A metal-free and a solvent-free synthesis of thio-amides and amides: an efficient Friedel–Crafts arylation of isothiocyanates and isocyanates

Abstract

A rapid, metal-free and solvent-free (very low loading of solvent in few cases) reaction conditions for synthesizing thioamides and amides using a Bronsted super acid such as triflic acid has been developed. This method shows a broad substrate scope with a variety of electron-rich arenes including thiophene derivatives. The reaction works well for both aromatic as well as aliphatic isothiocyanates. Most of the thioamides are obtained in excellent yields in short reaction times and in most of the examples, a simple work up procedure has been developed which does not require further purification.

---

Introduction

Thioamides are important structural motifs that are found in a variety of biologically active molecules¹ and are building blocks for a number of pharmaceutically active compounds.² Although a very few thioamide derivatives are found in natural products,³ one of the best-known among them is closthioamide, which is a potent antibiotic.^3,4 It has been demonstrated by the Hertweck group that the thioamide functional group in the closthioamide is responsible for the antibiotic properties of closthioamide, whereas the corresponding amide analogue, closamide, is not a potent antibiotic.⁴ Thioamides also find innumerous application as important precursors and intermediates in organic synthesis, which can be attributed to their reactivity.⁵ Further, thioamides are important precursor for synthesizing a variety of pharmaceutically important compounds such as 1,3,5-triazine-2,4-(1H,3H)-diones,⁶ triones,⁷ 4-aminoquinazoline derivatives,⁸ 2-aryl benzothiazoles,⁹ tetrazoles¹⁰ and metal–complex ligand such as mesoionic thiazol-5-ylidenes¹¹ (Scheme 1A). Further, they find utility in asymmetric synthesis,¹² vulcanizing agents, lubrication agents etc.¹³ Thioamides serve as important ligands and are known to selectively chelate with metal ions.¹⁴ Recently, thioamides were found to exhibit supra molecular polymerization, which is useful in designing novel supra molecular scaffolds.¹⁵ The drug molecules used for the treatment of mycobacterium infection (tuberculosis and leprosy) invariably contain thioamide moieties (Scheme 1B).¹⁶

Scheme 1 Utility of thioamides.

Although, there are number of methods available for synthesizing thioamides, the synthesis of thioamide is still a challenging task. The conventional method of thionation of amides for synthesizing thioamides employs Lawesson's reagent or P₄S₁₀.¹⁷ Similarly, aldehydes, ketones carboxylic acids and nitriles are converted to their thioamides using reagents such as thioacetamide, thioacid, dithiophosphoric acid etc.¹⁸ Other widely used method for the synthesis of thioamide is the Willgerodt–Kindler reaction, which employs ketones, elemental sulfur and secondary amines.¹⁹ However, most of these methods suffer from limitations such as cumbersome isolation methods, tedious purification procedures and more importantly the by-products of these reactions, which is generated in substantial amount, needs proper disposable measures. Very commonly used sulfur transferring reagents such as Lawesson's reagent and P₄S₁₀ are very foul smelling, hazardous, and need proper care and handling till purification of the desired product. Considering the environmental impact and difficulties associated in handling and disposal of these hazardous wastes, the user-friendly and green methods are well sought for synthesizing thioamides. Interestingly, the reaction between phenylisothiocyanate and arene under Friedel–Crafts conditions is useful method employed for the synthesis of thioamide (Gattermann reaction),²⁰ which has been modified over the time.^21,22 For example, thioamides and their derivatives have been synthesized by Jagodzinski using improved reaction conditions which showed a broad substrate scope.²² However, these Friedel–Crafts and related methods are also associated with the problems of generating a large amount of aluminum wastes, use of hazard solvent like CS₂ and often result in low yields of the products. Due to these reasons, synthesis of thioamides, still remain as a challenging task. In pursuit of our quest in developing new strategies for synthesizing a variety of sulfur and phosphorous compounds,²³ herein we report a synthesis of thioamides and amides using a simple, rapid and high yielding method that involves reusable catalyst,²⁴ and readily available starting materials with broad substrate scope. Additionally, a simple method for purification is developed (Scheme 2) and moreover, this method does not generate hazardous waste materials and the TfOH can be recycled.

Scheme 2 Synthesis of thioamides.

Results and discussion

The studies were started with a proposal that the isothiocyanates can react with aromatic systems in the presence of Bronsted acids to form the corresponding thioamides. Hence we began screening studies by treating phenylisothiocyanate (1a, 1 equiv.) with excess of TfOH (5 equiv.) and excess of anisole (2a, 5 equiv.) at ambient conditions. The reaction proceeded well to furnish the corresponding thioamide (3aa) in near quantitative yield in 10 min (96%, entry 1, Table 1). Interestingly, the product was isolated in good purity by filtration after quenching the reaction mixture with water (5 mL). Further screening study was continued to find the suitability of other mineral acids. Although, the similar reaction with H₂SO₄ was promising, the reaction required large amount of acid, excess of anisole and longer reaction time (entries 2–5, Table 1). The reaction with con. HCl was not fruitful in forming the product 3aa (entry 6, Table 1). Nevertheless, the reactions using HClO₄ afforded the thioamide in 80% yield (entries 7 and 8). Similarly, the reaction of 1a with 2a using organic acids such as CH₃COOH, TFA, MeSO₃H, or PTSA, formed the corresponding thioamide in lower yields (entries 9–13, Table 1). With the lead that the TfOH serves better than other acids, further optimization studies were conducted to find the optimal reaction conditions using TfOH (entries 14–21). Although, most of the reactions proceeded well under the solvent-free conditions, in few cases the yields obtained in the solvent-free reactions were low. Therefore, solvent screening studies revealed that DCE is the most suitable solvent for the reaction whereas solvents such as CH₃CN, THF, DMF, and DMSO, or acetone are not suitable solvents as the reactions in these solvents did not afford the expected product (entries 22–30, Table 1). These studies revealed that the reaction of phenylisothiocyanate (1a, 1 equiv.) and anisole (2a, 1.5 equiv.) in TfOH (2 equiv.) at ambient temperature can lead to the corresponding thioamide (3aa) in 5 min (entry 19, Table 1).

Table 1 Screening studies^a

Entry	2a (equiv.)	Bronsted acid (equiv.)	Solvent^b	Time	Yield^c (%)
a Reaction conditions: 1a (1 mmol).b 0.5 mL of solvent was used.c Isolated yields, nr = no reaction.
1	5	TfOH (5)	None	10 min	96
2	5	H2SO4 (2)	None	12 h	57
3	5	H2SO4 (10)	None	12 h	70
4	5	H2SO4 (20)	None	12 h	70
5	1.5	H2SO4 (10)	None	12 h	40
6	5	HCl (10)	None	12 h	nr
7	5	HClO4 (10)	None	12 h	80
8	1.5	HClO4 (10)	None	12 h	Trace
9	5	CH3COOH	CH3COOH	12	nr
10	5	TFA (5)	None	12 h	Trace
11	1.5	CH3SO3H (2)	None	10 min	4
12	1.5	CH3SO3H (2)	None	12 h	16
13	1.5	PTSA (2)	None	12 h	nr
14	5	TfOH (2)	None	10 min	95
15	5	TfOH (1)	None	2 h	65
16	1	TfOH (2)	None	10 min	79
17	1.3	TfOH (2)	None	10 min	83
18	1.5	TfOH (2)	None	10 min	96
19	1.5	TfOH (2)	None	5 min	96
20	1.5	TfOH (2)	None	2 min	58
21	1.5	TfOH (1.5)	None	10 min	65
22	1.5	TfOH (2)	DCE	5 min	69
23	1.5	TfOH (2)	DCE	10 min	89
24	1.5	TfOH (2)	DCE	15 min	89
25	1.5	TfOH (2)	DCM	15 min	nr
26	1.5	TfOH (2)	CH3CN	15 min	nr
27	1.5	TfOH (2)	THF	15 min	nr
28	1.5	TfOH (2)	DMF	15 min	nr
29	1.5	TfOH (2)	DMSO	15 min	nr
30	5	TfOH (2)	Acetone	15 min

