Electrochemical Synthesis of 3,5-Bis(acyl)-1,2,4-thiadiazoles through n-Bu₄NI-mediated Oxidative Dimerization of α-Oxothioamides

Abstract

An electrochemical synthesis of 3,5-bis(acyl)-1,2,4-thiadiazoles by the oxidative dimerization of α-oxothioamides with assistance of tetra-n-butylammonium iodide (TBAI) as electrolyte and mediator under constant current electrolysis (CCE) is reported. Herein, this approach is an example for S–N bond construction through the electrochemical method. Furthermore, the required intermediates α-oxothioamides are synthesized by the reaction of α-oxodithioesters with ammonium chloride in the presence of sodium acetate. The probable mechanism for the formation of final products is also presented. This strategy resulted in good to excellent yields of title compounds.

1. Introduction

1,2,4-Thiadiazole motif represent a pivotal class of heterocyclic compounds being ubiquitous in both medicinal chemistry and drug discovery. The number of scientific studies on these compounds has amplified in recent years. An illustrative example of this trend is cefozopran (SCE-2787), which is one of the most effective compounds against thigh muscle infection. It is also a drug, which is commercially available with interesting antibiotic activity.^1–4 Besides, 1,2,4-thiadiazole derivatives show anticancer,⁵ anti-inflammatory⁶ and antibiotic activity.⁷ Further, they are adenosine receptor antagonists,⁸ muscarinic receptor agonists,⁹ angiotensin II receptor antagonists¹⁰ and sphingosine 1-phosphate receptor agonists.¹¹ Besides, they show inhibitory activities on acetylcholinesterases,¹² glycogen synthase kinase¹³ and cysteine dependent enzymes.¹⁴ Some biologically active 1,2,4-thiadiazoles are listed in Fig. 1. Because of these applications, synthesis of 5-membered 1,2,4-thiadiazoles and investigation of their chemical properties and biological behaviour has accelerated and various approaches have been reported for their syntheses.¹⁵

Figure 1.

Some biologically active 1,2,4-thiadiazoles.

The construction of S–N, S–O and N–O bond is a noteworthy transformation in modern synthetic organic chemistry. The derivatives of novel 1,2,4-thiadiazoles were synthesized by oxidative dimerization of α-oxothioamides using molecular iodine is reported earlier from our laboratory.¹⁶ By considering the importance of 1,2,4-thiadiazoles, several methods that use thioamides as substrates have been developed for the synthesis of 1,2,4-thiadiazole derivatives.^17–25 However, all of these methods require stoichiometric amounts of oxidizing agents. Most commonly used oxidants are o-iodoxylbenzoic acid (IBX) with tetraethylammonium bromide,²⁶ iodoxolone based hypervalent iodine,²⁷ hydrogen peroxide,²⁸ N-bromosuccinimide²⁹ and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).³⁰ The synthetic approach towards electrochemical synthesis of 1,2,4-thiadiazoles via oxidative cyclization of thioamides in the presence of ammonium iodide has been elegantly resolved by Pan and Tang’s group.³¹

In continuation of our impressive works in organic synthesis,^32–40 we have recently reported the synthesis of 1,2,4-thiadiazole derivatives by the oxidative cyclization of α-oxothioamides in the presence of molecular iodine (Scheme 1a).¹⁶ To the best of our knowledge, α-oxothioamides have not been explored for the electrochemical synthesis of 1,2,4-thiadiazoles. In our extended attempts in electro-organic synthesis,^41–46 we present electrochemical synthesis of 1,2,4-thiadiazoles from α-oxothioamides in this article (Scheme 1b).

Scheme 1.

Our previous and present work.

