Visible-light photocatalysed Synthesis of Bioactive Benzo[b]thiophenes via Intramolecular C−S Bond Formation

doi:10.21203/rs.3.rs-2948452/v1

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Visible-light photocatalysed Synthesis of Bioactive Benzo[b]thiophenes via Intramolecular C−S Bond Formation

https://doi.org/10.21203/rs.3.rs-2948452/v1

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Visible light driven synthesis of substituted benzo[b]thiophenes from phenylethenethiol under an air atmosphere at room temperature is reported, using eosin Y as an organophotoredox catalyst by intramolecular C−S bond formation. This process accepts a wide range of functional groups tolerance and generates benzo[b]thiophenes under highly environmentally benign conditions via transition-metal-free organic photoredox catalysis.

Substituted benzo[b]thiophenes are heterocycles of vital significance because of its occurrence in bioactive molecules [1–2], which include their use as HIV-1 reverse transcriptase inhibitors, antidepressants, and tubulin polymerization inhibitors [3–5]. These heterocycles also consist the basic structural unit present in commercial drugs, such as raloxifene [6–8] and arzoxifene [9–11], (selective estrogen receptor modulators) [12], Zileuton [13–14] (inhibitor of 5-lipoxygenase), Ipragliflozin [15–17] (type 2 diabetes), and Sertaconazole [18] (antifungal agent) (Fig. 1). Furthermore, benzo[b]thiophene-containing substances have been linked to antitubulin [19], antimitotic [20], urotensin-II receptors antagonistic [21], S1PR4 agonistic [22], anti- tubercular [23], and antinociceptive [24] activities in recent studies. Additionally, a lot of benzo[b]thiophenes may be used in the manufacturing of optoelectronic materials [25–30].

The use of UV or visible light to generate intramolecular C-S bonds has recently drawn more attention. Initially, the previously reported techniques for the synthesis of benzo[b]thiophene have been reported in literature due to their significance [31–39]. There are numerous prospects for the development of environmentally friendly and sustainable protocols for organic synthesis because solar energy (visible light) is a pure, easy-to-use, and limitless energy source [40–43]. Several trailblazing scientists [44, 45] have focused on the conversion of solar energy into chemical energy for chemical reactions and have also created a promising technique for using photoredox catalysts to initiate single electron transfer (SET) processes [46–48]. Recently, metal-free organic dyes such eosin Y, fluorescein, rose bengal, nile red, perylene, and rhodamine B have been employed as superior substitutes for transition metal photoredox catalysts, both economically and environmentally. In the current study, we focused on further exploring how a photoredox catalyst that emits visible light can be used to cyclize phenylethenethiol in an environmentally friendly manner. In keeping with our ongoing research into environmentally friendly synthetic methods [49–74], herein we proposed the application of a natural organic dye eosin Y, as photocatalyst using visible blue led to promote the transition-metal free chemical transformation under mild reaction conditions. (Scheme 1).

In order to work out the envisaged protocol, a key reaction was conducted with phenylethenethiol 1(a–n) in DMF containing 2 mol % of eosin Y under an air atmosphere (without air bubbling) by irradiation with blue light (blue LEDs, λmax = 467 nm) at rt. The reaction delivered the desired benzo[b]thiophenes 2(a–n) with moderate to excellent yield. (Table 1).

Table 1 Optimization of reaction conditions^a

Entry	Photocatalyst	Catalyst loading (mol%)	Solvent	Base	Time (h)	Yield^b (%)
1	Eosin Y	2	DMF	ⁱPr₂Net	5	92
2	Rose Bengal	2	DMF	ⁱPr₂Net	5	86
3	Fluorescein	2	DMF	ⁱPr₂Net	5	76
4	Benzophenone	2	DMF	ⁱPr₂Net	5	71
5	Eosin Y	2	MeOH	DBU	5	61
6	Eosin Y	2	EtOH	DABCO	5	63
7	Eosin Y	2	DMSO	Et₃N	5	56
8	Eosin Y	1	DMF	ⁱPr₂Net	5	62
9	Eosin Y	3	DMF	ⁱPr₂Net	5	92
10	Eosin Y	2	DMF	ⁱPr₂Net	5	42^c
11	Eosin Y	2	DMF	ⁱPr₂Net	8	Trace^d
12	-	-	DMF	ⁱPr₂Net	8	n.d.^e

^aReaction conditions: phenylethenethiol (1.0 mmol), eosin Y (2.0 mol%), ⁱPr₂NEt (2.0 equiv.), DMF (3.0 mL), blue LEDs 3 W, irradiation under an air atmosphere at rt.

^bIsolated yield of the product (2a).

^cThe reaction was carried out using 20 W CFL (compact fluorescent lamp).