---

The scope of this reaction was explored and the results are presented in the following section. A variety of electron rich arenes (2a–2j) were reacted with phenyl isocyanate (1a) under the optimal reaction conditions. As can be seen in Table 2, anisole (2a) and 1,2-dimethoxybenzene (2b) underwent a facile reaction with phenylisothiocyanate (1a) in a solvent-free conditions furnishing the corresponding thioamides 3aa and 3ab in 96 and 98% yield, respectively. However, the reaction of 1a with phenol (2c) 2,6-dimethylphenol (2d), pyrocatechol (2e), and 2-methoxyphenol (2f) required DCE as the solvent to afford the corresponding thioamides 3ac, 3ad, 3ae, and 3af in good yields (67, 90, 79 and 79% respectively). Although the solvent-free reactions of 1a with diphenyl ether (2g), and methyl(phenyl)sulfane (2h), resulted in the formation of their thioamides 3ag, and 3ah in lower yields (28 and 28%, respectively). However, the same reactions in the solvent DCE resulted in the formation of thioamides 3ag, and 3ah in 99, and 78%, yields, respectively. The bromosubstituted substrate such as 2-bromophenol (2i) was less reactive under the optimal reaction conditions and afforded the corresponding thioamide 3ai in moderate yield (56%). As expected, the reaction of phenylisothiocyanate (1a) with tert-butylbenzene (2j) resulted in the formation of the corresponding thioamide (3aj) in low yield (10%).

Table 2 Reaction of electron-rich arenes with phenylisothiocyanate^a

a Reaction conditions: 1a (1 mmol), 2 (arenes, 1.5 mmol).b Isolated yields.c Solvent free reaction (5–10 min).d Solvent free reaction (1 h).e DCE (0.5 mL, 10–15 min).f tert-Butyl benzene (1 mL, 60 °C, 6 h). rt = room temperature.

---

Further scope of this reaction was explored by treating a variety of isothiocyanates with anisole or phenol derivatives and results are presented in Table 3. A variety of aromatic isothiocyanates containing electron-donating or electron-withdrawing groups on phenyl ring underwent a facile reaction with electron rich arenes to furnish their corresponding thioamides in excellent yields. Hence, a solvent-free reaction of 1-isothiocyanato-4-methylbenzene (1b) with anisole (2a) proceeded well to furnish the corresponding thioamide 3ba in 95% yield. Similarly, a variety of aromatic isothiocyanates such as 1-isothiocyanato-4-methylbenzene (1b), 1-isothiocyanato-3,5-dimethylbenzene (1c),2-isothiocyanatonaphthalene (1d),1-isothiocyanato-4-methoxybenzene (1e), and 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (1f) reacted well with 1,2-dimethoxybenzene (2b) under a solvent-free condition to afford the corresponding thioamides 3bb, 3cb, 3db, 3eb, and 3fb in good to excellent yields (95, 98, 81, 93, and 98% yields, respectively). The reaction of anisole (2a) with isothiocyanates such as 1-chloro-4-isothiocyanatobenzene (1g), 1-isothiocyanato-3-nitrobenzene (1h), and 1-isothiocyanato-4-nitrobenzene (1i) in DCE furnished their corresponding thioamides 3ga, 3ha, and 3ia in 85, 83 and 85% yields, respectively. The reaction of pyrocatechol (2e) with 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (1f) in DCE resulted in the formation of the thioamide 3fe in near quantitative yield (99% yield). The reaction of aliphatic isothiocyanate such as cyclohexyl isothiocyanate (1j) was found to proceed well with 1,2-dimethoxyanisole (20b) and 2,6-dimethylphenol (2h) to give the corresponding thioamides 3jb and 3jd in excellent yields (96% and 80%, respectively). These successful reaction of pyrocatechol (1g) and dimethylphenol (2h) with isocyanates indicate that the reaction of phenols is facile and OH group survives the reaction conditions.

Table 3 Reaction of substituted isothiocyanates^a

a Reaction conditions: 1a (1 mmol), 2 (arenes, 1.5 mmol).b Isolated yields.c Solvent-free reaction (5–10 min).d DCE (0.5 mL, 10–15 min).e Solvent-free reaction (30 min). rt = room temperature.

---

The successful reaction of a variety of isothiocyanates with electron rich arenes such as anisole and phenol derivatives led us to explore the reaction of isothiocyanates with unactivated heteroaromatic compounds such as thiophene and its derivatives. As can be seen in Table 4, the reaction of isothiocyanates with thiophene and its derivatives is highly regioselective and a new –C=S bond is formed exclusively at C-2 carbon of thiophene. The reaction of phenylisothiocyanate (1a) with thiophene (4a), 2-methylthiophene (4b), and 3-methylthiophene (4c), under a solvent-free condition, resulted in the formation of the corresponding thiocyanates 5aa, 5ab, and 5ac in good to moderate yields (89, 91, and 53%, respectively). The reaction of isothiocyanates 1-isothiocyanato-4-methoxybenzene (1e), and 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (1f) with thiophene (4a) furnished their corresponding thioamides 5ea (58%) and 5fa (81%). Under the optimal reaction conditions, aliphatic isothiocyanate such as cyclohexylisothiocyanate (1j) underwent a facile reaction with thiophene (4a) and furnished its thioamide 5ad in excellent yield (90%). The reaction of 2,5-dimethylthiophene (4d) with phenylisothiocyanate (1a) was also proceeded successfully and afforded the corresponding thioamide 5ad in good yield (90%).

Table 4 Reaction of thiophene derivatives with isothiocyanates^a

a Reaction conditions: 1 (1 mmol), 4 (1.5 mmol).b Isolated yields, rt = room temperature.

---

After successful synthesis of thioamides, we turned our attention towards the similar reactions of isocyanates to explore the possibility of synthesizing amides (Table 5). Although, amides are easily accessible via a nucleophilic substitution reaction between acyl halides with amines, the present strategy provides an alternative method using Friedel–Crafts type reaction of isocyanate as the amide source to form the corresponding amide. Interestingly, literature survey revealed that there are only a few reports known for the reaction of isocyanates with arenes to obtain amides by employing metal catalysts.²⁵ As the present strategy provides an opportunity of rapid reaction between isocyanate and electron rich arenes and thiophene, to form amides, following experiments have been performed. As can be seen in Table 5 the phenyl isocyanate (6a) reacted rapidly (<5 min) with 1,2-dimethoxybenzene (2a), and thiophene (4a) under solvent-free conditions at room temperature to form 7, and 8 in excellent yields (93, and 87%, respectively). However, the similar reaction of aliphatic isocyanate such as isopropylisocyanate with thiophene in DCE resulted in the formation of the corresponding amide 9 in excellent yield (92%).

