Unveiling the potency of a phenalenyl-based photocatalyst for intramolecular dehydrogenative lactonization

Abstract

Here, an intramolecular dehydrogenative lactonization reaction has been accomplished by combining a phenalenyl-based organic photocatalyst and a Co(III) co-catalyst. Due to its extremely high excited state redox potential, the phenalenyl motif could directly oxidise carboxylic acid derivatives to generate carboxyl free radicals without the assistance of an external base. This protocol allows access to multiple 4-aryl-2H-chromen-2-ones by using the external oxidant K₂S₂O₈ and shows diverse functional group tolerance for biaryl-2-carboxylic acids. Moreover, the reaction was performed on a bulk scale with a very good yield.

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In the past few decades, visible-light-induced photoredox catalysis has become a powerful synthetic tool for creating molecular diversity.^1,2 Although polypyridyl complexes of heavier transition metals³ like Ru and Ir that use the energy of photons to architect several molecular complexities have dominated photocatalysis in the past, it is clear that an organic photocatalyst with careful design can offer the following benefits: (a) sustainability, (b) tolerance of a wide range of functional groups, (c) cost effectiveness, and (d) lesser unwanted side reactions. As a result, successful efforts have been made to design organic photocatalysts⁴ which essentially facilitate several chemical transformations that were previously challenging and difficult to carry out using standard chemical protocols. Despite the fact that these organic photocatalysts have led to significant improvements in a number of chemical transformations, efforts are ongoing to create novel organic photocatalysts⁵ with excited state potentials up to +2.5 V vs. Ag/AgCl (Scheme 1a), enabling the oxidation of readily available starting materials for the creation of high-energy radical centres.

Scheme 1 Potential range of conventional photocatalysts and our newly developed photocatalyst.

In recent years, the phenalenyl moiety⁶ has been studied extensively as a Lewis acid⁷ and a strong reducing agent⁸ in the ground state to replicate a number of transition-metal catalysed reactions.

With our ongoing efforts to design new photochemical transformations, while demonstrating the photoactivity of this moiety, a very low magnitude of reduction potential (−0.21 V vs. Ag/AgCl, Fig. 1a) for PC₁ was observed. This low reduction potential led to a high redox potential (vs. Ag/AgCl) of PC₁ in the excited state. In the UV-visible spectrum, the presence of bands around 420–480 nm makes this bench stable PC₁ susceptible to absorbing blue light (Fig. 1b). When we recorded the emission spectra to check the photostability of PC₁, no decrease in the emission intensity of PC₁ was noticed after 5 times excitation at 440 nm (Fig. 1c), which indicated that photobleaching did not occur with PC₁. Furthermore, from the fluorescence decay curve, the emission lifetime of PC₁ was found to be τ = 2.85 ns (amplitude weighted), which indicates that it might act as a potent photocatalyst (Fig. 1d). In fact, we have recently been able to offer a phenalenyl-based scaffold (Scheme 1b) as a potent photooxidant for the azolation of an unactivated feedstock arenes.⁹ Therefore, with the knowledge of the above photophysical properties and our literature precedent, one might anticipate that this phenalenyl photocatalyst (PC₁) would readily oxidise carboxylic acid derivatives (with E_ox > +2.0 V vs. Ag/AgCl) in the presence of light in order to generate a high energy carboxyl free radical and we reasoned that PC₁ could be used for intramolecular cyclization to convert biaryl-2-carboxylic acids into the bioactive benzo-3,4-coumarin core (Scheme 2).

Fig. 1 Properties of the photocatalyst (PC₁): (a) one electron reduction of PC₁, (b) normalized absorption and emission, (c) photostability of the catalyst, and (d) fluorescence decay curve (lifetime of PC₁).

Scheme 2 Literature precedents and our approach.

Numerous attempts to create such coumarin scaffolds have met with success owing to the extensive application of the benzo-3,4-coumarin skeletal unit in a broad range of pharmaceuticals, fluorescent materials, and other fine chemicals (Scheme 2a).¹⁰ The most common methods typically call for harsh reaction conditions and the use of transition metals (Cu, Co, and Ag) and lanthanides (Ce).¹¹ Nevertheless, photoinduced LMCT of Cu, Ce and Fe at ambient temperature is well known¹² for intramolecular lactonization. While Mes-Acr⁺ and other organic photocatalytic pathways¹³ have received a lot of attention for this transformation, an oxidising agent in stoichiometric proportions is necessary. While it is critical to gain an appreciation for the benefits of metal mediated and electrically driven¹⁴ synthesis of coumarin derivatives, the use of stoichiometric amount of electrolytes/additives remained a concern that necessitated atom-economical approaches. Considering these constraints, we set out to evaluate the efficiency of a phenalenyl based organic photocatalyst to induce intramolecular dehydrogenative lactonization.

