Chemoselective Ullmann Reaction of α-Trisubstituted Thioamides: Synthesis of Novel 2-Iminobenzothiolanes

Anwesha Bhattacharya; Annaram Thirupathi; Pradeep Natarajan; Saravanan Peruncheralathan

doi:10.1021/acsomega.1c03410

. 2021 Aug 4;6(32):21169–21180. doi: 10.1021/acsomega.1c03410

Chemoselective Ullmann Reaction of α-Trisubstituted Thioamides: Synthesis of Novel 2-Iminobenzothiolanes

Anwesha Bhattacharya ¹, Annaram Thirupathi ¹, Pradeep Natarajan ¹, Saravanan Peruncheralathan ^1,^*

PMCID: PMC8375098 PMID: 34423225

Abstract

New classes of unexplored benzo[b]thiolanes are synthesized from trisubstituted thioamides through copper-catalyzed intramolecular S-arylation of thioamides for the first time. This method provides good to excellent yields with fully controlled chemoselectivity. Unusually, iminobenzo[b]thiolanes are very stable under mild acidic conditions. A plausible mechanism is proposed for the chemoselective S-arylation process.

Introduction

Benzothiophene is a predominant structural core compound in drugs and device materials.¹⁻⁴ In particular, 2-aminobenzothiophenes show various biological activities, such as acetyl-CoA carboxylase inhibitor, tubulin polymerization, and mycobacterium inhibition.⁵ They are also precursors for the synthesis of the well-known drug raloxifene and its analogues.⁶ Therefore, several elegant synthetic methods have been developed for the construction of 2-aminobenzothiophene derivatives,⁷ whereas those for the 2-iminobenzothiophene core remain elusive in the literature.^8,9 Recently, a 2-iminothiophene-fused polyaromatic compound A were synthesized from thioamides (Figure 1).¹⁰ The photophysical studies show emission in the range of 500–606 nm with quantum yields up to 0.64.¹⁰ Hence, compound A has been considered a potential core for developing optical device materials. Furthermore, the 2-aminobenzothiolane core is found in marine alkaloid makaluvamine F, which has potent cytotoxicity.¹¹ Hydrolysis of 2-iminobenzothiophenes 1 provides unknown classes of 2-oxobenzothiolanes 2 (Figure 1).¹² They are S-analogues of 2-oxindole derivatives. The indole derivatives are found in numerous natural products such as horsfiline, a 3,3′-spiro-2-oxindole alkaloid, alstonisine, gelsemine, and spirotryprostatin B.¹² Until now, the synthesis of 2-oxobenzothiolanes has not been reported, whereas synthesis of benzothiolane and its 3-oxo derivatives is well developed.^11a^,^13,14 Hence, developing a new protocol to synthesize 2-iminobenzothiolanes and their 2-oxo derivatives is highly desirable for therapeutic and materials science applications.

Selected 2-imino-fused thiophenes and 2-aminobenzo[b]thiolane.

Thioamides are versatile synthons and are extensively used in the synthesis of heterocyclic building blocks.¹⁵ Notably, a wide range of thiazoles and their benzo derivatives is synthesized by inter/intramolecular S-alkylation and arylation of appropriate thioamides with the respective electrophilic partners.^16,17 They proceed through either metal or metal-free reaction conditions. Similarly, thiophenes are prepared from thioamides and biselectrophiles.¹⁸ However, thioamides are rarely employed as reactive partners to synthesize 2-aminobenzothiophenes compared to benzothiazole synthesis.¹⁹ The chemoselective S-arylation of thioanilides has significant limitations. Recently, Olofsson and co-workers reported intermolecular chemoselective S-arylation of thioamides with diaryliodonium salts affording arylthioimidates.²⁰ We recently reported copper-catalyzed intramolecular S-arylation of thioamides at room temperature providing 2-aminobenzothiophenes in good to excellent yields.²¹ Due to our ongoing interest in chemoselective heterocycle synthesis,²² herein we wish to report a chemoselective Ullmann reaction of α-trisubstituted thioamides under ligand-free conditions affording new classes of 2-iminobenzothiolanes for the first time.

Results and Discussion

The required trisubstituted thioamides 3 were prepared from α-(2-bromoaryl)-propanenitriles 4 or α-(2-bromophenyl)-propanoate 6 and aromatic/alkyl isothiocyanates 5 in the presence of NaHMDS affording the corresponding thioamides 3a–y in moderate to good yields (Table S1, Supporting Information). Spectral and analytical data characterized all newly synthesized 2-(2-bromoaryl)-2-cyano/carbmethoxy-N-substituted propanethioamide derivatives 3a–y. Having all the thioamides 3a–y, we started to investigate the suitable conditions for a chemoselective intramolecular S-arylation process. Hence, thioamide 3a was chosen as the model substrate for this process. The optimization began with CuI, KO^tBu, and 1,10-phenanthroline at room temperature. The reaction was sluggish and afforded only 20% of the benzo[b]thiolane derivative 1a (Table 1, entry 1). Keeping the rest of the conditions the same, the reaction at different temperatures was studied. When the reaction was carried out at 60 °C, the yield of benzo[b]thiolane 1a increased to 42% (Table 1, entry 2). Subsequently, the reaction temperature was further raised to 90 °C, and the yield enhanced to 68% (Table 1, entry 3).