Table 5 Reaction of isocyanates with electron-rich arenes and thiophene^a

a Reaction conditions: 6 (1 mmol), arenes (1.5 mmol).b Isolated yields.c Solvent free reaction (<5 min).d DCE (0.5 mL, 10 min).

---

As isothiocyanates in a reaction with phenol under optimal conditions furnished their corresponding thioamides (Tables 2 and 3), we performed a similar reaction of phenylisocyanate (6a) with phenol (2c) under the optimal reaction conditions. Contrary to our expectation, this reaction furnished the corresponding carbamate 10 in 70% yield (Scheme 3).

Scheme 3 Reaction of isocyanate with phenol.

The application of this methodology of synthesizing thioamide has been exemplified in performing a reaction at preparative scale (Scheme 4). Hence, the reaction of phenylisothiocyanate (1a, 1 g, 7.41 mmol) and anisole (2a, 1.04 g, 9.63 mmol, 1.3 equiv.) was performed in solvent-free conditions. As can be seen, the reaction of 1a and 2a under solvent-free conditions at room temperature formed the corresponding thioamide 3aa in excellent yield (96%, 10 min). A comparison of the reaction of anisole and phenylisothiocyanate in TfOH and H₂SO₄ has been shown in Scheme 3. As can be seen, the reaction using H₂SO₄ required excess of anisole (2a, 5 equiv.) and extended reaction time (12 h) to furnish the corresponding thioamide in 81% yield.

Scheme 4 Preparative scale experiment.

Conclusions

In summary, we have explored a metal-free Friedel–Crafts type reaction of isothiocyanates and isocyanates with aromatic systems to obtain the corresponding thioamides as well as amides. The salient feature of these reactions are the reactions are carried out in the absence of solvents and the work-up procedure is very simple, and the reaction furnishes almost analytically pure products, which are isolated by simple filtration and does not need further purification. As thioamides are important building blocks for the synthesis of pharmaceutically important compounds and are useful biologically active compounds, this approach would be attractive and useful. A preparative scale synthesis has been shown to work equally well.

Experimental section

General experimental procedure for synthesis of thioamides (3aa, 3ab, 3ad, 3ae, 3ag, 3aj, 3ba–3jh – 18 example)

To a well-stirred, ice cold mixture of isothiocyanate (1 mmol) and arene (1.5 mmol) was added TfOH (2 mmol, 0.18 mL) drop wise during 1 min. The ice bath was then removed and the reaction mixture was stirred for 5–10 min at room temperature (the reaction mixture was stirred for 10–15 min while 0.5 mL of DCE was used as solvent). The reaction was quenched by adding water (3–5 mL) drop wise. The yellow solid precipitated out was filtered through a sintered funnel, washed with hexane (15 mL) and dried to afford pure yellow solid of expected thioamide.

Note 1. If the reaction mixture could not be stirred efficiently or when one of the reactants was a solid (isothiocyanate or arene), then DCE (0.3–0.5 mL for 1 mmol of isothiocyanate) was used as solvent to ensure proper stirring during the course of the reaction. For the synthesis of compounds such as 3ac, 3ad, 3ae, 3ha, 3ia, 3fg and 3jh the DCE (0.5 mL) was used as solvent.

Note 2. When DCE was used as solvent, the reaction mixture was stirred for 10–15 minutes; the reaction mixture was quenched by adding water (3–5 mL) drop wise and followed by addition of 20 mL excess of water. The crude compound was extracted into DCM (10 mL × 3) and the combined organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated, the yellow solid formed was filtered through a sintered funnel, washed with hexane (15 mL) and dried to afford pure yellow solid of expected thioamide.

Note 3. When the product was not well-precipitated after quenching with water, then 20 mL excess of water was added into the reaction mixture, the crude compound was extracted into DCM (10 mL × 3) and the combined organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated and the yellow solid formed was filtered through sintered funnel, washed with hexane (15 mL) and dried.

Note 4. The compounds such as 3ac, 3af, 3ai, 5aa, 5ab, 5ac, 5da, 5fa, 5ja, 5ad, 8 and 9 were obtained after purifying the crude compound by silica gel column chromatography.

Gram-scale synthesis of 4-methoxy-N-phenylbenzothioamide (3aa)

Procedure 1 (condition A). To a well-stirred, ice cold mixture of isothiocyanate (1 g, 7.41 mmol) and anisole (1.04 g, 9.63 mmol, 1.30 equiv.) was added TfOH (14.82 mmol, 2 equiv., 1.30 mL) drop wise during 3 min. The ice bath was then removed and the reaction mixture was stirred for 10 min. The reaction mixture was quenched by adding ice-cold water (50 mL) slowly over a period of 1–2 min. The yellow solid precipitated was filtered through a sintered funnel, washed with hexane (50 mL) and dried to afford pure yellow solid of 4-methoxy-N-phenylbenzothioamide (3aa) in 96% yield (1.73 g).

Procedure 1 (condition B). To a well-stirred, ice cold mixture of isothiocyanate (1 g, 7.41 mmol) and anisole (4.0 g, 37.05 mmol, 5.0 equiv.) was added H₂SO₄ (74.1 mmol, 10 equiv., 3.95 mL) drop wise during 5 min. The ice bath was then removed and the reaction mixture was stirred for 12 h. The reaction mixture was quenched by adding ice-cold water (50 mL) slowly over the period of 1–2 min. The yellow solid precipitated was filtered through a sintered funnel, washed with hexane (20–30 mL) and dried to afford pure yellow solid of 4-methoxy-N-phenylbenzothioamide (3aa) in 81% yield (1.46 g).

General experimental procedure for synthesis of amide (7, 8 and 9)

To a well-stirred, ice cold mixture of isocyanate (1 mmol) and arene (1.5 mmol) was added TfOH (2 mmol, 0.18 mL) drop wise during 1 min. The ice bath was then removed and the reaction mixture was stirred for 5 min (the reaction mixture was stirred for 10 min while using 0.5 mL of DCE as solvent). Then the reaction mixture was quenched by adding water (3–5 mL) drop wise. The white solid precipitated out was filtered through sintered funnel, washed with warm water (15–20 mL) followed by hexane (15–20 mL) and dried to afford white solid.

Note 5. The compound 7 was not further purified after filtration. The compounds 8 and 9 were obtained as a white solid by filtration and further purified by silica gel column chromatography (eluent 10–30% ethyl acetate/hexane).

Note 6. For the reaction between isopropyl isocyanate (6b) and thiophene (5a) the DCE 0.3 mL was used as solvent.

Experimental procedure for synthesising carbamate (10)

To a well-stirred, ice cold solution of phenyl isocyanate (6a, 1 mmol) and phenol (2c, 1.5 mmol) in DCE (0.3 mL) was added TfOH (2 mmol, 0.18 mL) drop wise during 1 min. The ice bath was then removed and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched by adding water (3–5 mL) drop wise followed by the addition of 30 mL of water and the crude compound was extracted into DCM (10 mL × 3). The combined organic layer was dried over anhydrous Na₂SO₄. The crude compound was purified by silica gel chromatography (eluent: 10% EtOAc/hexane) to afford the product 10 in 70% yield.