^dReaction was performed in the dark.

^eReaction was carried out without catalyst.

Following this experiment, a series of control experiments were performed, which indicates that an organic base is essential to give the desired product with high yield (92%) (Table 1, entry 1) and ⁱPr₂NEt was found to be the best base (Table 1, entry 1 versus 5, 6, 7). Next, the reaction conditions were optimized with respect to catalyst and eosin Y was found the best suitable catalyst. (Table 1, entry 1 versus 2, 3, 4). There was no product formation or it was formed in traces in the absence of any one of the reagents/ catalyst (Table 1, entries 11, 12). The reaction did not proceed satisfactorily when a household 20 W fluorescent lamp was used instead of blue LEDs (Table 1, entries 10 versus 1 These results establish that visible light, base, and photocatalyst all are essential for the reaction and supports this photocatalytic model of the reaction.

Next, the reaction conditions were optimized with respect to solvents and the catalyst used in the reaction. In all the tested solvents (DMF, DMSO, MeOH and EtOH) the yield of 2(a–n) was > 55% (Table 1), which indicates that the reaction is not very sensitive to reaction media. DMF was the best solvent in terms of the reaction time and yield (Table 1, entry 1), hence it was used throughout the synthesis. When the amount of the catalyst was decreased from 2 mol % to 1 mol %, the yield of 2(a–n) considerably reduced (Table 1, entry 8), but the use of 3 mol % of the catalyst did not affect the yield (Table 1, entry 9).

We next shifted our attention to exploring the adaptability of alternative substrates or anticipated reaction conditions, as we proceeded to search for the ideal reaction conditions for our model reaction (Table 2). The implementation of the present approach to a variety of phenylethenethiol including different substituents was investigated.

This clearly shows that the reaction is very mild and applicable to aryl and substituted aryl, tolerates considerable functional group variations like, NHCOMe, CO₂Me, COMe, CHO, MeO, Me, Cl, Br and NO₂ in the substrate 1(a–n), which results the desired product 2(a–n) in moderate to excellent yields (48–98%). However, phenylethenethiol with an electron-donating group on the aromatic ring appear to react faster and afford marginally higher yields in comparison to those bearing an electron withdrawing group.

On the basis of the above observations and the literature precedents, a plausible mechanism involving photoredox catalysis for the oxidative cyclization of phenylethenethiol is depicted in Scheme 2.

On absorption of visible light, the organophotoredox catalyst eosin Y (EY) is excited to its singlet state ¹EY* which through inter system crossing (ISC) comes to its more stable triplet state ³EY* and undergoes a single electron transfer (SET). ³EY* may undergo both reductive and oxidative quenching. [75–79] A SET from A to ³EY* generates thioacyl radical B, which undergoes intramolecular cyclization to form C followed by attack of O₂^{• −} to give the product 2, successively. The formation of superoxide radical anion O₂^{• −} during the reaction was confirmed by the detection of the resulting H₂O₂ using KI / starch indicator [80].

Experimental section

General information

Melting points were determined by open glass capillary method and are uncorrected. All chemicals used were reagent grade and were used as received. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AVANCE DPX (400 MHz and 100 MHz) FT spectrometer in CDCl₃ using TMS as an internal reference (chemical shift in δ, ppm).

General Procedure for the Synthesis of benzo[ b ]thiophenes 2(a–n)

A solution of a substituted phenylethenethiol 1(a–n) (1.0 mmol), eosin Y (2.0 mol %) and ⁱPr2NEt (2.0 equiv.) were added and the mixture was irradiated with blue LEDs (3 W, λmax = 467 nm) with stirring under an air atmosphere at rt for 5–8 h. After completion of the reaction (monitored by TLC), water (5 mL) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phase was dried over MgSO₄, filtered and evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography using a gradient mixture of hexane/ ethyl acetate as eluent to afford an analytically pure 2(a–n). All the products are known compounds and were characterized by the comparison of their spectral data with those reported in the literature.

Molecular Docking

Molecular docking is an accepted technique to identify bioactive compounds for drug development by calculating the binding affinity of the protein and ligand [81]. By using a computational technique called protein-ligand docking, it is possible to predict how and to what extent small compounds will bind to protein receptors. This molecular modelling technique [82–85] predicts the preferred orientation of one molecule to another when they are joined together to form a stable complex [86]. The pharmaceutical industry is well known for providing drugs development a high priority. By using online drug target prediction, also known as Swiss ADME-Target prediction, this compound, also referred to as a ligand, interacts with the specific protein that has been selected. Software Chimera 1.14 and Auto Dock Vina are used to dock 2-Phenylbenzo[b]thiophene molecule with 4FGL protein which belongs to oxidoreductase domain [87]. Table 3 provides a summary of the results, and Fig. 2 shows the best binding energy of -5.9 kcal/mol. A low binding energy value indicates that the compound is bioactive in nature and it indicates if the given ligand is suitable for the given proteins. The protein 4FGL contains 3 residues and the value of its Inhibition constant (KI) is 47.2.