Table 1. Optimization of S-Arylation of α-Trisubstituted Thioamide 3.

entry	3	Cu salt	base	solvent	temp (°C)	time (h)	yield (%)^a
1.	X = Br	CuI	KO^tBu	DMF	Rt	4	20^b
2.	X = Br	CuI	KO^tBu	DMF	60	3	42^b
3.	X = Br	CuI	KO^tBu	DMF	90	3	68^b
4.	X = Br	CuI	KO^tBu	DMF	90	3	77
5.	X = Br	CuI	Cs₂CO₃	DMF	90	3	77
6.	X = Br	CuI	K₃PO₄	DMF	90	3	85
7.	X = Br	CuI	Et₃N	DMF	90	3	91
8.	X = Br	CuI	K₂CO₃	DMF	90	3	69
9.	X = Br	CuI	Et₃N	toluene	90	3	91
10.	X = Br	CuI	Et₃N	dioxane	90	3	86
11.	X = Br	CuI	Et₃N	DMSO	90	3	92
12.	X = Br	CuBr	Et₃N	DMF	90	1.5	98
13.	X = Br	CuCl	Et₃N	DMF	90	1.5	92
14.	X = Br	Cu(OAc)₂	Et₃N	DMF	90	1.5	95
15.	X = I	CuBr	Et₃N	DMF	90	4	82
16.	X = Cl	CuBr	Et₃N	DMF	90	10	20
17.	X = Br	CuBr	Et₃N	DMF	90	2	83^c

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Isolated yields.

With 1,10-phenanthroline ligand (10 mol %).

TEMPO (1 equiv) was used, TEMPO-(2,2,6,6-Tetramethylpiperidin-1-yl)ox.

When the reaction was carried out in the absence of a ligand, to our surprise, thioamide 3a yielded 77% of product 1a (Table 1, entry 4). This indicates that the ligand did not affect the S-arylation process. The structure of 1a was also confirmed by single-crystal X-ray analysis (Table 1). To improve the reaction’s efficiency, we screened different bases such as Cs₂CO₃, K₃PO₄, Et₃N, and K₂CO₃, out of which Et₃N gave 91% of benzo[b]thiolane 1a (Table 1, entries 5–8). Furthermore, we screened solvents like toluene, dioxane, and dimethyl sulfoxide (DMSO) (Table 1, entries 9–11). Only DMSO gave a comparable yield to that of DMF. Next, copper salts were tested for optimization, such as CuCl, CuBr, and Cu(OAc)₂. We found that CuBr yielded 98% of 1a (Table 1, entries 12–14). Instead of aryl bromide, iodo and chloro derivatives were also examined. Aryl iodide gave 82% of benzo[b]thiolane 1a (Table 1, entry 15), whereas only 20% of 1a was observed after 10 h in the case of a chloro derivative (Table 1, entry 16). We did not find any trace amount of the N-arylated product during the optimization studies. In the presence of the radical scavenger TEMPO, we obtained 83% of benzo[b]thiolane 1a (Table 1, entry 17). This indicates that the S-arylation process does not proceed through a radical path.

The optimized reaction conditions were tested on the various trisubstituted thioamides 3b–y. Initially, N-aryl-substituted thioamides 3b–g were studied. The electron-donating groups on N-phenyl derivatives 3b,c gave the corresponding benzo[b]thiolanes 1b,c in 85–91% yields (Table 2). Similarly, the para-fluoro- and nitro-substituted N-phenyl thioamides 3d,e were smoothly transformed to benzo[b]thiolanes 1d,e in good to excellent yields (Table 2). The reaction was continued with ortho-substituted thioanilides 3f,g. The benzo[b]thiolanes 1f,g were obtained from the respective thioanilides 3f,g in 75–90% yields (Table 2). Next, we examined alkyl-substituted thioamides 3h–k under the optimized reaction conditions. The S-arylation of thioamides 3h–k took a bit longer reaction time of about 6–12 h to afford the corresponding benzo[b]thiolanes 1h–k in good to excellent yields (Table 2). Furthermore, we investigated the electron-donating group on 2-bromoaryl derivatives 3l–o. These derivatives 3l–o underwent a smooth S-arylation process yielding benzo[b]thiolanes 1l–o in good to excellent yields (Table 2). However, the halo-substituted thioamides 3p,q gave the S-arylated products 1p,q in 35–42% yields (Table 2). Interestingly, the sterically hindered arylbromo derivative 3r gave rise to benzo[b]thiolane 1r in 92% yield (Table 2). Next, we changed the methyl group at the α-trisubstituted thioamide to ethyl, benzyl, and allyl groups. Thus, ethyl- and benzyl-substituted thioamide derivatives 3s,t yielded the corresponding benzo[b]thiolanes 1s,t in 85–95% yields (Table 2). However, the allyl derivative 3u gave only 52% yield of the S-arylated product 1u and took a longer reaction time (Table 2). The ester motif-containing trisubstituted thioamide 3v was studied under identical conditions. The ester-containing benzo[b]thiolane 1v was obtained in 89% yield in 3.5 h (Table 2). Next, we focused our attention on synthesizing enantiomerically pure benzo[b]thiolanes from chiral α-trisubstituted thioamides. The chiral α-trisubstituted thioamides 3w–y were prepared in moderate to good yields with 1:1 diastereoisomers (Table S1, Supporting Information). The thioamides 3w–y were subjected to optimized conditions affording 2-iminobenzo[b]thiolanes 1w–y in 66–75% yields (Table 2).

Table 2. Scope of the Copper-Catalyzed S-Arylation of α-Trisubstituted Thioamides 3b–y^a.

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Isolated yields.