4-Methoxy-N-phenylbenzothioamide (3aa)^22b. Yellow solid; yield – 92% (224 mg); mp: 156–158 °C (lit.^20b 153–154 °C); R_f (30% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3154, 1601, 1507, 1346, 1248. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.54 (brs, 1H), 7.91 (d, J = 6.9 Hz, 2H), 7.77 (d, J = 6.0 Hz, 2H), 7.43 (s, 2H), 7.26 (s, 1H), 7.01 (d, J = 7.2 Hz, 2H), 3.83 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.4, 161.6, 140.2, 134.6, 129.5, 128.4, 126.0, 124.5, 113.1, 55.5. ESI-HRMS (m/z): calculated for C₁₄H₁₃NOS (M + Na): 266.0616, found (M + Na): 266.0615.

3,4-Dimethoxy-N-phenylbenzothioamide (3ab). Yellow solid; yield – 98% (267 mg); mp: 168–170 °C (lit²⁶ 159 °C); R_f (30% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3159, 1596, 1510, 1329, 1269, 1145. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.49 (brs, 1H), 7.74 (d, J = 7.5 Hz, 2H), 7.54 (s, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 3.83 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.4, 151.4, 147.7, 140.2, 134.4, 128.4, 126.1, 124.7, 120.8, 111.4, 110.6, 55.7, 55.5. ESI-HRMS (m/z): calculated for C₁₅H₁₅NO₂S (M + Na): 296.0721, found (M + Na): 296.0724.

4-Hydroxy-N-phenylbenzothioamide (3ac)^22b. Yellow solid; yield – 67% (77 mg); mp: 161–163 °C (lit.^21b 164–165 °C); R_f (30% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3310, 3226, 1599, 1504, 1361, 1192, 1165. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.42 (brs, 1H), 10.11 (brs, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.7, 160.4, 140.3, 133.1, 129.8, 128.4, 126.0, 124.6, 114.5. ESI-HRMS (m/z): calculated for C₁₃H₁₁NOS (M + Na): 252.0459, found (M + Na): 252.0454.

4-Hydroxy-3,5-dimethyl-N-phenylbenzothioamide (3ad). Yellow solid; yield – 90% (231 mg); mp: 184–186 °C; R_f (20% EtOAc/hexane) 0.25; IR (KBr, cm⁻¹): 3378, 3180, 1595, 1520, 1495, 1484, 1313, 1170. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.37 (brs, 1H), 8.92 (brs, 1H), 7.75 (d, J = 6.6 Hz, 2H), 7.56 (s, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.0 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 197.0, 156.4, 140.4, 133.1, 128.3, 128.2, 125.9, 124.5, 123.3, 16.7. ESI-HRMS (m/z): calculated for C₁₅H₁₅NOS (M + Na): 280.0772, found (M + Na): 280.0775.

3,4-Dihydroxy-N-phenylbenzothioamide (3ae). Yellow solid; yield – 79% (97 mg); mp: 161–163 °C; R_f (30% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3243, 1599, 1503, 1268, 1145, 1021. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.36 (brs, 1H), 9.45 (brs, 2H), 7.73 (s, 2H), 7.42–7.40 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 6.78 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.9, 148.9, 144.5, 140.4, 133.6, 128.4, 125.9, 124.5, 119.2, 116.1, 114.5. ESI-HRMS (m/z): calculated for C₁₃H₁₁NO₂S (M + Na): 268.0408, found (M + Na): 268.0408.

4-Hydroxy-3-methoxy-N-phenylbenzothioamide (3af). Yellow solid; yield – 78% (202 mg); mp: 158–160 °C; R_f (30% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3175, 1591, 1505, 1274, 1173. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.40 (brs, 1H), 9.74 (brs, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.54 (s, 1H), 7.46–7.40 (m, 3H), 7.25 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.6, 149.9, 146.7, 140.3, 133.1, 128.4, 126.1, 124.8, 121.4, 114.5, 112.1, 55.7. ESI-HRMS (m/z): calculated for C₁₄H₁₃NO₂S (M + Na): 282.0565, found (M + Na): 282.0565.

4-Phenoxy-N-phenylbenzothioamide (3ag)^22b. Yellow solid; yield – 99% (302 mg); mp: 131–132 °C (lit^22b 127–129 °C); R_f (10% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3337, 1591, 1500, 1490, 1347, 1264. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.67 (brs, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.47–7.41 (m, 4H), 7.28–7.20 (m, 2H), 7.10 (d, J = 7.5 Hz, 2H) 7.04 (d, J = 7.7 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.3, 159.4, 155.7, 140.1, 137.2, 130.3, 129.7, 128.5, 126.2, 124.35, 124.31, 119.5, 117.1. ESI-HRMS (m/z): calculated for C₁₉H₁₅NOS (M + Na): 328.0772, found (M + Na): 328.0770.

4-(Methylthio)-N-phenylbenzothioamide (3ah). Yellow solid; yield – 78% (202 mg); mp: 162–163 °C; R_f (20% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3152, 1587, 1521, 1338, 1249. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.67 (brs, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 7.28 Hz, 1H), 2.53 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.5, 142.4, 140.1, 138.4, 128.5, 128.1, 126.2, 124.6, 124.4, 14.3. ESI-HRMS (m/z): calculated for C₁₄H₁₃NS₂ (M + Na): 282.0387, found (M + Na): 282.0388.

3-Bromo-4-hydroxy-N-phenylbenzothioamide (3ai). Yellow solid; yield – 56% (172 mg); mp: 174–176 °C; R_f (30% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3345, 3115, 1594, 1532, 1497, 1405. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.56 (brs, 1H), 11.00 (brs, 1H), 8.06 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.20 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 194.9, 156.9, 140.1, 134.3, 132.3, 129.0, 128.5, 126.2, 124.5, 115.3, 108.6. ESI-HRMS (m/z): calculated for C₁₃H₁₀BrNOS (M + Na): 329.9564, found (M + Na): 329.9564.

4-(tert-Butyl)-N-phenylbenzothioamide (3aj)^22b. Yellow solid; yield – 16% (43 mg); mp: 131–132 °C (lit^22b 136–137 °C); R_f (5% EtOAc/hexane) 0.5; IR (KBr, cm⁻¹): 1618, 1586, 1340, 1261, 1207. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.67 (brs, 1H), 7.85 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.14 Hz, 1H), 1.32 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 197.4, 153.6, 140.1, 128.4, 127.3, 126.1, 124.8, 123.9, 34.6, 30.9. ESI-HRMS (m/z): calculated for C₁₇H₁₉NS (M + Na): 292.1136, found (M + Na): 292.1136.

4-Methoxy-N-(p-tolyl)benzothioamide (3ba). Yellow solid; yield – 95% (244 mg); mp: 174–176 °C (lit.²⁷ 172 °C); R_f (20% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3164, 1600, 1510, 1244. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.47 (brs, 1H), 7.9 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 3.83 (s, 3H), 2.32 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.1, 161.6, 137.7, 135.3, 134.6, 129.4, 128.8, 124.4, 113.1, 55.4, 20.7. ESI-HRMS (m/z): calculated for C₁₅H₁₅NOS (M + Na): 280.0772, found (M + Na): 280.0768.