To reach our goal, we employed 2-phenylbenzoic acid (1a) as the model substrate under the photochemical conditions. To our delight, by utilizing PC₁ (5 mol%) as the photocatalyst and Co^III(dmgH)₂PyCl (10 mol%) as the co-catalyst in MeCN with 440 nm Kessil lamp irradiation for 24 h under an argon atmosphere, we obtained the desired product 2a in 98% yield (Table 1, entry 1). On varying the solvents from MeCN to DCE, DMF and MeOH, the yield decreased to 92%, 80% and 77%, respectively (Table 1, entry 2). When the reaction mixture was irradiated with 456 nm and 427 nm light, the formation of the desired product decreased slightly and 2a was produced in 91% and 96% yields, respectively (Table 1, entry 3). Furthermore, on changing the co-catalyst to Co^III(acac)₃, the yield of 2a reduced drastically (Table 1, entry 4). On changing the photocatalyst from PC₁ to PC₂, we were unable to detect traces of the desired product (Table 1, entry 5). Control experiments revealed that the presence of the photocatalyst and co-catalyst and visible light irradiation was crucial for the dehydrogenative lactonization under ambient conditions (Table 1, entries 6–8). More importantly, the literature^13d suggests that a base is necessary to reduce the oxidation potential of 1a. However, PC₁ having a very high excited state potential could directly oxidise 1a. Therefore, this protocol does not necessitate an extraneous base for the transformation, making it more atom economical.

Table 1 Optimization of the reaction parameters^a

Entry	Variation from the standard conditions	Yield^b (%)
a Standard reaction conditions unless specified: [1,1′-biphenyl]-2-carboxylic acid (1a, 0.2 mmol), PC1 (5 mol%), Co^III(dmgH)2PyCl (10 mol%), MeCN (2 mL), 440 nm Kessil lamp irradiation, 24 h, room temperature (rt), Ar atmosphere. b Yield of 2a determined by gas chromatography (GC) using benzophenone as the internal standard.
1	None	98
2	DCE, DMF, MeOH instead of MeCN	92, 80, 77
3	427 nm and 456 nm	96, 91
4	Co^III(acac)3 instead of Co^III(dmgH)2PyCl	<5
5	PC2 instead of PC1	n.d.
6	No PC1	<5
7	No Co^III(dmgH)2PyCl	8
8	No light irradiation	0

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With the optimized conditions in hand, we sought to explore the substrate scope of this photoinduced dehydrogenative lactonization protocol. Substituents on the aryl rings of 2-phenylbenzoic acid significantly determined the outcome of the reaction (Table 2). As a result, the electronic and steric effects of various groups attached to the reactants were examined, leading to the production of a wide range of products with yields ranging from good to excellent (up to 96%). Initially, the substrates in which electron-donating substituents were attached to the Ar₂ ring were examined. To our delight, the desired products having electron-donating –Me (2b, 85%), –OMe (2c, 83%) and –^tBu (2d, 82%) groups at the 4-position of Ar₂ were obtained in good yields. Furthermore, excellent yields were obtained when substrates with electron-withdrawing groups such as –CF₃ (2e, 85%), –OCF₃ (2f, 89%), –F (2g, 90%) and –Cl (2h, 84%) at the 4-position of the Ar₂ ring were subjected to the lactonization conditions. When the reactant containing a 4-Ph group on the Ar₂ ring was employed in the reaction, the corresponding product 2i was obtained in 77% yield. When biaryl-2-carboxylic acid bearing a methyl substituent at the meta position was employed under the reaction conditions, the desired product was formed in a good yield (2j, 74%) with the regioisomeric ratio (rr) = 2.3 : 1. Furthermore, on varying the substituents on the Ar₁ and Ar₂ rings simultaneously, we obtained the corresponding products in good to excellent yields. When we made a substitution on the Ar₁ ring with the –Me group and no group on the Ar₂ ring, we obtained the desired product 2k in 89% yield. Next, keeping the –Me group fixed, groups on the Ar₂ ring were varied from –Me, –OMe, –F to –Cl, giving products 2l (80%), 2m (81%), 2n (90%) and 2o (88%). When naphthalene was utilized as one of the aryl groups, the desired product 2p was furnished in a good yield (74%).

Table 2 Substrate scope for the synthesis of benzo-3,4-coumarins^a,b

a Standard reaction conditions unless specified: [1,1′-biaryl]-2-carboxylic acid (1, 0.2 mmol), PC₁ (5 mol%), Co^III(dmgH)₂PyCl (10 mol%), MeCN (2 mL), 440 nm Kessil lamp irradiation, 24 h, room temperature (rt), Ar atmosphere. b Isolated yields from the two reaction mixtures at the 0.2 mmol scale each.