Finally, we attempted to synthesize S-analogues of 2-oxindole derivatives. Thus, newly synthesized 2-iminobenzo[b]thiolane 1a was subjected to hydrolysis conditions; to our surprise, the imine functionality was relatively rigid to hydrolysis. The 2-iminobenzo[b]thiolane 1a was subjected to 10 equivalents of triflic acid at 60 °C, resulting in the hydrolysis of the nitrile moiety. The imine functionality remained intact. The structure of 7a was also confirmed by single-crystal X-ray analysis (Scheme 1). However, 1a was subjected to concentrated H₂SO₄ under a neat condition, which resulted in the cleavage of the heterocycle and hydrolysis of nitrile and imine functionalities yielding 2-(2-mercaptophenyl)-2-methyl-N-phenylmalonamide 8a in a quantitative yield (Scheme 1). A similar result was observed in the presence of conc. HCl. However, 8a was obtained in 68% yield (Scheme 1). Furthermore, our attempts to reduce the imine moiety of 1a failed.²³

To understand the chemoselective S-arylation process mechanism, as aforementioned the S-arylation process proceeds through an ionic pathway instead of a radical path (Table 1, entry 17). The S-center of thioamide is more nucleophilic than the N-center. Hence, first, thioamide 3 forms a coordinate complex A with the copper salt. In a base, complex A is transformed to the copper(I)thiolate complex B, which is also stabilized by N-center coordination. Next, complex B undergoes an intramolecular oxidative addition affording the copper(III) complex C. This step is crucial, which is influenced by the nature of aryl halides and nitrogen substituents. Finally, the complex C undergoes reductive elimination to afford the S-arylated product 1 and regenerated the Cu(I) catalyst (Scheme 2). The oxidative addition of 2-chlorophenyl derivative 3z is slow and less efficient; hence, a lower yield of 1a was observed (Table 1, entry 15). Electron-deficient 2-bromoaryl thioamides 3p,q undergo a slow oxidative addition process; therefore, lower yields were obtained (Table 2). Electron-rich N-alkyl thioamides 3h–k form a strong coordinate complex B. Thus, these complexes require a longer reaction time to complete the oxidative process.

Conclusions

We have demonstrated a simple approach for synthesizing unexplored 2-imino-3,3′-alkylcyanobenzo[b]thiolanes via the copper-catalyzed S-arylation of α-trisubstituted thioamides for the first time. This catalytic process is highly chemoselective. We have prepared a series of all-carbon quaternary-centered 2-iminobenzo[b]thiolanes in good to excellent yields. Interestingly, we found that the 2-imino moiety is very stable under mild acidic conditions, whereas the thiolane ring was cleaved under a neat acidic condition. Overall, we demonstrated that the Ullmann reaction is a powerful tool for synthesizing a new class of S-heterocycles without using any ligands. Currently, the application of 3,3′-disubstituted-2-iminobenzothiolanes is undergoing in our laboratory.

Experimental Section

General Information

All reactions were performed using the standard vial technique with a rubber septum. All solids were weighed in air. Dioxane, Cs₂CO₃, K₃PO₄, KO^tBu, and K₂CO₃ were purchased from Aldrich, Acros, Merck, Spectrochem, or Alfa Aesar and used as received. CuI, CuBr, CuCl, Cu(OAc)₂, and 1,10-phenanthroline were purchased from Aldrich. Dried DMF, DMSO, toluene, and Et₃N were used. Isothiocyanates were synthesized from substituted anilines, and few isothiocyanates were purchased from Aldrich. All other reagents were purchased from common suppliers and used without further purification. Flash chromatography was performed using a Merck silica gel (230–400 mesh). Fractions were monitored by thin-layer chromatography (TLC) on precoated silica gel 60 F₂₅₄ plates (Merck & Co.) and were visualized by a UV light. Nuclear magnetic resonance (NMR) spectroscopy data were recorded using Bruker ARX 400 and 700 spectrometers. ¹³C and ¹H NMR spectra were recorded in CDCl₃ and CD₃SOCD₃ referenced according to signals of deutero solvents. Electrospray ionization high-resolution mass spectrometry (ESI HR-MS) measurements were performed using a Bruker micrOTOF-Q II mass-spectrometer.

General Procedure for the Synthesis of Thioamides 3a–aa

To a stirring suspension of corresponding 2-(2-bromoaryl)propanenitriles²⁴ (6.0 mmol, 1.0 equiv) in THF, NaHMDS (1.0 M in THF) was added dropwise at 0 °C. After being further stirred for 15 min at room temperature, a solution of isothiocyanates (6.6 mmol, 1.2 equiv) in THF was added to the reaction mixture at 0 °C followed by further stirring for 15–45 min at room temperature. After the starting materials (monitored by TLC) were completely consumed, the reaction mixture was quenched with a saturated NH₄Cl solution and extracted with ethyl acetate (EtOAc). The combined organic layer was washed with water (3 × 25 mL) and brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated under a reduced pressure. The crude products were purified by flash chromatography using hexane and EtOAc as the eluents.

2-(2-Bromophenyl)-2-cyano-N-phenylpropanethioamide (3a)

Yield: 75% (0.258 g); pale yellow solid; R_f: 0.35 in 30% EtOAc in hexanes; mp: 124–125 °C; IR (ν cm^–1) =2974, 2362, 2243, 1530, 1406, 1344, 1160, 1036, 1004, 808, 754; ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.34–7.29 (m, 2H), 2.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.6, 138.1, 135.5, 135.2, 131.1, 129.4, 129.2, 128.0, 127.7, 124.6, 124.4, 119.7, 56.7, 29.6. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₃BrN₂S [M + H]⁺: 345.0056 and 347.0044; found: 345.0051 and 347.0035.

2-(2-Bromophenyl)-2-cyano-N-(4-methoxyphenyl)propanethioamide (3b)

Yield: 91% (0.340 g); pale yellow solid; R_f: 0.32 in 30% EtOAc in hexanes; mp: 127–129 °C; IR (ν cm^–1) = 3628, 3306, 2352, 1732, 1698, 1656, 1564, 746; ¹H NMR (400 MHz, CD₃SOCD₃) δ 10.73 (s, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CD₃SOCD₃) δ 199.1, 158.3, 136.4, 135.0, 132.7, 131.4, 131.0, 128.7, 127.3, 124.6, 120.7, 114.2, 57.5, 55.7, 27.8. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₅BrN₂OS [M + H]⁺: 375.0161 and 377.0146; found: 375.0166 and 377.0141.