3,4-Dimethoxy-N-(p-tolyl)benzothioamide (3bb). Yellow solid; yield – 95% (273 mg); mp: 163–165 °C; R_f (20% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3197, 1596, 1512, 1269, 1145. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.43 (brs, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.53 (s, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 3.83 (s, 6H), 2.32 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.1, 151.3, 147.7, 137.7, 135.4, 134.4, 128.8, 124.6, 120.8, 111.4, 110.5, 55.7, 55.5, 20.7. ESI-HRMS (m/z): calculated for C₁₆H₁₇NO₂S (M + Na): 310.0878, found (M + Na): 310.0876.

N-(3,5-Dimethylphenyl)-3,4-dimethoxybenzothioamide (3cb). Yellow solid; yield – 98% (295 mg); mp: 156–157 °C; R_f (30% EtOAc/hexane) 0.5; IR (KBr, cm⁻¹): 3195, 1595, 1513, 1274, 1173, 1145. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.40 (brs, 1H), 7.54–7.52 (m, 2H), 7.34 (s, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 3.83 (s, 6H), 2.29 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.3, 151.3, 147.7, 140.1, 137.5, 134.5, 127.6, 122.4, 120.9, 111.3, 110.6, 55.7, 55.5, 20.9. Calculated for C₁₇H₁₉NO₂S (M + Na): 324.1034, found (M + Na): 324.1033.

3,4-Dimethoxy-N-(naphthalen-2-yl)benzothioamide (3db). Yellow solid; yield – 81% (262 mg); mp: 151–153 °C; R_f (30% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3243, 1599, 1503, 1347, 1268, 1145. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.70 (brs, 1H), 8.01–7.96 (m, 2H), 7.82–7.77 (m, 3H), 7.55 (brs, 4H), 7.10 (s, 1H), 3.87 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 198.5, 151.7, 147.8, 136.9, 133.8, 132.9, 129.2, 128.2, 127.6, 126.4, 126.3, 125.4, 123.2, 121.2, 111.5, 110.6, 55.8, 55.6. ESI-HRMS (m/z): calculated for C₁₉H₁₇NO₂S (M + Na): 346.0878, found (M + Na): 346.0876.

3,4-Dimethoxy-N-(4-methoxyphenyl)benzothioamide (3eb)²⁸. Yellow solid; yield – 93% (282 mg); mp: 164–165 °C (lit.²⁹ 154–155 °C); R_f (30% EtOAc/hexane) 0.25; IR (KBr, cm⁻¹): 3163, 1514, 1270, 1146. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.40 (brs, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.54 (s, 2H), 7.03 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 8.7 Hz, 2H), 3.83 (s, 6H), 3.78 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 195.8, 157.2, 151.3, 147.7, 134.3, 133.2, 126.2, 120.8, 113.5, 111.3, 110.5, 55.7, 55.5, 55.3. ESI-HRMS (m/z): calculated for C₁₆H₁₇NO₃S (M + Na): 326.0827, found (M + Na): 326.0823.

N-(3,5-Bis(trifluoromethyl)phenyl)-3,4-dimethoxybenzothioamide (3fb). Yellow solid; yield – 98% (400 mg); mp: 159–161 °C; R_f (20% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹) 3289, 1512, 1377, 1279, 1263, 1164, 1130. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.89 (brs, 1H), 8.63 (s, 2H), 7.99 (s, 1H), 7.61–7.58 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 3.853 (s, 3H) 3.847 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 197.9, 152.0, 147.8, 141.9, 134.1, 130.3 (q, J = 32.8 Hz), 124.5, 123.6 (q, J = 278.9 Hz), 121.3, 119.0, 111.4, 110.7, 55.8, 55.6; ESI-HRMS (m/z): calculated for C₁₇H₁₃ F₆NO₂S (M + H): 410.0649, found (M + H): 410.0659.

N-(4-Chlorophenyl)-4-methoxybenzothioamide (3ga). Yellow solid; yield – 79% (220 mg); mp: 186–187 °C; R_f (20% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3149, 2973, 1601, 1504, 1488, 1305, 1246, 1175, 837. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.47 (brs, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 3.83 (s, 3H), 2.32 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 196.76, 161.79, 139.12, 134.43, 129.84, 129.57, 128.39, 126.12, 113.23, 55.52; ESI-HRMS (m/z): calculated for C₁₄H₁₂ClNOS (M + H): 278.0406, found (M + Na): 278.0404.

4-Methoxy-N-(3-nitrophenyl)benzothioamide (3ha). Yellow solid; yield – 83% (119 mg); mp: 152–154 °C; R_f (20% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3345, 1602, 1521, 1345, 1259. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.60 (brs, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 197.5, 162.0, 147.5, 141.2, 134.3, 130.5, 129.8, 129.7, 120.5, 118.6, 113.3, 55.6. ESI-HRMS (m/z): calculated for C₁₄H₁₂N₂O₃S (M + Na): 311.0466, found (M + Na): 311.0467.

4-Methoxy-N-(4-nitrophenyl)benzothioamide (3ia). Yellow solid; yield – 85% (122 mg); mp: 191–193 °C; R_f (20% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3134, 1596, 1506, 1340, 1305, 1252, 1171. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.19 (brs, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.18 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 3.84 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 197.9, 162.1, 146.1, 143.9, 134.7, 129.8, 124.2, 123.9, 113.3, 55.6. ESI-HRMS (m/z): calculated for C₁₄H₁₂N₂O₃S (M + Na): 311.0466, found (M + Na): 311.0464.

N-(3,5-Bis(trifluoromethyl)phenyl)-3,4-dihydroxybenzothioamide (3fe). Yellow solid; yield – 99% (189 mg); R_f (40% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3307, 1608, 1515, 1381, 1277. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 11.76 (brs, 1H), 9.79 (brs, 1H), 9.37 (brs, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.469 (d, J = 1.8 Hz, 1H), 7.33 (dd, J₁ = 8.3 Hz, J₂ = 1.9 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 198.1, 149.6, 144.7, 142.0, 133.1, 130.2 (q, J = 32.9 Hz), 124.3, 123.17 (q, J = 271 Hz), 119.6, 118.7, 116.2, 114.6; ESI-HRMS (m/z): calculated for C₁₄H₁₂BrNOS (M + Na): 343.9721, found (M + Na): 343.9721.

N-cyclohexyl-3,4-dimethoxybenzothioamide (3jb). Yellow solid; yield – 96% (268 mg); mp: 162–164 °C; R_f (20% EtOAc/hexane) 0.25; IR (KBr, cm⁻¹): 3228, 3193, 2936, 2854, 1541, 1510, 1268, 1242, 1144, 1021. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 9.78–9.77 (m, NH, 1H), 7.38–7.35 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 4.44–4.37 (m, CHNH, 1H), 3.80 (s, 6H), 1.98–1.96 (m, 2H); 1.78–1.75 (m, 2H), 1.65–1.62 (m, 1H), 1.45–1.27 (m, 4H), 1.19–1.11 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 194.7, 151.0, 147.6, 133.8, 120.3, 111.6, 110.4, 55.7, 55.5, 55.0, 30.7, 25.1, 24.8; ESI-HRMS (m/z): calculated for C₁₅H₂₁NO₂S (M + Na): 302.1191, found (M + Na): 302.1194.