2. Experimental Section

2.1 Materials and methods

The reagents and solvents utilized in this study were purchased from commercial suppliers in India and employed without additional purification. To monitor reactions, TLC (thin-layer chromatography) was conducted using commercially available precoated plates (MERCK 60F254) with a thickness of 0.25 mm, and UV light was employed for visualization purposes. NMR spectra were recorded using an Agilent NMR spectrometer, with chemical shifts (δ) reported in ppm. CDCl₃ used as the solvent with TMS as the reference. Coupling constants (J) were expressed in Hz. Mass spectra were obtained using a Water-SynaptG2 mass spectrometer. For the elucidation of molecular structures, single-crystal X-ray diffraction data were collected using a Bruker Apex II CCD diffractometer, utilizing both Cu and Mo sources at room temperature via the monochrome beam method. The structures were established through full-matrix least-squares methods employing the SHELKS program.

2.2 Synthesis of 1,2,4-thiadiazoles

The α-oxothioamides (0.5 mmol) and n-Bu₄NI (10 mol%) were placed in a 25 mL three-necked round-bottomed flask, equipped with a RVC (100 PPI, 1 cm × 1 cm × 1.2 cm) anode and a platinum plate (1 cm × 1 cm) cathode. A mixture of 2.5 mL of MeOH and 2.5 mL of MeCN was added to the flask. Electrolysis was conducted at room temperature, employing a constant current of 10 mA until the complete consumption of the substrate, as determined by TLC analysis, which typically required approximately 1.5 h. The resultant reaction mixture was subsequently concentrated, and the residue was subjected to chromatography over silica gel, utilizing an elution solvents ethyl acetate/hexane, yielding the desired products.

2.2.1 Characterization data

(1,2,4-Thiadiazole-3,5-diyl)bis(phenylmethanone) (3a): Yellow solid; 85 % Yield (R_f = 0.625 in Hexane/EtOAc 70 : 30 v/v); mp: 65–66 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2985, 1741, 1595, 1275; ¹H NMR (CDCl₃, 400 MHz) δ: 8.54 (d, J = 8.0 Hz, 2H, Ar-H), 8.21 (d, J = 8.0 Hz, 2H, Ar-H), 7.62 (t, J = 4.0 Hz, 2H, Ar-H), 7.52–7.44 (m, 4H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 188.7, 185.0, 183.1, 171.7, 135.8, 135.5, 134.8, 134.1, 132.0, 131.8, 129.6, 129.2; HRMS (ESI) [M+H]⁺ calculated C₁₆H₁₀N₂O₂S 295.0541 found 295.0544.

(1,2,4-Thiadiazole-3,5-diyl)bis(p-tolylmethanone) (3b): Gummy liquid; 85 % Yield (R_f = 0.625 in Hexane/EtoAc 70 : 30 v/v); IR (KBr): ν_max(Nujol)/cm⁻¹ 2989, 1743, 1599, 1278; ¹H NMR (CDCl₃, 400 MHz) δ: 8.45 (d, J = 4.0 Hz, 2H, Ar-H), 8.11 (d, J = 8.0 Hz, 2H, Ar-H), 7.31–7.24 (m, 4H, Ar-H), 2.40 (s, 3H, CH₃), 2.38 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 188.4, 184.8, 182.8, 171.4, 139.0, 138.7, 135.6, 133.8, 131.6, 131.5, 128.9, 128.6, 21.7, 21.6; HRMS (ESI) [M+H]⁺ calculated C₁₈H₁₄N₂O₂S 323.0854 found 323.0856.

(1,2,4-Thiadiazole-3,5-diyl)bis((4-methoxyphenyl)methanone) (3c): Yellow solid; 85 % Yield (R_f = 0.5 in Hexane/EtOAc 70 : 30 v/v); mp: 135–136 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2986, 1740, 1598, 1276; ¹H NMR (CDCl₃, 400 MHz) δ: 8.59 (d, J = 8.0 Hz, 2H, Ar-H), 8.22 (d, J = 8.0 Hz, 2H, Ar-H), 6.97–6.92 (m, 4H, Ar-H), 3.84 (s, 6H, OCH₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 189.4, 183.6, 181.1, 172.0, 165.9, 165.1, 134.6, 134.2, 128.8, 127.0, 114.9, 114.5, 56.3, 56.2; HRMS (ESI) [M+H]⁺ calculated C₁₈H₁₄N₂O₄S 355.0753 found 355.0754.