2-(2-Bromophenyl)-2-cyano-N-(p-tolyl)propanethioamide (3c)

Yield: 73% (0.261 g); pale yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 180–182 °C; IR (ν cm^–1) = 3427, 2362, 1638, 1517, 1371, 1036; ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.4 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.5, 137.8, 135.7, 135.5, 135.2, 130.9, 129.8, 129.4, 128.2, 124.6, 124.3, 119.8, 56.44, 28.7, 21.2. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₅BrN₂S [M + H]⁺: 359.0212 and 361.0192; found: 359.0227 and 361.0206.

2-(2-Bromophenyl)-2-cyano-N-(4-fluorophenyl)propanethioamide (3d)

Yield: 68% (0.261 g); pale yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 139–141 °C; IR (ν cm^–1) = 3308, 1700, 1507, 1413, 1217, 833, 769; ¹H NMR (400 MHz, CDCl₃) 7.74–7.69 (m, 2H), 7.54 (s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.46–7.43 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 8.4 Hz, 2H), 2.19 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.0, 160.1 (d, J = 245.2 Hz), 135.2, 134.1, 132.6 (d, J = 3.0 Hz), 131.1, 129.1, 128.4, 123.7, 122.7 (d, J = 8.0 Hz), 119.4, 115.9 (d, J = 22.5 Hz), 50.1, 24.2; ¹⁹F NMR (376 Hz, CDCl₃) δ −116.23; HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₂BrFN₂S [M + H]⁺: 384.9781 and 386.9751; found: 384.9770 and 386.9760.

2-(2-Bromophenyl)-2-cyano-N-(4-nitrophenyl)propanethioamide (3e)

Yield: 70% (0.271 g); R_f: 0.26 in 30% EtOAc in hexanes; mp: 185–187 °C; IR (ν cm^–1) = 3303, 2927, 2362, 1336, 756, 667. ¹H NMR (400 MHz, CD₃SOCD₃) δ 11.23 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.80–7.78 (m, 4H), 7.59 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CD₃SOCD₃) δ 200.8, 145.7, 145.6, 136.2, 135.1, 131.6, 131.1, 128.8, 126.6, 124.7, 124.6, 120.4, 58.0, 27.7. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₂BrN₃O₂S [M + H]⁺: 389.9914 and 391.9895; found: 389.9906 and 391.9886.

2-(2-Bromophenyl)-2-cyano-N-(2-methoxyphenyl)propanethioamide (3f)

Yield: 75% (0.280 g); yellow solid; R_f: 0.32 in 30% EtOAc in hexanes; mp: 154–156 °C; IR (ν cm^–1) = 3628, 3306, 2352, 1732, 1698, 1656, 1564, 746; ¹H NMR (400 MHz, CDCl₃) δ 9.71 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 2.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 194.2, 150.1, 135.7, 135.2, 130.8, 129.4, 127.98, 127.80, 127.2, 125.1, 121.4, 120.5, 119.7, 110.5, 57.8, 56.1, 28.7. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₅BrN₂OS [M + H]⁺: 375.0161 and 377.0139; found: 375.0161 and 377.0141.

2-(2-Bromophenyl)-2-cyano-N-(2-(trifluoromethyl)phenyl)propanethioamide (3g)

Yield: 75% (0.309 g); yellow solid; R_f: 0.26 in 30% EtOAc in hexanes; mp: 200–202 °C; IR (ν cm^–1) = 3207, 3006, 2349, 2253, 1505, 1450, 1319, 1125, 746, 675; ¹H NMR (700 MHz, CDCl₃) δ 8.87 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.67–7.63 (m, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 2.36 (s, 3H). ¹³C NMR (175 MHz, CDCl₃) δ 199.5, 135.9 (q, J = 1.22 Hz), 135.3, 135.2, 132.7, 131.2, 129.1, 128.8, 128.2, 128.0, 126.6 (q, J = 5.0 Hz), 125.0, 124.9 (q, J = 30.1 Hz), 123.3 (q, J = 271.7 Hz), 119.4, 57.1, 28.3; ¹⁹F NMR (376 Hz, CDCl₃) δ −60.88. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₂BrF₃N₂S [M + H]⁺: 412.9929 and 414.9903; found: 412.9918 and 414.9909.

N-Benzyl-2-(2-bromophenyl)-2-cyanopropanethioamide (3h)

Yield: 60% (0.215 g); pale yellow solid; R_f: 0.28 in 30% EtOAc in hexanes; mp: 148–150 °C; IR (ν cm^–1) = 3253, 2359, 1588, 1558, 1513, 1373, 1202, 1029, 748, 638, 502; ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.39–7.29 (m, 5H), 4.87 (s, 1H), 4.88 (s, 1H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 135.5, 135.3, 135.1, 130.8, 129.2, 129.0, 128.4, 128.3, 128.1, 124.5, 119.6, 55.5, 51.1, 28.7. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₅BrN₂S [M + H]⁺: 359.0212 and 361.0168; found: 359.0192 and 361.0192.

2-(2-Bromophenyl)-2-cyano-N-isopropylpropanethioamide (3i)

Yield: 56% (0.174 g); pale yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 133–135 °C; IR (ν cm^–1) = 3744, 3303, 2961, 2347, 1735, 1700, 1656, 1559, 833, 647; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 4.66–4.58 (m, 1H), 2.21 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H), 1.27 (d, J = 6.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 196.5, 135.6, 134.9, 130.7, 129.2, 127.9, 124.5, 119.6, 55.4, 48.5, 28.7, 20.9, 20.5. HR-MS (ESI-TOF) m/z: cal. for C₁₃H₁₅BrN₂S [M + H]⁺: 311.0212 and 313.0185; found: 311.0207 and 313.0192.

