Photoredox-Catalyzed Decarboxylative Cross-Coupling Reaction to Synthesis Unsymmetrical Diarylmethanes

The photoredox-catalyzed decarboxylative cross-coupling reaction of aryl acetic acids and aryl nitriles has been achieved under an argon atmosphere in high yields. This method provides a fast way to obtain prevalent aryl acetic acids from an abundant natural source. A tentative radical mechanism has been proposed.


Introduction
Diarylmethane motifs play a prominent role in the natural, bioactive and pharmaceutical product industries [1,2].Some examples of anticancer agents include anastrozole [3], pitracoxin [4] and diindolemethane [5] (Figure 1).Anastrozole and letrozole are known to have pharmacological activity against breast cancer.Pharmacological experiments have shown that piritrexim has a significant inhibitory effect on dihydrofolate reductase of leukemia cells and is mainly used in the treatment of malignant tumors.Diindolemethane is present in cruciferous plants and also exhibits anticancer effects.Beclobrate [6] is a potent drug used to lower lipids and is about 20 times more effective than clofibrate.It also has some inhibition activity on platelet aggregation.Terfenadine is a second-generation antihistamine that is more selective to H1 receptors than the first generation and less irritating to the central nervous system [7].It has been reported that some molecules containing diarylmethane skeleton may have a certain inhibitory effect on COVID-19 [8].Carboxylic acids are widely employed as raw materials in organic synthesis because of their features of low toxicity, high stability and rich reserves.3-indoleacetic acid (IAA) was detected by Salkowski in 1885 [9], who demonstrated that it can not only regulate the growth of plants but can also facilitate other aspects of plant development.In addition, the IAA industry is currently maintaining a stable market growth [10].Therefore, the transformation of IAA and synthesis of diarylmethanes are highly appealing in organic chemistry due to their significant importance.
Scheme 1.The conventional methods toward synthesis of diarylmethanes.

Results
Initially, our investigations focused on the blue LED irradiation of 3-indoleacetic acid (IAA) 1a and 1,4-dicyanobenzene (1,4-DCB) 2a in DMSO under argon atmosphere using 2 mol% of fac-Ir(ppy)3 in the presence of K2CO3 at room temperature.To our delight, the diarylmethane 3a was given in 82% isolated yield (Table 1, entry 1).No reaction took place Scheme 1.The conventional methods toward synthesis of diarylmethanes.