(1,2,4-Thiadiazole-3,5-diyl)bis((3-methoxyphenyl)methanone) (3d): Yellow solid; 78 % Yield (R_f = 0.525 in Hexane/EtoAc 70 : 30 v/v); mp: 140–142 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2989, 1749, 1597, 1278; ¹H NMR (CDCl₃, 400 MHz) δ: 8.26 (d, J = 8.0 Hz, 1H, Ar-H), 8.04 (s, 1H, Ar-H), 7.83 (d, J = 4.0 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.47–7.40 (m, 2H, Ar-H), 7.21 (d, J = 4.0 Hz, 2H, Ar-H), 3.86 (s, 6H, (OCH₃)₂); ¹³C NMR (CDCl₃, 100 MHz) δ: 188.0, 184.1, 182.2, 170.9, 159.8, 159.6, 136.4, 134.6, 130.1, 129.7, 129.3, 124.3, 124.0, 114.8, 114.5, 114.4, 55.6, 55.3; HRMS (ESI) [M+H]⁺ calculated C₁₈H₁₄N₂O₄S 355.0753 found 355.0758.

(1,2,4-Thiadiazole-3,5-diyl)bis((4-bromophenyl)methanone) (3e): Yellow Solid; 68 % Yield (R_f = 0.55 in Hexane/EtOAc 70 : 30 v/v); mp: 178–180 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2995, 1748, 1600, 1271; ¹H NMR (CDCl₃, 400 MHz) δ: 8.42 (d, J = 8.0 Hz, 2H, Ar-H), 8.09 (d, J = 12.0 Hz, 2H, Ar-H), 7.66–7.61 (m, 4H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 192.0, 187.1, 185.5, 174.8, 138.0, 136.9, 136.6, 136.5, 136.2, 136.0, 135.3, 134.0; HRMS (ESI) [M+H]⁺ calculated C₁₆H₈Br₂N₂O₂S 449.8673 found 449.8675.

4,4′-(1,2,4-Thiadiazole-3,5-dicarbonyl)dibenzonitrile (3f): Yellow solid; 75 % Yield (R_f = 0.45 in Hexane/EtOAc 70 : 30 v/v); mp: 188–190 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2995, 2250, 1741, 1599, 1274; ¹H NMR (CDCl₃, 400 MHz) δ: 8.66 (d, J = 8.0 Hz, 2H, Ar-H), 8.35 (d, J = 8.0 Hz, 2H, Ar-H), 7.83–7.79 (m, 4H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 187.1, 182.3, 181.1, 170.2, 138.0, 136.2, 132.5, 132.2, 131.5, 131.2, 118.2, 117.6, 117.4, 117.3; HRMS (ESI) [M+H]⁺ calculated C₁₈H₈N₄O₂S 345.0446 found 345.0459.

(1,2,4-Thiadiazole-3,5-diyl)bis((4-nitrophenyl)methanone) (3g): Brown solid; 70 % Yield (R_f = 0.475 in Hexane/EtAc 70 : 30 v/v); mp: 194–196 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2982, 1725, 1585, 1276; ¹H NMR (CDCl₃, 400 MHz) δ: 8.73 (d, J = 9.2 Hz, 2H, Ar-H), 8.42 (d, J = 8.0 Hz, 2H, Ar-H), 8.36–8.16 (m, 4H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 191.6, 186.5, 185.4, 174.7, 155.8, 155.2, 144.1, 142.2, 136.7, 135.5, 128.7, 128.3; HRMS (ESI) [M+H]⁺ calculated C₁₆H₈N₄O₆S 385.0243 found 385.0245.