2-(2-Bromophenyl)-2-cyano-N-ethylpropanethioamide (3j)

Yield: 64% (0.190 g); yellow solid; R_f: 0.28 in 30% EtOAc in hexanes; mp: 122–124 °C; IR (ν cm^–1) = 3628, 2934, 2362, 2339, 1611, 1561, 1438, 1420, 1004, 665. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 3.74 (q, J = 6.4 Hz, 2H), 2.24 (s, 3H), 1.30 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.8, 135.6, 135.0, 130.7, 129.2, 128.0, 124.5, 119.7, 55.4, 41.8, 28.7, 12.5. HR-MS (ESI-TOF) m/z: cal. for C₁₂H₁₃BrN₂S [M + H]⁺: 297.0056 and 299.0037; found: 297.0058 and 299.0035.

2-(2-Bromophenyl)-N-(tert-butyl)-2-cyanopropanethioamide (3k)

Yield: 58% (0.188 g); yellow solid; R_f: 0.28 in 30% EtOAc in hexanes; mp: 128–130 °C. IR (ν cm^–1) = 2969, 2934, 2867, 2238, 1651, 1472, 1130, 987, 756, 439; ¹H NMR (700 MHz, CDCl₃) δ 7.69 (d, J = 9.1 Hz, 1H), 7.59 (s, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 8.4 Hz, 1H), 2.24 (s, 3H), 1.57 (s, 9H). ¹³C NMR (175 MHz, CDCl₃) δ 196.1, 135.8, 134.9, 130.6, 129.3, 127.9, 124.7, 119.9, 56.9, 56.6, 28.9, 27.0. HR-MS (ESI-TOF) m/z: cal. for C₁₄H₁₇BrN₂S [M + H]⁺: 325.0369 and 327.0355; found: 325.0377 and 327.0348.

2-(2-Bromo-4,5-dimethoxyphenyl)-2-cyano-N-phenylpropanethioamide (3l)

Yield: 73% (0.295 g); pale yellow solid; R_f: 0.32 in 30% EtOAc in hexanes; mp: 222–224 °C; IR (ν cm^–1) = 3447, 2253, 1517, 1467, 1299, 1004, 741; ¹H NMR (400 MHz, CD₃SOCD₃) δ 10.60 (s, 1H), 7.46–7.35 (m, 4H), 7.33 (s, 1H), 7.32–7.27 (m, 1H), 7.24 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 2.30 (s, 3H). ¹³C NMR (100 MHz, CD₃SOCD₃) δ 200.1, 150.3, 148.4, 139.8, 129.0, 127.7, 127.5, 126.2, 120.8, 117.9, 115.4, 114.6, 58.1, 56.5, 56.3, 28.2. HR-MS (ESI-TOF) m/z: cal. for C₁₈H₁₇BrN₂O₂S [M + H]⁺: 405.0267 and 407.0230; found: 405.0253 and 407.0247.

2-(6-Bromo-3,4-methylenedioxyphenyl)-2-cyano-N-phenylpropanethioamide (3m)

Yield: 72% (0.280 g); yellow solid; R_f: 0.31 in 30% EtOAc in hexanes; mp: 174–176 °C; IR (ν cm^–1) = 3450, 2349, 1529, 1395, 1256, 1004, 735; ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.39–7.27 (m, 2H), 7.27–7.19 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.07 (s, 2H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.0, 149.2, 148.1, 138.0, 129.2, 128.4, 127.8, 124.5, 119.8, 116.2, 114.9, 109.4, 102.7, 56.6, 29.2. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₃BrN₂O₂S [M + H]⁺: 388.9954 and 390.9917; found: 388.9938 and 390.9934.

2-(6-Bromo-2,3-dimethoxyphenyl)-2-cyano-N-phenylpropanethioamide (3n)

Yield: 73% (0.295 g); pale yellow solid; R_f: 0.31 in 30% EtOAc in hexanes; mp: 174–176 °C; IR (νcm^–1) = 3450, 2240, 1723, 1518, 1456, 1290, 1012, 736; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.48–7.32 (m, 3H), 7.29–7.24 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.43 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.8, 153.3, 150.1, 138.4, 130.5, 129.4, 129.1, 127.6, 124.4, 121.0, 114.0, 113.6, 61.6, 56.1, 55.6, 29.4. HR-MS (ESI-TOF) m/z: cal. for C₁₈H₁₇BrN₂O₂S [M + H]⁺: 405.0267 and 407.0236; found: 405.0251 and 407.0247.

2-(6-Bromo-2,3-dimethoxyphenyl)-2-cyano-N-(p-tolyl)propanethioamide (3o)

Yield: 70% (0.293 g); yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 146–148 °C; IR (ν cm^–1) = 3447, 2237, 1732, 1517, 1467, 1299, 1004, 741, 656; ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.9, 153.3, 150.0, 137.7, 135.8, 130.5, 129.7, 129.4, 124.4, 121.1, 113.9, 113.7, 61.6, 56.2, 55.6, 29.5, 21.3. HR-MS (ESI-TOF) m/z: cal. for C₁₉H₁₉BrN₂O₂S [M + H]⁺: 419.0423 and 421.0420; found: 419.0434 and 421.0403.

2-(2-Bromo-4-chlorophenyl)-2-cyano-N-phenylpropanethioamide (3p)

Yield: 65% (0.246 g); pale yellow solid; R_f: 0.31 in 30% EtOAc in hexanes; mp: 129–131 °C; IR (ν cm^–1) = 3442, 2362, 2238, 1641, 1520, 670; ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 7.71 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.51–7.39 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 2.32 (s, 3H). ¹³C NMR (175 MHz, CDCl₃) δ 196.9, 137.9, 136.2, 134.7, 134.5, 130.0, 129.2, 128.2, 127.9, 125.0, 124.3, 119.4, 55.6, 28.9. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₂BrClN₂S [M + H]⁺: 378.9666 and 380.9668; found: 378.9681 and 380.9645.

