.57 (d, J = 7.2 Hz, 3 H). 13C NMR (101 MHz, chloroform-d): δ = 174.4, 161.0, 149.1, 142.3 (d, J = 7.7 Hz), 140.2, 135.4, 135.0, 130.6 (d, J = 3.8 Hz), 129.7, 129.2 (d, J = 3.3 Hz), 129.1, 128.4, 127.1, 127.0, 126.8, 126.1, 123.7 (d, J = 3.4 Hz), 122.7, 121.8, 120.5, 117.8, 115.4 (d, J = 23.7 Hz), 52.3, 44.9, 18.4. 19F NMR (376 MHz, chloroform-d): δ = –117.19. HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H24N2O2: 451.1816; found: 451.1821. 2-Phenyl-3-(4-{4-[2-(pyridin-2-yloxy)propoxy]phenoxy}phenyl)-2H-indazole (3s)White solid (72.9 mg, 71%); mp 171.1–172.3 °C. 1H NMR (400 MHz, chloroform-d): δ = 8.21–8.16 (m, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.62–7.57 (m, 1 H), 7.53–7.22 (m, 8 H), 7.16 (ddd, J = 8.4, 6.6, 0.7 Hz, 1 H), 7.08–7.02 (m, 2 H), 7.01–6.93 (m, 4 H), 6.91–6.86 (m, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 5.65–5.58 (m, 1 H), 4.23 (dd, J = 9.9, 5.3 Hz, 1 H), 4.11 (dd, J = 9.8, 4.8 Hz, 1 H), 1.52 (d, J = 6.4 Hz, 3 H). 13C NMR (101 MHz, chloroform-d): δ = 163.1, 158.9, 155.7, 149.2, 149.0, 146.8, 140.3, 138.7, 135.1, 131.0, 129.0, 128.3, 127.0, 126.0, 123.7, 122.4, 121.6, 121.4, 120.5, 117.7, 117.3, 116.8, 115.9, 111.7, 71.0, 69.2, 17.0. HRMS (ESI-TOF): m/z [M + H]+ calcd for C33H28N3O3: 514.2125; found: 514.2136.
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