(1,2,4-Thiadiazole-3,5-diyl)bis((3-nitrophenyl)methanone) (3h): Yellow solid; 78 % Yield (R_f = 0.525 in Hexane/EtOAc 70 : 30 v/v); mp: 200–202 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2992, 1748, 1586, 1283; ¹H NMR (CDCl₃, 400 MHz) δ: 9.44 (s, 1H, Ar-H), 9.27 (s, 1H, Ar-H), 8.98 (d, J = 8.0 Hz, 1H, Ar-H), 8.67 (d, J = 8.0 Hz, 1H, Ar-H), 8.66–8.53 (m, 2H, Ar-H), 7.83–7.81 (m, 2H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 187.0, 181.1, 180.3, 169.9, 148.4, 136.7, 136.4, 136.2, 136.1, 134.5, 130.2, 129.8, 129.1, 128.2, 126.1, 125.8; HRMS (ESI) [M+H]⁺ calculated C₁₆H₈N₄O₆S 385.0243 found 385.0247.

(1,2,4-Thiadiazole-3,5-diyl)bis(furan-2-ylmethanone) (3i): Black Solid; 65 % Yield (R_f = 0.525 in Hexane/EtOAc 70 : 30 v/v); mp: 185–186 °C; IR (KBr): ν_max(Nujol)/cm⁻¹ 2996, 1743, 1596, 1276; ¹H NMR (CDCl₃, 400 MHz) δ: 8.32 (d, J = 4.0 Hz, 1H, Ar-H), 7.93 (d, J = 3.6 Hz, 1H, Ar-H), 7.83 (d, J = 0.8 Hz, 1H, Ar-H), 7.77 (d, J = 1.0 Hz, 1H, Ar-H), 6.67 (t, J = 4.0 Hz, 1H, Ar-H), 6.63 (t, J = 4.0 Hz, 1H, Ar-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 186.9, 170.0, 168.8, 150.5, 150.3, 149.1, 148.9, 126.4, 124.5, 124.4, 113.5, 112.9; HRMS (ESI) [M+H]⁺ calculated C₁₂H₆N₂O₄S 275.0127 found 275.0126.

3. Results and Discussion

At the outset, we prepared the required α-oxothioamides 2, based on our earlier reported protocol (Scheme 2).¹⁶ Thus, α-oxothioamides were obtained in good yields by the reaction of α-oxodithioesters 1 with stoichiometric amount of ammonium chloride in the presence of anhydrous sodium acetate in acetonitrile solvent.

Scheme 2.

Synthesis of α-oxothioamides.

Initially, we commenced a model reaction in an undivided cell by using NH₄I (10 mol%) as an electrolyte for the optimization of the reaction conditions in methanolic acetonitrile (1 : 1). Thus, 3,5-bis(benzoyl)-1,2,4-thiadiazole 3a was obtained in 62 % yield (Scheme 3, Table 1, entry 1). Later, change of supporting electrolyte by n-Bu₄NI (10 mol%) had changed the reaction efficiency and surprisingly 85 % yield of 3a was obtained (Table 1, entry 2). Reducing the amount of n-Bu₄NI to 5 mol% resulted in reduced product yield (Table 1, entry 3). The use of NaI (Table 1, entry 4) as electrolyte reduced the yield of product 3a to 15 %. Furthermore, we conducted an experiment without electrolyte (Table 1, entry 5), which yielded only trace amount of product 3a. This experiment demonstrated that electrolyte is essential for the oxidative cyclization of 2a. Further, a reaction in methanol alone gave only 20 % of 3a (Table 1, entry 6). Besides, in water only trace amount of product was obtained (Table 1, entry 7). In acetonitrile alone, 3a was formed in 55 % yield (Table 1, entry 8). While in a mixture of acetonitrile and water (1 : 1), and methanol and water (1 : 1), 3a was formed in 50 % and 45 % respectively (Table 1, entries 9 and 10). Overall, these studies indicated that 10 mol% of n-Bu₄NI is the optimal electrolyte for the formation of thiadiazole 3a. Further, electrolysis using n-Bu₄NClO₄ and n-Bu₄NBF₄ did not furnish any product, which indicated that iodide source is essential for the formation of 3a (Table 1, entries 11 and 12).