Table 3

Molecular docking and hydrogen bonding with centromere-related protein inhibitors protein targets.
Target Molecule	2-Phenylbenzo[b]thiophene
Protein (PDB ID)	4FGL
No. of Residues	3
Bond Distance (A⁰)	3.18
Inhibition constant (micromolar)	47.2
Binding energy (Kcal mol^− 1)	-5.9
Reference RMSD (Å)	10.87

Drug- likeness

The structural properties of the ligands in pharmaceutical study play a significant role to provide accurate and effective results for guidelines, also known as drug-likeness. In this technique, numbers of rules are used such as Veber rule, BBB rule, QED, Ghose filter, Lipinski's rule, MDDR-like rule and CMC-50 rules [88]. To identify whether a chemical molecule has the chemical and physical properties that would make it likely to be an orally active medicine in humans, Lipinski's rule [89] is a widely used filtering criteria. Efficiency is achieved when the 2-Phenylbenzo[b]thiophene and its derivatives are subjected to the drug-likeness criteria. Numerous activities are shown by these compounds. The vital ADME parameters, including the blood-brain barrier penetration (BBB) log kp, hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), topological polar surface area (TPSA), bioavailability score and molar refractivity (MR) are calculated for the standard compound and its derivatives and are shown in Table 4. It is recommended that both HBA and HBD readings should be below 10. The molecules in this particular case all have values that are less than 3. The highest value for TPSA should be 140 A². For the target molecule and its derivatives, this ranges from 28.24 to 74.06. Table 4 shows that the bioavailability score of 2-Phenylbenzo[b]thiophene and its derivative is equal to 0.55 and that the skin's permeability (log Kp) is between − 3.97 and − 4.45. Additionally, all the target molecules have the relevant value of GI absorption. In addition, the molar refractivity should be around 40–130 [90]. The MR values of 2-Phenylbenzo[b]thiophene, 2-(4-nitrophenyl)benzo[b]thiophene and 5-methyl-2-(p-toly)benzo[b]thiophene are 67.26,76.08 and 77.19. According to the comparison described above, the title molecule, 2-Phenylbenzo[b]thiophene, and its derivatives are valuable building blocks that are commonly used in the development of a variety of substances with biological activity and medicines.

Table:4 ADME properties of 2-Phenylbenzo[b]thiophene and its derivative.

ADME properties	2-Phenylbenzo-[b]thiophene	2-(4-nitrophenyl)benzo-[b]thiophene	5-methyl-2-(p-toly)benzo- [b]thiophen
HBA	0	2	0
HBD	0	0	0
TPSA A²	28.24	74.06	28.24
MR	67.26	76.08	77.19
GI absorption	High	High	High
BBB permeant	Yes	No	Yes
CPY1A2 inhibitor	Yes	Yes	Yes
Log k_p (cm s^− 1)	-0.05	-4.45	-3.97
Lipinski violations	0	0	1
Bioavailability score	0.55	0.55	0.55

HBA- hydrogen bond acceptor, HBD- hydrogen bond donor, TPSA-topological polar surface area, MR- molar refractivity, GI- gastrointestinal, BBB- blood-brain barrier penetration and log k_p- skin permeability.

In conclusion, we have developed visible light induced protocol for the synthesis of bioactive benzo[b]thiophenes, via C-S bond formation at room temperature. This method includes a novel organocatalysed protocol for the synthesis of benzo[b]thiophenes directly via cyclization of phenylethenethiol in a one-pot procedure by using inexpensive eosin Y as a powerful organophotoredox catalyst, which is superior to all other methods. The range of substrates for visible light photoredox reactions has been expanded by this synthesis. The present strategy also provides many advantages of green chemistry, notably high atom economy, shortened reaction time, one-pot consolidated methodology, and high efficiency. Molecular docking studies carried out on the 4FGL protein associated with the oxidoreductase domain exhibited binding energy of − 5.9 kcal mol^− 1 resulting it's application in the medicinal field.

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Table 2 is available in the Supplementary Files section.

Schemes 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

Table2.docx
SIFile.pdf
GA.png
scheme1.png
Scheme 1. Synthesis of benzo[b]thiophenes.
scheme2.png
Scheme 2. Plausible mechanism for visible-light mediated photocatalysed synthesis of benzo[b]thiophenes.

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Visible-light photocatalysed Synthesis of Bioactive Benzo[b]thiophenes via Intramolecular C−S Bond Formation

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