N-cyclohexyl-4-hydroxy-3,5-dimethylbenzothioamide (3jd)^22b. Yellow solid; yield – 80% (210 mg); mp: 212–214 °C (lit.^22b 222–224 °C); R_f (20% EtOAc/hexane) 0.25; IR (KBr, cm⁻¹): 3249, 3054, 2933, 1547, 1393, 1324, 1209, 1178. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 9.63–9.62 (m, NH, 1H), 8.75 (brs, OH, 1H), 7.39 (s, 2H), 4.38 (brs, CHNH, 1H), 2.19 (s, 6H), 1.95–1.93 (m, 2H); 1.77–1.74 (m, 2H), 1.65–1.62 (m, 1H), 1.40–1.27 (m, 4H), 1.15–1.12 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 195.1, 155.8, 132.2, 127.9, 123.1, 54.8, 30.7, 25.2, 24.8, 16.6. ESI-HRMS (m/z): calculated for C₁₅H₂₁ NOS (M + Na): 286.1242, found (M + H): 286.1245.

N-Phenylthiophene-2-carbothioamide (5aa)^22a. Yellow solid; yield – 89% (195 mg); mp: 94–97 °C (lit.^22a 94–95 °C); R_f (10% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3294, 1544, 1375, 1350, 1172. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.54 (brs, 1H), 7.88 (brs, 1H), 7.85 (d, J = 5.0 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.23–7.21 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 186.7, 148.2, 139.4, 134.8, 128.5, 128.2, 126.4, 125.1, 125.0. ESI-HRMS (m/z): calculated for C₁₁H₉NS₂ (M + H): 220.0255, found (M + Na): 220.025.

5-Methyl-N-phenylthiophene-2-carbothioamide (5ab). Yellow solid; yield – 91% (212 mg); mp: 123–125 °C; R_f (20% EtOAc/hexane) 0.5; IR (KBr, cm⁻¹): 1517, 1446, 1335; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.39 (brs, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 2.46 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 186.5, 149.2, 145.7, 139.5, 128.5, 126.9, 126.2, 125.2, 125.1, 15.4. ESI-HRMS (m/z): calculated for C₁₂H₁₁NS₂ (M + Na): 256.0231, found (M + Na): 256.0238.

4-Methyl-N-phenylthiophene-2-carbothioamide (5ac). Yellow solid; yield – 53% (123 mg); mp: 93–95 °C (lit.^22c 70–71 °C in CCl₄); R_f (20% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3189, 1506, 1206, 714, 696. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.48 (brs, 1H), 7.79 (s, 2H), 7.63 (d, J = 5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 6.965 (d, J = 4 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 189.2, 142.4, 139.7, 135.3, 131.1, 128.9, 128.6, 126.2, 123.6, 15.4; ESI-HRMS (m/z): calculated for C₁₂H₁₁NS₂ (M + Na): 256.0231, found (M + H): 256.0233.

N-(4-Methoxyphenyl)thiophene-2-carbothioamide (5ea)^22a. Yellow solid; yield – 58% (144 mg); mp: 123–125 °C (lit.^22a 129–130.5 °C); R_f (30% EtOAc/hexane) 0.5; IR (KBr, cm⁻¹): 3244, 1511, 1362, 1247, 1238. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.45 (brs, 1H), 7.86 (d, J = 3.5 Hz, 1H), 7.83 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.21 (t, J = 4.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 186.3, 157.4, 148.1, 134.6, 132.4, 128.2, 126.6, 124.7, 113.7, 55.3. ESI-HRMS (m/z): calculated for C₁₂H₁₁NOS₂ (M + Na): 272.0180, found (M + Na): 272.0179.

N-(3,5-Bis(trifluoromethyl)phenyl)thiophene-2-carbothioamide (5fa). Yellow solid; yield – 81% (287 mg); mp: 104–106 °C; R_f (10% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3327, 1560, 1378, 1277, 1173, 1128. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.86 (brs, 1H), 8.55 (s, 2H), 8.00 (s, 1H), 7.27 (t, J = 4.44 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 187.9, 147.7, 141.2, 135.9, 130.3 (q, J = 33.0 Hz), 128.5, 126.0, 125.0, 123.1 (q, J = 271.0 Hz), 119.3, 119.1; ESI-HRMS (m/z): calculated for C₁₃H₇F₆NS₂ (M + H): 356.0002, found (M + H): 356.0005.

N-Cyclohexylthiophene-2-carbothioamide (5ja). yellow solid; yield – 70% (158 mg); mp: 122–124 °C; R_f (10% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3272, 2921, 2852, 1537, 1531, 983. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 9.84–9.82 (m, NH, 1H), 7.74–7.71 (m, 2H), 4.37–4.34 (m, CHNH, 1H), 1.95–1.92 (m, 2H); 1.78–1.75 (m, 2H), 1.65–1.62 (m, 1H), 1.44–1.24 (m, 4H), 1.19–1.12 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 185.0, 147.3, 133.7, 127.9, 124.1, 54.9, 30.8, 24.8; ESI-HRMS (m/z): calculated for C₁₁H₁₅ NS₂ (M + Na): 248.0544, found (M + H): 248.0570.

2,5-Dimethyl-N-phenylthiophene-3-carbothioamide (5ad)^22a. Yellow solid; yield – 90% (222 mg); mp: 93–95 °C (lit.^22a 93–93.5 °C); R_f (10% EtOAc/hexane) 0.3; IR (KBr, cm⁻¹): 3222, 1539, 1490, 1387, 1351. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 11.53 (brs, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.43–7.40 (m, 2H), 7.25 (t, J = 7.2 Hz, 1H), 6.89 (s, 1H), 2.46 (s, 3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 192.1, 141.3, 139.6, 134.7, 134.5, 128.5, 127.1, 126.1, 123.6, 14.6, 14.1; ESI-HRMS (m/z): calculated for C₁₃H₁₃NS₂ (M + Na): 270.0387, found (M + Na): 270.0386.

3,4-Dimethoxy-N-phenylbenzamide (7)³⁰. White solid; yield – 93% (239 mg); mp: 164–166 °C (lit.³¹ 160–162 °C); R_f (30% EtOAc/hexane) 0.2; IR (KBr, cm⁻¹): 3318, 1646, 1512, 1320, 1271; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 10.07 (brs, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.37–7.33 (m, 2H), 7.10–7.07 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 164.9, 151.6, 148.3, 139.3, 128.6, 127.0, 123.5, 121.0, 120.5, 111.0, 110.9, 55.7, 55.6; ESI-HRMS (m/z): calculated for C₁₅H₁₅ NO₃ (M + Na): 280.0950, found (M + H): 280.0951.

N-Phenylthiophene-2-carboxamide (8)³⁰. White solid; yield – 86% (174 mg); mp: 140–141 °C (lit.³⁰ 136–138 °C); R_f (20% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3307, 1632, 1616, 1596, 1538, 1445, 1322. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 10.22 (brs, 1H), 8.02 (d, J = 3.4 Hz, 1H), 7.85 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 4.3 Hz, 1H), 7.10 (t, J = 7.28 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 159.90, 140.07, 138.71, 131.88, 129.11, 128.70, 128.08, 123.78, 120.41. ESI-HRMS (m/z): calculated for C₁₁H₉ NOS (M + Na): 226.0303, found (M + H): 226.0291.

N-Isopropylthiophene-2-carboxamide (9). White solid; yield – 92% (155 mg); mp: 139–142 °C (lit.³² 138–140 °C); R_f (30% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3288, 2971, 1614, 1539. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm), 8.20 (d, J = 7.0 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.70–7.69 (m, 1H), 7.12–7.10 (m, 1H), 4.08–3.99 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 160.2, 140.5, 130.4, 127.74, 127.72, 41.0, 22.3; ESI-HRMS (m/z): calculated for C₈H₁₁NOS (M + Na): 192.0459, found (M + Na): 192.0456.