Scheme 3.

Synthesis of 3,5-bis(benzoyl)-1,2,4-thiadiazole.

Table 1. Reaction condition optimization for the synthesis of (1,2,4-thiadiazole-3,5-diyl)bis(phenylmethanone) 3a.

Entry	Solvent	Electrolyte	Yield (%)
1	CH3CN : CH3OH (1 : 1)	NH4I	62
2	CH3CN : CH3OH (1 : 1)	n-Bu4NI (10 mol%)	85
3	CH3CN : CH3OH (1 : 1)	n-Bu4NI (5 mol%)	45
4	CH3CN : CH3OH (1 : 1)	NaI	15
5	CH3CN : CH3OH (1 : 1)	—	Trace
6	CH3OH	n-Bu4NI	20
7	H2O	n-Bu4NI	Trace
8	CH3CN	n-Bu4NI	55
9	CH3CN : H2O	n-Bu4NI	50
10	CH3OH : H2O	n-Bu4NI	45
11	CH3CN : CH3OH (1 : 1)	n-Bu4NClO4	0
12	CH3CN : CH3OH (1 : 1)	n-Bu4NBF4	0

With the optimized reaction condition in hand, we next investigated the substrate scope for the synthesis of 1,2,4-thiadiazoles (Scheme 4, Table 2). Thus, various α-oxothioamides 2, bearing electron donating groups (methyl, methoxy, bromo) at meta and para positions furnished 1,2,4-thiadiazoles 3b-e in 68–85 % yield (Table 2, entries 2–5). After that, we performed cyclization reactions using various α-oxothioamides having electron withdrawing substituents (nitrile and nitro) on meta-/para-positions yielded 1,2,4-thiadiazoles 3f-h in 70–78 % (Table 2, entries 6–8). Furthermore, the heteroaryl substituted thioamide (R = 2-furyl) proceeded smoothly to give corresponding product 3i in 65 % yield (Table 2, entry 9).

Scheme 4.

Synthesis of 3,5-bis(acyl)-1,2,4-thiadiazole.

Table 2. Substrate scope.

Entry	R (2,3)	3	% Yield
1	C6H5	3a	85
2	4-MeC6H4	3b	85
3	4-MeOC6H4	3c	85
4	3-MeOC6H4	3d	78
5	4-BrC6H4	3e	68
6	4-CNC6H4	3f	75
7	4-NO2C6H4	3g	70
8	3-NO2C6H4	3h	78
9	2-Furyl	3i	65

Reaction conditions: Reticulated vitreous carbon (RVC) anode, Pt plate cathode, undivided cell, constant current = 10 mA, 2a (0.5 mmol), n-Bu₄NI (10 mol%), MeOH (2.5 mL) and MeCN (2.5 mL), 1.5–2 h.

The derivatives of all 1,2,4-thiadiazole are confirmed by IR, NMR and HRMS. We failed to synthesize 1,2,4-thiadiazoles with substituents at ortho position and aliphatic substituents since we were unable to synthesize the corresponding ortho position substituted and aliphatic α-oxothioamides. These are the limitations of this method. Further, synthesis of 3a was performed in 5 mmol scale which afforded usual product in 83 % yield.

Finally, we constructed an experiment under optimized reaction condition, in which two different α-oxothioamides 2b and 2c were treated with n-Bu₄NI which afforded an inseparable mixture of (1,2,4-thiadiazole-3,5-diyl)bis((4-methoxyphenyl)methanone) 3c, 4,4′-(1,2,4-thiadiazole-3,5-dicarbonyl)dibenzonitrile 3f, 4-(3-(4-methoxybenzoyl)-1,2,4-thiadiazole-5-carbonyl)benzonitrile 3j and 4-(5-(4-methoxybenzoyl)-1,2,4-thiadiazole-3-carbonyl)benzonitrile 3k in 20 %, 20 %, 15 % and 18 % respectively which are observed in LCMS (Scheme 5). The ORTEP diagram for one of the thiadiazoles (1,2,4-thiadiazole-3,5-diyl)bis(furan-2-ylmethanone) 3i is given in Fig. 2.⁴⁷

Scheme 5.