2-(2-Bromo-4-fluorophenyl)-2-cyano-N-phenylpropanethioamide (3q)

Yield: 72% (0.261 g); white solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 133–135 °C; IR (ν cm^–1) = 3427, 2359, 2236, 1656, 1530, 1222, 670; ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 7.61–7.57 (m, 3H), 7.48–7.40 (m, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 6.8 Hz, 1H), 2.32 (s, 3H). ¹³C NMR (175 MHz, CDCl₃) δ 197.2, 162.5 (d, J = 253.4 Hz), 138.0, 132.0 (d, J = 3.5 Hz), 130.5 (d, J = 8.7 Hz), 129.2, 127.9, 125.1 (d, J = 9.4 Hz), 124.3, 122.5 (d, J = 24.7 Hz), 119.5, 115.1 (d, J = 21.0 Hz), 55.7, 29.0; ¹⁹F NMR (376 Hz, CDCl₃) δ −109.71. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₂BrFN₂S [M + H]⁺: 384.9781 and 386.9769; found: 384.9788 and 386.9760.

2-(2-Bromo-3,5-di-tert-butylphenyl)-2-cyano-N-phenylpropanethioamide (3r)

Yield: 55% (0.251 g); pale yellow solid; R_f: 0.58 in 30% EtOAc in hexanes; mp: 178–180 °C; IR (ν cm^–1) = 3338, 3262, 2962, 2871, 2360, 2238, 1710, 1500, 1462, 1393, 1237, 1071, 885, 646, 488; ¹H NMR (700 MHz, CDCl₃) δ 8.68 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.48 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 2.38 (s, 3H), 1.58 (s, 9H), 1.38 (s, 9H). ¹³C NMR (175 MHz, CDCl₃) δ 199.2, 150.4, 150.0, 138.2, 136.4, 129.1, 127.6, 127.1, 124.9, 124.4, 122.9, 120.5, 59.2, 38.1, 35.2, 31.2, 30.2, 29.9. HR-MS (ESI-TOF) m/z: cal. for C₂₄H₂₉BrN₂S [M + H]⁺: 457.1306 and 459.1286; found: 457.1308 and 459.1288.

2-(2-Bromophenyl)-2-cyano-N-phenylpent-4-enethioamide (3s)

Yield: 60% (0.222 g); pale yellow solid; R_f: 0.5 in 30% EtOAc in hexanes; mp: 102–104 °C; IR (ν cm^–1) = 3841, 3004, 2347, 1697, 1558, 1541, 1269, 753, 664; ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 7.62–7.53 (m, 4H), 7.37 (t, 3H), 7.28–7.19 (m, 2H), 2.81–2.73 (m, 1H), 2.61–2.53 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 196.0, 137.9, 136.7, 136.2, 130.6, 129.7, 129.2, 127.9, 127.9, 124.4, 124.3, 118.7, 61.1, 33.8, 9.8. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₆BrN₂S [M + H]⁺: 358.0139 and 360.0119; found: 358.0139 and 360.0139.

2-(2-Bromophenyl)-2-cyano-N-3-diphenylpropanethioamide (3t)

Yield: 96% (0.404 g); yellow solid; R_f: 0.6 in 30% EtOAc in hexanes; mp: 150–152 °C; IR (ν cm^–1) = 3745, 3004, 2986, 2349, 1697, 1469, 1257, 763, 755; ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.65 (d, J = 8.0 Hz, 4H), 7.58 (d, J = 8.0 Hz, 3H), 7.40–7.36 (m, 3H), 7.31–7.24 (m, 6H), 7.21–7.17 (m, 1H), 7.08 (d, J = 7.6 Hz, 2H), 3.97 (d, J = 12.4 Hz, 1H), 3.72 (d, J = 12.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 196.0, 137.6, 136.4, 136.2, 133.5, 130.65, 130.57, 129.4, 129.0, 128.6, 128.4, 127.9, 127.8, 124.8, 124.5, 118.6, 61.1, 44.9. HR-MS (ESI-TOF) m/z: cal. for C₂₂H₁₇BrN₂S [M + H]⁺: 443.0188 and 445.0168; found: 443.0183 and 445.0144.

2-(2-Bromophenyl)-2-cyano-N-phenylpent-4-enethioamide (3u)

Yield: 74% (0.274 g); yellow solid; R_f: 0.32 in 30% EtOAc in hexanes; mp: 125–127 °C; IR (ν cm^–1) = 3343, 3274, 2359, 1595, 1467, 1374, 1076, 753, 641, 489; ¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.49–7.44 (m, 3H), 7.37–7.29 (m, 2H), 6.93–5.93 (m, 1H), 5.47–5.37 (m, 2H), 3.55 (dd, J = 13.0, 7.6 Hz, 1H), 3.36 (dd, J = 13.0, 6.9 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 195.2, 137.9, 135.4, 135.2, 130.6, 130.1, 129.7, 129.2, 127.9, 127.9, 124.5, 124.4, 122.1, 118.5, 60.1, 44.3. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₆BrNO₂S [M + H]⁺: 393.0032 and 395.0011; found: 393.0037 and 395.0023.