4-Hydroxy-N-phenylbenzamide (10)³³. White solid; yield – 70% (153 mg); mp: 125–127 °C (lit.³⁴ 126–127 °C); R_f (10% EtOAc/hexane) 0.4; IR (KBr, cm⁻¹): 3044, 1718, 1598, 1534, 1491, 1318, 1224, 1202. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.45 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.20 (m, 2H), 7.11 (t, J = 7.3 Hz, 1H), 6.94 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 151.6, 150.5, 137.3, 129.4, 129.1, 125.7, 123.9, 121.6, 118.7. ESI-HRMS (m/z): calculated for C₁₃H₁₁NO₂ (M + Na): 236.0687, found (M + Na): 236.0688.

Acknowledgements

The financial support from IISc, DST (New-Delhi) and RL Fine Chem is gratefully acknowledged. Authors thank Prof. Guru Row, T. N., Mr Pavan, M. S., and Mr Hosamani, A. for their help in X-ray crystal structure determination and Dr Ramesha, A. R. for useful discussion. B. V. V. thanks CSIR for a senior fellowship.

Notes and references

1. (a) K.-L. Yu, A. F. Torri, G. Luo, C. Cianci, K. Grant-Young, S. Danetz, L. Tiley, M. Krystal and N. A. Meanwell, Bioorg. Med. Chem. Lett., 2002, 12, 3379; (b) M. M. Gottesman, T. Fojo and S. E. Bates, Nat. Rev. Cancer, 2002, 2, 48; (c) G. Szakacs, J. K. Paterson, J. A. Ludwig, C. Booth-Genthe and M. M. Gottesman, Nat. Rev. Drug Discovery, 2006, 5, 219; (d) P. Angehrn, E. Goetschi, H. Gmuender, P. Hebeisen, M. Hennig, B. Kuhn, T. Luebbers, P. Reindl, F. Ricklin and A. Schmitt-Hoffmann, J. Med. Chem., 2011, 54, 2207; (e) R. J. Cremlyn, An Introduction to Organosulfur Chemistry, John Wiley and Sons, Chichester, 1996; (f) D. M. Yajko, P. S. Nassos and W. K. Hadley, Antimicrob. Agents Chemother., 1987, 31, 117; (g) S. P. Ebert, B. Wetzel, R. L. Myette, G. Conseil, S. P. C. Cole, G. A. Sawada, T. W. Loo, M. C. Bartlett, D. M. Clarke and M. R. Detty, J. Med. Chem., 2012, 55, 4683; (h) C. R. Nishida and P. R. Ortiz de Montellano, Chem.–Biol. Interact., 2011, 192, 21.
2. (a) Z. Kaleta, B. T. Makowski, T. Soos and R. Dembinski, Org. Lett., 2006, 8, 1625; (b) M. Kriek, F. Martins, R. Leonardi, S. A. Fairhurst, D. J. Lowe and P. L. Roach, J. Biol. Chem., 2007, 282, 17413; (c) M. Abai, J. D. Holbrey, R. D. Rogersz and G. Srinivasan, New J. Chem., 2010, 34, 1981; (d) D. A. Oare, M. A. Sanner and C. H. Heathcock, J. Org. Chem., 1990, 55, 132; (e) T. B. Nguyen, L. Ermolenko and A. Al-Mourabit, Org. Lett., 2012, 14, 4274; (f) E. Bellale, M. Naik, B. V. Varun, A. Ambady, A. Narayan, S. Ravishankar, V. Ramachandran, P. Kaur, R. McLaughlin, J. Whiteaker, S. Morayya, S. Guptha, S. Sharma, A. Raichurkar, D. Awasthy, V. Achar, P. Vachaspati, B. Bandodkar, M. Panda and M. Chatterji, J. Med. Chem, 2014, 57, 6572; (g) P. Wipf and S. Venkatraman, J. Org. Chem., 1996, 61, 8004; (h) O. I. Zbruyev, N. Stiasni and C. O. Kappe, J. Comb. Chem., 2003, 5, 145; (i) O. A. Attanasi, S. Berretta, L. D. Crescentini, G. Favi, P. Filippone, G. Giorgi, S. Lillini and F. Mantellini, Tetrahedron Lett., 2007, 48, 2449.
3. S. Banala and R. D. Süssmuth, ChemBioChem, 2010, 11, 1335.
4. T. Lincke, S. Behnken, K. Ishida, M. Roth and C. Hertweck, Angew. Chem., Int. Ed., 2010, 49, 2011.
5. (a) T. S. Jagodzinski, Chem. Rev., 2003, 103, 197; (b) A. Padwa, L. S. Beall, T. M. Heidelbaugh, B. Liu and S. M. Sheehan, J. Org. Chem., 2000, 65, 2684; (c) H. Prokopcová and C. O. Kappe, J. Org. Chem., 2007, 72, 4440; (d) W.-S. Lo, W.-P. Hu, H.-P. Lo, C.-Y. Chen, C.-L. Kao, J. K. Vandavasi and J.-J. Wang, Org. Lett., 2010, 12, 5570; (e) L. J. Goossen, M. Blanchot, K. S. M. Salih, R. Karch and A. R. Nass, Org. Lett., 2008, 10, 4497.
6. I. Shibuya, K. Honda, Y. Gama and M. Shimizu, Heterocycles, 2000, 53, 929.
7. T. Takido and K. Itabashi, Synthesis, 1985, 430.
8. I. Shibuya, Y. Gama and M. Shimizu, Heterocycles, 2001, 55, 381.
9. (a) H. Wang, L. Wang, J. Shang, X. Li, H. Wang, J. Gui and A. Lei, Chem. Commun., 2012, 48, 76; (b) S. K. Alla, P. Sadhu and T. Punniyamurthy, J. Org. Chem., 2014, 79, 7502.
10. P. S. Chaudhari, S. P. Pathare and K. G. Akamanchi, J. Org. Chem., 2012, 77, 3716.
11. (a) D. Mendoza-Espinosa, G. Ung, B. Donnadieu and G. Bertrand, Chem. Commun., 2011, 47, 10614; (b) K. T. Potts, E. Houghton and U. P. Singh, J. Org. Chem., 1974, 39, 3627; (c) K. T. Potts, J. Baum and E. Houghton, J. Org. Chem., 1974, 39, 3631; (d) K. T. Potts, S. J. Chen, J. Kane and J. L. Marshall, J. Org. Chem., 1977, 42, 1633; (e) M. Baudy and A. Rober, J.C.S. Chem. Commun., 1976, 23.
12. Y. Suzuki, R. Yazaki, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2009, 48, 5026.
13. W. Bauer and K. Kühlein, Houben-Weyl's Methoden der Organischen Chemie, Georg Thieme Verlag: Stuttgart, New York, 1985; vol. E5, pp. 1218–1279.
14. (a) E. Malinowska, Z. Brzozka, K. Kasiura, R. J. M. Egberinkand and D. N. Reinhoudt, Anal. Chim. Acta, 1994, 298, 253; (b) K. R. Benchekroun, C. Picard, P. Tisnes and L. Cazaux, J. Inclusion Phenom. Macrocyclic Chem., 1999, 34, 277; (c) S. Kagaya, H. Miyazaki, M. Ito, K. Tohda and T. Kanbara, J. Hazard. Mater., 2010, 175, 1113.