Results
Initially, our investigations focused on the blue LED irradiation of 3-indoleacetic acid (IAA) 1a and 1,4-dicyanobenzene (1,4-DCB) 2a in DMSO under argon atmosphere using 2 mol% of fac-Ir(ppy) 3 in the presence of K 2 CO 3 at room temperature.To our delight, the diarylmethane 3a was given in 82% isolated yield (Table 1, entry 1).No reaction took place when the reaction was performed without LED irradiation or without fac-Ir(ppy) 3 , resulting in the recovery of substrates 1a and 2a (Table 1, entries 2-3).When fac-Ir(ppy) 3 as the photosensitizer was replaced by [Ir(dtbbpy)(ppy) 2 ]PF 6 , the yield dropped to 53% (Table 1, entry 4).Furthermore, nearly no product was detected when the other photosensitizers including organic photocatalysts eosin Y and rose bengal were employed (Table 1, entries 5-7).The yield of the decarboxylation cross-coupling reaction dropped to 30% in the absence of a base (Table 1, entry 8).This reaction could also proceed when using other bases, such as K 3 PO 4 , NaOAc and CsF, but the yields decreased to some extent (Table 1, entries 9-11).In addition, DMSO was more optimal than other solvents for the transformation, (Table 1, entries [12][13][14].while the reaction did not occur when DCM was used as the solvent (Table 1, entry 12).The desired product was given with good yield in MeCN and DMA (Table 1, entries [13][14].Finally, we found that only trace amounts of diarylmethane were obtained when the reaction was performed under an air atmosphere (Table 1, entry 15).This result implies a radical involved mechanism in the reaction because of the biradical feature of the O 2 molecule.photosensitizer was replaced by [Ir(dtbbpy)(ppy)2]PF6, the yield dropped to 53 entry 4).Furthermore, nearly no product was detected when the other photo including organic photocatalysts eosin Y and rose bengal were employed (Tab 5-7).The yield of the decarboxylation cross-coupling reaction dropped to 30% sence of a base (Table 1, entry 8).This reaction could also proceed when using o such as K3PO4, NaOAc and CsF, but the yields decreased to some extent (Tab 9-11).In addition, DMSO was more optimal than other solvents for the trans (Table 1, entries [12][13][14].while the reaction did not occur when DCM was used vent (Table 1, entry 12).The desired product was given with good yield in DMA (Table 1, entries [13][14].Finally, we found that only trace amounts of diar were obtained when the reaction was performed under an air atmosphere (Ta 15).This result implies a radical involved mechanism in the reaction because o ical feature of the O2 molecule.With the above optimal conditions in hand, we examined the scope of acids with 1,4-DCB to decarboxylative cross-coupling reaction.As shown in aryl acetic acid derivatives 1a-1h reacted smoothly with 2a to obtain the unsy diarylmethanes 3a-3h in good to excellent yields.First, alkyl and methoxy heterocyclic acids could provide the corresponding products in yields of 73% (3c) and 75% (3d), respectively.Moreover, phenyl acetic acid derivatives can a this desired transformation (3e-3g).Homoveratric acid was coupled to 1,4-DCB product 3f in 83% yield.It is worth noting that the medicine molecule Naprox erated with the mild reaction conditions to obtain target product 3h in mode which is the property of non-steroidal anti-inflammatory group agents.This synthetic potential of our approaches to medicinal chemistry.With the above optimal conditions in hand, we examined the scope of aryl acetic acids with 1,4-DCB to decarboxylative cross-coupling reaction.As shown in Table 2, all aryl acetic acid derivatives 1a-1h reacted smoothly with 2a to obtain the unsymmetrical diarylmethanes 3a-3h in good to excellent yields.First, alkyl and methoxy substituted heterocyclic acids could provide the corresponding products in yields of 73% (3b), 76% (3c) and 75% (3d), respectively.Moreover, phenyl acetic acid derivatives can also deliver this desired transformation (3e-3g).Homoveratric acid was coupled to 1,4-DCB to furnish product 3f in 83% yield.It is worth noting that the medicine molecule Naproxen was tolerated with the mild reaction conditions to obtain target product 3h in moderate yields, which is the property of non-steroidal anti-inflammatory group agents.This implies the synthetic potential of our approaches to medicinal chemistry.
In addition, the practicality of this decarboxylative cross-coupling reaction was further proved by a gram-scale reaction (Scheme 2).When the reaction was carried out under photoredox-catalyzed method, the objected unsymmetrical diarylmethanes 3a could be gained in high isolated yield (69%).A series of control experiments were achieved to gain more information about the decarboxylative cross-coupling reaction mechanism between aryl acetic acids and aryl nitriles (Scheme 3).Initially, the reaction of 3-indoleacetic acid (1a) with 1,4-DCB (2a) was conducted in the presence of radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine) under standard reaction conditions (Scheme 3A), and only a trace amount of compound 3a was perceived, and TEMPO-trapping compounds could be discerned by HRMS In addition, the practicality of this decarboxylative cross-coupling reaction was further proved by a gram-scale reaction (Scheme 2).When the reaction was carried out under photoredox-catalyzed method, the objected unsymmetrical diarylmethanes 3a could be gained in high isolated yield (69%).A series of control experiments were achieved to gain more information about the decarboxylative cross-coupling reaction mechanism between aryl acetic acids and aryl nitriles (Scheme 3).Initially, the reaction of 3-indoleacetic acid (1a) with 1,4-DCB (2a) was conducted in the presence of radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine) under standard reaction conditions (Scheme 3A), and only a trace amount of compound 3a was perceived, and TEMPO-trapping compounds could be discerned by HRMS In addition, the practicality of this decarboxylative cross-coupling reaction was further proved by a gram-scale reaction (Scheme 2).When the reaction was carried out under photoredox-catalyzed method, the objected unsymmetrical diarylmethanes 3a could be gained in high isolated yield (69%).In addition, the practicality of this decarboxylative cross-coupling reaction was fur ther proved by a gram-scale reaction (Scheme 2).When the reaction was carried out unde photoredox-catalyzed method, the objected unsymmetrical diarylmethanes 3a could be gained in high isolated yield (69%).A series of control experiments were achieved to gain more information about the decarboxylative cross-coupling reaction mechanism between aryl acetic acids and aryl ni triles (Scheme 3).Initially, the reaction of 3-indoleacetic acid (1a) with 1,4-DCB (2a) was conducted in the presence of radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine under standard reaction conditions (Scheme 3A), and only a trace amount of compound 3a was perceived, and TEMPO-trapping compounds could be discerned by HRMS A series of control experiments were achieved to gain more information about the decarboxylative cross-coupling reaction mechanism between aryl acetic acids and aryl nitriles (Scheme 3).Initially, the reaction of 3-indoleacetic acid (1a) with 1,4-DCB (2a) was conducted in the presence of radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine) under standard reaction conditions (Scheme 3A), and only a trace amount of compound 3a was perceived, and TEMPO-trapping compounds could be discerned by HRMS (Scheme 3A), and homocoupling dimer could be detected by HRMS too (Scheme 3A).Then, the radical intermediate in the reaction was compromised by some cyclizations [42] (Scheme 3B).Dienes caused addition/cyclization compatible with intramolecular radical addition based upon HRMS analysis.Finally, the light on/off experiment (Scheme 3C) also verifies that the reaction involves a radical process [43].These control experiments reveal that this reaction involved radical intermediates.
Molecules 2024, 29, x FOR PEER REVIEW 6 of 12 (Scheme 3A), and homocoupling dimer could be detected by HRMS too (Scheme 3A).Then, the radical intermediate in the reaction was compromised by some cyclizations [42] (Scheme 3B).Dienes caused addition/cyclization compatible with intramolecular radical addition based upon HRMS analysis.Finally, the light on/off experiment (Scheme 3C) also verifies that the reaction involves a radical process [43].These control experiments reveal that this reaction involved radical intermediates.Guided by the above experimental results and previous literature [44][45][46][47][48][49], a plausible mechanism is presented in Scheme 4 for a photoredox-catalyzed decarboxylative crosscoupling reaction.In the first place, the irradiation of photocatalyst PC [Ir(ppy)3] with visible light produces a photoexcited state PC*[*Ir(ppy)3], which is a strong reductant (E1/2 red [Ir IV /*Ir III ] = −1.73V vs. SCE) [50].We assumed that the reduction of 1,4-DCB (E1/2 red = −1.61V vs. SCE) [51] by single electron transfer to form the corresponding radical anion intermediate A and oxidized photocatalyst PC −e [Ir IV (ppy)3] would be easy.Then, the PC −e [Ir IV (ppy)3] is a strong oxidant (E1/2 red = +0.77V vs. SCE) and could undergo a single electron transfer with 3-indoleacetic acid substrate [52] to deliver the radical intermediate B with the elimination of CO2, together with regenerating PC [Ir III (ppy)3] and finishing the photoredox cycle.Finally, the radical-radical coupling of intermediate A with B and then aromatization with loss of CN − would produce the diarylmethane.