Methyl 2-(2-bromophenyl)-2-methyl-3-(phenylamino)-3-thioxopropanoate (3v)

Yield: 70% (0.264 g); yellow solid; R_f: 0.32 in 30% EtOAc in hexanes; mp: 102–104 °C; IR (ν cm^–1) = 3189, 3061, 2949, 2359, 1717, 1497, 1255, 1032, 741, 557, 460; ¹H NMR (400 MHz, CDCl₃) δ 12.49 (s, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.65–7.54 (m, 2H), 7.51–7.40 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 201.39, 177.6, 141.8, 139.2, 133.4, 129.4, 128.9, 128.8, 127.2, 126.9, 125.2, 123.8, 63.1, 53.8, 29.0. HR-MS (ESI-TOF) m/z: cal. for C₁₇H₁₆BrNO₂S [M + H]⁺: 378.0158 and 380.0143; found: 378.0161 and 380.0138.

2-(2-Bromophenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3w)

Yield: 72% (0.268 g); yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 132–134 °C; IR (ν cm^–1) = 3357, 3287, 3061, 2931, 2359, 2239, 1509, 1392, 1049, 995, 545; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.49–7.38 (m, 5H), 5.77–5.74 (m, 1H), 2.26 (s, 3H), 1.68 (d, J = 6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 196.7, 140.6, 135.7, 135.2, 134.9, 130.7, 128.9, 128.1, 127.9, 126.4, 124.5, 119.6, 55.4, 55.5, 28.6, 19.3. HR-MS (ESI-TOF) m/z: cal. for C₁₈H₁₇N₂SBr [M + H]⁺: 373.0369 and 375.0348; found: 373.1061 and 375.0361.

2-(2-Bromo-4,5-dimethoxyphenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3x)

Yield: 79% (0.342 g); pale yellow solid; R_f: 0.30 in 30% EtOAc in hexanes; mp: 94–96 °C; IR (ν cm^–1) = 3289, 2934, 2841, 2359, 1596, 1390, 1262, 1172, 1022, 855, 667; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (400 MHz) δ 7.93 (s, 1H), 7.39–7.35 (m, 5H), 7.095 (s, 1H), 7.03 (s, 1H), 5.75–5.71 (m, 1H), 3.879 (s, 6H), 2.21 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.0, 150.1, 148.5, 140.3, 128.9, 128.2, 127.5, 126.8, 119.8, 117.6, 114.9, 112.3, 56.4, 55.54, 55.50, 55.1, 28.8, 19.4. HR-MS (ESI-TOF) m/z: cal. for C₂₀H₂₁BrN₂O₂S [M + H]⁺: 433.0580 and 435.0568; found: 433.0583 and 435.0560.

2-(6-Bromo-3,4-methylenedioxyphenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3y)

Yield: 75% (0.312 g); yellow solid; R_f: 0.34 in 30% EtOAc in hexanes; mp: 142–144 °C; IR (ν cm^–1) = 3353, 2902, 2359, 1725, 1657, 1480, 1389, 1125, 699, 430; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (700 MHz, CDCl₃) δ 7.79 (s, 1H), 7.44–7.29 (m, 5H), 7.06 (s, 1H), 7.01 (s, 1H), 6.04 (s, 2H), 5.72–5.70 (m, 1H), 2.17 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H). ¹³C NMR (175 MHz, CDCl₃) δ 197.2, 149.0, 147.9, 140.2, 129.0, 128.9, 128.2, 119.6, 116.0, 114.7, 109.1, 102.5, 55.5, 55.4, 55.0, 29.3, 19.4. HR-MS (ESI-TOF) m/z: cal. for C₁₉H₁₇BrN₂O₂S [M + H]⁺: 417.0267 and 419.0247; found: 417.0266 and 419.0245.

2-(2-Chlorophenyl)-2-cyano-N-phenylpropanethioamide (3z)

Yield: 74% (0.222 g); viscous liquid; R_f: 0.30 in 30% EtOAc in hexanes; IR (ν cm^–1) = 3230, 2996, 2984, 2290, 1734, 1479, 1235, 1018, 735, 565; ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36–7.33 (m, 4H), 7.24 (t, J = 8.0 Hz, 1H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.6, 138.0, 134.6, 134.4, 131.9, 130.9, 129.2, 128.9, 127.8, 127.6, 124.4, 119.8, 54.8, 28.2. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₃ClN₂S [M + H]⁺: 301.0561; found: 301.0548.

2-(2-Iodophenyl)-2-cyano-N-phenylpropanethioamide (3aa)

Yield: 70% (0.274 g); viscous liquid; R_f: 0.32 in 30% EtOAc in hexanes; IR (ν cm^–1) = 3234, 3012, 2997, 2306, 1729, 1468, 1249, 1006, 729, 640; ¹H NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.47–7.43 (m, 2H), 7.37–7.33 (m, 1H), 2.43 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.4, 142.7, 138.0, 130.9, 129.7, 129.4, 129.2, 128.9, 127.8, 124.3, 119.8, 99.2, 59.2, 29.4. HR-MS (ESI-TOF) m/z: cal. for C₁₆H₁₃IN₂S [M + H]⁺: 414.9736; found: 414.9743.

Procedure for Optimization of Benzo[b]thiolane 1a

An oven-dried 8 mL reaction vial was charged with copper salt (5 mol %), base (1.5 mmol), the respective thioamide 3a (0.5 mmol) in a solvent (2.0 mL). The mixture was stirred at 90 °C for 2.5–3.5 h. The reaction mixture was monitored by TLC. After the starting material was completely consumed, the reaction mixture was purified by flash chromatography using hexane and EtOAc as the eluents.

General Procedure for the Synthesis of Benzo[b]thiolanes 1

An oven-dried 8 mL reaction vial was charged with CuBr (5 mol %), Et₃N (0.75 mmol), and respective thioamides 3a–y in 2.0 mL of DMF solvent, which was stirred at 90 °C for 2.5–12 h. The reaction mixture was monitored by TLC. After the starting material was completely consumed, the reaction mixture was purified by flash chromatography using hexane and EtOAc as the eluents.