Heterocyclization of different α-oxothioamides.

Figure 2.

ORTEP diagram of thiadiazole 3i.

Based on the previous reports^16,31 we proposed a plausible mechanism for the electrolytic oxidative dimerization of α-oxothioamides 2 to get 1,2,4-thiadiazoles in Scheme 6. First, at anode, the iodide was oxidized to I₂ by the loss of two electrons. Subsequently this iodine reacted with substrate 4 (tautomer of 2) to furnish intermediate 5. The intermediate 5 and another thioamide 2 undergo an intermolecular nucleophilic substitution to form intermediate 6. Finally, intramolecular cyclization in 6 and aromatization of intermediate 7 via the cathodic elimination of hydrogen sulfide afforded the desired product 3.

Scheme 6.

Plausible mechanism of formation of 3,5-diacyl-1,2,4-thiadiazoles.

4. Conclusions

In summary, we have demonstrated a new strategy for the synthesis of various 3,5-diacyl-1,2,4-thiadiazoles through the n-Bu₄NI-mediated oxidative dimerization of α-oxothioamides. The generality of the protocol was exemplified by using various α-oxothioamides bearing electron donating, withdrawing and heteroaryl substituents. Finally, a reaction between two different α-oxothioamides with the assistance of n-Bu₄NI as a mediator yielded all four possible expected 1,2,4-thiadiazoles. This method is superior over our previously reported method which used equivalent amount of iodine (oxidant).¹⁶ Only, catalytic amount of iodine source is enough to achieve this transformation and hence atom economy of the method is high. Further, applications of α-oxothioamides for the synthesis of various heterocycles are underway in our laboratory.

Acknowledgment

RNS thanks IOE Project (Vide No. MVV./IOE/PROJECT FELLOW/ 684 /2019-20) Dated 01.01.2020. KSR thanks Indian Science Congress Association (ISCA) for providing Asutosh Mookerjee Fellowship and CSIR for Emeritus scientist fellowship.

Data Availability Statement

The data that support the findings of this study are openly available under the terms of the designated Creative Commons License in J-STAGE Data at https://doi.org/10.50892/data.electrochemistry.24751959.

• 1) An electrochemical synthesis of 3,5-bis(acyl)-1,2,4-thiadiazoles by the oxidative dimerization of α-oxothioamides with assistance of tetra-n-butylammonium iodide (TBAI) as electrolyte and mediator under constant current electrolysis (CCE) is reported. Herein, this approach is an example for S–N bond construction through the electrochemical method. Furthermore, the required intermediates α-oxothioamides are synthesized by the reaction of α-oxodithioesters with ammonium chloride in the presence of sodium acetate. The probable mechanism for the formation of final products is also presented. This strategy resulted in good to excellent yields of title compounds.

CRediT Authorship Contribution Statement

Mahadev Shivaraj: Methodology (Equal)

Rajaghatta N Suresh: Methodology (Equal)

Toreshettahally R Swaroop: Conceptualization (Equal)

Manikyanahally N Kumara: Supervision (Equal)

Kanchugarakoppal S Rangappa: Supervision (Lead)

Kempegowda Mantelingu: Supervision (Supporting)

Adaganahalli Boregowda Mamatha Devi: Methodology (Lead)

Madihalli Prasanna Manasa: Methodology (Lead)

Muddegowda Umashankara: Supervision (Equal)

Conflict of Interest

The authors declare no conflict of interest in the manuscript.

Funding

IOE Project: MVV./IOE/PROJECT FELLOW/ 684 /2019-20

Footnotes

M. Shivaraj and R. N Suresh: Both authors contributed equally.

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