General Information
All materials, reagents and solvents were purchased from commercial suppliers and were used without further purification.Analytical TLC was performed with silica gel GF254 plates, and the products were visualized by UV detection.Flash chromatography was carried out using silica gel 200-300.The 1 H NMR (400 or 600 MHz) and 13 C NMR (151 MHz) spectra were measured with CDCl3 as solvent.All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.High-resolution mass spectra (HR-MS) were recorded under electrospray ionization (ESI) conditions.

General Information
All materials, reagents and solvents were purchased from commercial suppliers and were used without further purification.Analytical TLC was performed with silica gel GF254 plates, and the products were visualized by UV detection.Flash chromatography was carried out using silica gel 200-300.The 1 H NMR (400 or 600 MHz) and 13 C NMR (151 MHz) spectra were measured with CDCl 3 as solvent.All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.High-resolution mass spectra (HR-MS) were recorded under electrospray ionization (ESI) conditions.

General Procedure for Light-Promoted Decarboxylative Cross-Coupling Reaction between Aryl Acetic Acids and 1,4-Dicyanobenzene
Aryl acetic acids (1, 0.2 mmol), 1,4-dicyanobenzene (2a, 0.1 mmol), K 2 CO 3 (1 equiv.)and fac-Ir(ppy) 3 (2 mol%) were successively added to a dried reaction tube (10 mL) with a magnetic stirring bar.Air was then withdrawn and backfilled with argon 3 times.Subsequently, degassed DMSO (1 mL) was injected into the tube by syringe.Then, the resulting reaction mixture was performed at room temperature under blue LED (6 W) irradiation for 3-24 h.The reaction progress was monitored by TLC.After the reactions were completed, the reaction mixture was diluted with water (10 mL) and washed with EA (3 × 10 mL).The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under (50 mL) and washed with EA (3 × 50 mL).The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The residue was purified by column chromatography (ethylacetate/n-Hexane = 1:8) to afford the desired compound 3a (1.2056 g, 69%).

The Light On/Off Experiment
Following the literature procedure [53], to a dried reaction tube (10 mL) with a magnetic stirring bar were added 3-Indoleacetic acid (1a, 0.2 mmol), 1,4-dicyanobenzene (2a, 0.1 mmol), K 2 CO 3 (1 equiv.)and fac-Ir(ppy) 3 (2 mol%) successively.Air was then withdrawn and backfilled with argon 3 times.Subsequently, degassed DMSO (1 mL) was injected into the tube by syringe.Then, the resulting reaction mixture was performed at room temperature under blue LED (6 W) irradiation.eight identical reactions were carried out simultaneously and yield was determined by 1 H NMR of the crude mixture using 1,3,5trimethylbenzene (13.9 µL, 0.10 mmol, 0.5 equiv.)as internal standard.The experiments with continuous intervals of irradiation and dark periods led to total interruption of the reaction proceed in the absence of light, and reactivity is restored under further light (The details are in the Supplementary Materials).These results indicated that light is an essential component of the reaction.

Conclusions
In summary, we have described a photoredox-catalyzed decarboxylative cross-coupling reaction of aryl acetic acids and aryl nitriles achieved under an argon atmosphere in high yields.A tentative radical mechanism has been proposed.Further studies of the detailed reaction mechanism and application are underway in our laboratory.

Table 1 .
Screening of reaction conditions a .

Table 1 .
Screening of reaction conditions a .

Table 2 .
Scope of the decarboxylative cross-coupling reaction of various aryl acetic acids with 1,4-DCB a,b .

Table 2 .
Scope of the decarboxylative cross-coupling reaction of various aryl acetic acids with 1,4-DCB a,b .

Table 3 .
Scope of the decarboxylative cross-coupling reaction of various aryl nitriles with 3-indo leacetic acid a,b .

Table 3 .
Scope of the decarboxylative cross-coupling reaction of various aryl nitriles with 3-indoleacetic acid a,b .