15. T. Mes, S. Cantekin, D. W. R. Balkenende, M. M. M. Frissen, M. A. J. Gillissen, B. F. M. De Waal, I. K. Voets, E. W. Meijer and A. R. A. Palmans, Chem.–Eur. J., 2013, 19, 8642 and references therein.
16. (a) F. Wang, R. Langley, G. Gulten, L. G. Dover, G. S. Besra, W. R. Jacobs Jr and J. C. Sacchettini, J. Exp. Med., 2007, 204, 73; (b) T. T. Fajardo, R. S. Guinto, R. V. Cellona, R. M. Abalos, E. C. Dela Cruz and R. H. Gelber, Am. J. Trop. Med. Hyg., 2006, 74, 457.
17. (a) B. S. Pedersen and S. O. Lawesson, Bull. Soc. Chim. Belg., 1977, 86, 693; (b) B. S. Pedersen, S. Scheibye, N. H. Nilson and S.-O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87, 223; (c) S. Scheibye, B. S. Pedersen and S.-O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87, 229; (d) B. S. Pedersen, S. Scheibye, N. H. Nilson, K. Clausen and S.-O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87, 293; (e) S. Scheibye, B. S. Pedersen and S.-O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87, 299; (f) J. Z. Wislicenus, Chemistry, 1869, 324; (g) T. Ozturk, E. Ertas and O. Mert, Chem. Rev., 2007, 107, 5210; (h) L. Henry, Ann. Chem. Pharm., 1869, 148, 152; (i) V. Polshettiwar, Synlett, 2004, 2245.
18. (a) A. K. Yadav, V. P. Srivastava and L. D. S. Yadav, Tetrahedron Lett., 2012, 53, 7113 and references therein; (b) N. Borthakur and A. Goswami, Tetrahedron Lett., 1995, 36, 6745; (c) J. J. Bodine and M. K. Kaloustian, Synth. Commun., 1982, 12, 787; (d) M. L. Boys and V. L. Downs, Synth. Commun., 2006, 36, 295; (e) S. Goswami, A. C. Mait and N. K. Das, Synth. Commun., 2007, 28, 233; (f) A. Manaka and M. Sato, Synth. Commun., 2005, 5, 761; (g) N. M. Yousif, Tetrahedron, 1989, 45, 4599; (h) S. A. Benner, Tetrahedron Lett., 1981, 22, 1851.
19. (a) C. Willgerodt, Ber. Dtsch. Chem. Ges., 1888, 21, 534; (b) K. Kindler, Liebigs Ann. Chem., 1923, 431, 187; (c) L. D. Priebbenow and C. Bolm, Chem. Soc. Rev., 2013, 42, 7870; (d) O. I. Zbruyev, N. Stiasni and C. O. Kappe, J. Comb. Chem., 2003, 5, 145; (e) K. Okamoto, T. Yamamoto and T. Kanbara, Synlett, 2007, 2687; (f) T. B. Nguyen, L. Ermolenko and A. A. Mourabit, Org. Lett., 2012, 14, 4274; (g) P. P. Sagar, S. C. Pramod and G. A. Krishnacharya, Appl. Catal., A, 2012, 425–426, 125.
20. (a) A. Friedmann and L. Gattermann, Ber. Dtsch. Chem. Ges., 1892, 25, 3525; (b) K. Tust and L. Gattermann, Ber. Dtsch. Chem. Ges., 1892, 25, 3528.
21. (a) P. Karrer and E. Weiss, Helv. Chim. Acta, 1929, 12, 554; (b) F. Mayer and A. Mombour, Ber. Dtsch. Chem. Ges. A, 1929, 62, 3528; (c) H. Revier and S. Kunz, Helv. Chim. Acta, 1932, 15, 376; (d) R. N. Hurd and G. Delamater, Chem. Rev., 1961, 61, 45; (e) R. D. Desai, J. Indian Chem. Soc., 1968, 43, 193; (f) P. A. S. Smith and R. O. Kan, J. Org. Chem., 1964, 29, 2261; (g) E. P. Papadopoulos, J. Org. Chem., 1976, 41, 962.
22. (a) T. Jagodzinski, E. Jagodzinska and Z. Jabłonski, Tetrahedron, 1986, 42, 3683; (b) T. Jagodzinski, Synthesis, 1988, 717; (c) T. Jagodzinski, E. Jagodzinska, T. Dziembowska and B. Szczodrowska, Bull. Soc. Chim. Belg., 1987, 96, 449.
23. (a) M. R. Maddani and K. R. Prabhu, J. Org. Chem., 2010, 75, 2327; (b) J. Dhineshkumar and K. R. Prabhu, Org. Lett., 2013, 16, 326; (c) B. V. Varun and K. R. Prabhu, RSC Adv., 2013, 3, 3079; (d) B. V. Varun and K. R. Prabhu, J. Org. Chem., 2014, 79, 9655.
24. (a) B. L. Booth and T. A. E. Fekky, J. Chem. Soc., Perkin Trans. 1, 1979, 2441; (b) M. Aramaki, T. Hamana, H. Sakaguchi and T. Suenaga, US5004829 1991, see summary.
25. (a) R. Leuckart and M. Schmidt, J. fuer Prak. Chem., 1890, 41, 301; (b) T. Koike, M. Takahashi, N. Arai and A. Mori, Chem. Lett., 2004, 33, 1364; (c) W. K. Su, J. J. Li and D. W. Yang, J. Indian Chem. Soc., 2004, 81, 885.
26. F. Brueggemann, J. Prakt. Chem., 1896, 53, 252.
27. K. K. Ginwala and J. P. Trivedi, J. Indian Chem. Soc., 1963, 40, 897.
28. H. Xu, H. Deng, Z. Li, H. Xiang and X. Zhou, Eur. J. Org. Chem., 2013, 7054.
29. M. F. G. Stevens, C. J. McCall, P. Lelievald, P. Alexander, A. Richter and D. E. Davies, J. Med. Chem., 1994, 37, 1689.
30. K. N. Kumar, K. Sreeramamurthy, S. Palle, K. Mukkanti and P. Das, Tetrahedron Lett., 2010, 51, 899.
31. B. Narasimhan, S. Ohlan, R. Ohlan, V. Judge and R. E. Narang, J. Med. Chem., 2009, 44, 689.
32. M. J. Laws, C. H. Schiesser, J. M. White and S.-L. Zheng, Aust. J. Chem., 2000, 53, 277.
33. (a) M. Hutchby, C. E. Houlden, J. G. Ford, S. N. G. Tyler, M. R. Gagné, G. C. Lloyd-Jones and K. I. B. Milburn, Angew. Chem., Int. Ed., 2009, 48, 8721; (b) M. Aresta, C. Berloco and E. Quaranta, Tetrahedron, 1995, 51, 8073; (c) R. Hron and B. S. Jursic, Tetrahedron Lett., 2014, 55, 1540.
34. L. Rand, A. B. Lateef and J. A. Reeder, J. Org. Chem., 1971, 36, 2295.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C spectra and spectral data for all compounds and crystal structure data (3af) are available. CCDC 1021399. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra12944j

---