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After achieving success in generalizing the scope of 2-arylbenzoic acids, we moved on to diversify the substrate scope by using 3,3-diarylacrylic acid derivatives to synthesize 4-aryl coumarins. It is worth noting that the 4-aryl coumarin skeleton is known as a member of the flavonoid family and is present in many natural products having mostly anticancer properties and many other biological activities.¹⁵ However, under the optimized conditions, 3,3-diphenylacrylic acid did not lead to efficient conversion to the desired product 2q. Therefore, we screened different reaction parameters, and it was observed that when K₂S₂O₈ was used as the oxidant (Table 3), the desired product 2q was obtained in an excellent yield (90%). Therefore, we utilized the newly developed optimized conditions for the lactonization of 3,3-diarylacrylic acids. In this transformation as well, the electronics of the carboxylic acid moiety played a pivotal role in the formation of the desired products. Electron-donating substituents such as 4-Me, 3,5-dimethyl and ^tBu yielded the corresponding products 2r (86%), 2s (83%) and 2t (83%) in good yields. However, when electron-withdrawing groups were embedded in the aryl core, comparatively higher yields of the desired products were observed. When the aryl rings were substituted with 4-OCF₃ and 4-CF₃ groups, the desired products 2u and 2v were obtained in 88% and 85% yields, respectively. Excellent yields were also obtained in the case of halo-substituents such as –F (2w, 92%), –Cl (2x, 94%) and –Br (2y, 88%).

Table 3 Substrate scope for the synthesis of 4-aryl-2H-chromen-2-ones^a,b

a Standard reaction conditions unless specified: 3,3-diarylacrylic acids (1, 0.2 mmol), PC₁ (5 mol%), K₂S₂O₈ (2.0 equiv.), MeCN (2 mL), 440 nm Kessil lamp irradiation, 24 h, room temperature (rt), Ar atmosphere. b Isolated yields from the two reaction mixtures at the 0.2 mmol scale each.

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Once the scope of the reaction was understood, numerous spectroscopic studies were performed to deduce the reaction mechanism. No discernible changes in the absorption spectra were initially seen when we conducted UV-Vis investigations (see the ESI‡) of PC₁ with the subsequent addition of 1a, indicating that there was no ground state complexation between PC₁ and 1a. Fluorescence quenching studies were then carried out to determine whether the interactions were occurring at the excited state, and these studies revealed a gradual decline in the fluorescence intensity of PC₁ upon sequential addition of 1a (see the ESI‡). Since we obtained a straight line with a positive slope (Fig. 2a) when we plotted the Stern–Volmer graph, it is possible to infer from these studies that PC₁ and 1a are interacting at the excited state. Furthermore, no signal was detected during the EPR experiments when PC₁ and 1a were combined (Fig. 2b, black trace). However, after exposing this mixture to 440 nm radiation for 6 h, a clear signal was obtained with a g value of 2.007, indicating the formation of a delocalized carbon-centered radical species¹⁶ which was believed to be the radical anion species (PC₁˙⁻) of PC₁ in the ground state (Fig. 2b, red trace) after comparing it to the simulated spectrum (Fig. 2b, blue trace).

Fig. 2 (a) Fluorescence quenching study (Stern–Volmer plot) and (b) EPR analysis.

In order to further support the radical formation during the course of the reaction, the model reaction was performed in the presence of commonly used radical scavengers like butylated hydroxytoluene (BHT) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). In both cases, the formation of a small amount of products (Scheme 3) suggested that radical intermediacy was the dominant pathway for the reaction to occur.

Scheme 3 Radical scavenging analysis.

Based on the above results, a plausible mechanism has been shown in Scheme 4. When exposed to visible light, PC₁ first experiences photoexcitation, resulting in PC₁*, which is then intercepted by 1a to produce intermediate I and itself is converted to PC₁˙⁻.

Scheme 4 Proposed mechanism.

Simultaneously, I transforms into II through intramolecular cyclization. Intermediate II then undergoes SET with intermediate III to give IV and finally produce 2a. Intermediate IV captures the proton to produce V, which is converted to VI with the expulsion of H₂.

Additionally, we were able to scale up (Scheme 5) the reaction to the 5.0 mmol scale with a good yield of the desired product 2a.

Scheme 5 Bulk scale synthesis.

Conclusions

In summary, by combining a phenalenyl-based organic photocatalyst with a Co(III/II) catalyst, we have demonstrated a new photochemical method for intramolecular dehydrogenative lactonization to synthesize bioactive coumarin molecules. Along with gram scale lactonization, the scope of the reaction is broad as several electron-donating and electron-withdrawing groups, as well as reactive functionalities, are tolerated in this procedure. The feasible mechanism was finally discovered to be proceeding through the reductive quenching of PC₁, which was extensively studied using CV, UV-visible spectra analysis, and EPR analysis.

Author contributions

SRR conceived the idea. PPS and VP performed the experiments. PPS and VP prepared the ESI.‡ All authors discussed the results and contributed to the conceptualization of the project and editing the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

SRR thanks SERB (CRG/2022/002306) for financial support. VP thanks MHRD (GoI) for the Prime Minister's Research Fellowship. The authors acknowledge CRF, IIT Delhi for instrument facilities.

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Footnotes

† Dedicated to Prof. Goverdhan Mehta on the occasion of his 80^th birthday.

‡ Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3qo01662e

§ These authors contributed equally.

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