3-Cyano-3-methyl-2-phenyliminobenzo[b]thiolane (1a)

Reaction time: 1.5 h; yield: 98% (0.129 g); pale yellow solid; R_f = 0.28 in 30% EtOAc in hexane; mp = 119–121 °C; IR (KBr, ν cm^–1): 3449, 2364, 1653, 1448, 1113, 667; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.36–7.30 (m, 2H), 7.26–7.21 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 2.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 150.2, 135.7, 135.3, 130.3, 129.4, 126.9, 125.9, 124.6, 123.1, 119.7, 119.4, 52.0, 28.8. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₂N₂S: 265.0794; found: 265.0799.

3-Cyano-3-methyl-2-(4-methoxyphenyl)iminobenzo[b]thiolane (1b)

Reaction time: 1.5 h; yield: 91% (0.134 g); pale yellow solid; R_f = 0.33 in 30% EtOAc in hexane; mp = 143–145 °C; IR (KBr, ν cm^–1): 2929, 2840, 2190, 1641, 1505, 1244, 838, 702; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.19–7.10 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.06 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 170.4, 155.6, 145.3, 135.6, 134.2, 130.6, 127.5, 125.4, 124.8, 123.4, 120.2, 118.9, 52.3, 28.98, 28.99. HR-MS (ESI-TOF), m/z: [M + H] + cal. for C₁₇H₁₄N₂OS: 295.0900; found: 295.0908.

3-Cyano-3-methyl-2-(4-methylphenyl)iminobenzo[b]thiolane (1c)

Reaction time: 2 h; yield: 85% (0.129 g); brown viscous liquid; R_f = 0.29 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2950, 2365, 1270, 1018, 759, 665; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 7.6 Hz, 1H), 7.38–7.29 (m, 2H), 7.26–7.23 (m, 3H), 6.99 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 147.6, 135.72, 135.69, 135.4, 130.2, 129.9, 126.9, 124.6, 123.1, 119.8, 119.5, 52.0, 28.8, 21.1. HR-MS (ESI-TOF), m/z: [M + Na]⁺ cal. for C₁₇H₁₄N₂S: 301.0770; found: 301.0787.

3-Cyano-3-methyl-2-(4-fluorophenyl)iminobenzo[b]thiolane (1d)

Reaction time: 1.5 h; yield: 79% (0.111 g); pale yellow solid; R_f = 0.28 in 30% EtOAc in hexane; mp = 148–150 °C; IR (KBr, ν cm^–1): 3335, 2150,1683, 1509, 1410, 1220, 838, 761; ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.65 (m, 2H), 7.49–7.46 (m, 1H), 7.42–7.39 (m, 2H), 7.35–7.30 (m, 1H), 7.05–7.00 (m, 2H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 160.2 (d, J = 244.2 Hz), 135.2, 134.1, 132.7 (d, J = 2.9 Hz), 131.1, 129.2, 128.5, 123.8, 122.8 (d, J = 8.3 Hz), 119.4, 115.9 (d, J = 22.7 Hz), 50.1, 24.2; ¹⁹F NMR (376 Hz, CDCl₃) δ −116.19. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₁N₂SF: 283.0700; found: 283.0732.

3-Cyano-3-methyl-2-(4-nitrophenyl)iminobenzo[b]thiolane (1e)

Reaction time: 1 h; yield: 97% (0.149 g); pale yellow solid; R_f = 0.28 in 30% EtOAc in hexane; mp = 147–149 °C; IR (KBr, ν cm^–1): 3335, 2253, 1683, 1509, 1410, 1220, 838, 761; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.42–7.38 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 2.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 155.6, 145.3, 135.6, 134.1, 130.6, 127.5, 125.4, 124.8, 123.3, 120.2, 118.9, 52.3, 28.8. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₁N₃O₂S: 310.0645; found: 310.0617.

3-Cyano-3-methyl-2-(2-methoxyphenyl)iminobenzo[b]thiolane (1f)

Reaction time: 1.5 h; yield: 90% (0.132 g); pale yellow solid; R_f = 0.32 in 30% EtOAc in hexane; mp = 106–108 °C; IR (KBr, ν cm^–1): 3469, 2837, 2240, 1651, 1589, 1490, 1254, 751, 712; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 7.2 Hz, 1H), 7.36–7.26 (m, 2H), 7.23–7.17 (m, 2H), 7.01–6.96 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 2.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 149.6, 139.6, 136.0, 135.4, 130.2, 126.8, 126.7, 124.6, 123.0, 121.1, 119.8, 119.3, 112.3, 112.3, 55.9, 51.6, 28.8. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₇H₁₄N₂OS: 295.0900; found: 295.0914.

3-Cyano-3-methyl-2-(2-trifluoromethylphenyl)iminobenzo[b]thiolane (1g)

Reaction time: 2.5 h; yield: 75% (0.124 g); pale yellow solid; R_f = 0.25 in 30% EtOAc in hexane; mp = 106–108 °C; IR (KBr, ν cm^–1): 3851, 2949, 2258, 1700, 1507, 1289, 665; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.0 Hz, 1H), 7.62–7.56 (m, 2H), 7.39–7.30 (m, 3H), 7.26 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 2.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.1, 148.56, 148.55, 135.8, 134.6, 133.1, 130.5, 127.2, 126.8 (q, J = 9.5 Hz), 125.3, 124.8, 123.5 (q, J = 271.6 Hz), 120.8 (q, J = 30.8 Hz), 119.2, 118.9, 51.9, 28.4; ¹⁹F NMR (376 Hz, CDCl₃) δ −61.44. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₇H₁₁F₃N₂S: 333.0668; found: 333.0666.

3-Cyano-3-methyl-2-(benzyl)iminobenzo[b]thiolane (1h)

Reaction time: 6 h; yield: 65% (0.090 g); pale yellow solid; R_f = 0.28 in 30% EtOAc in hexane; mp = 84–86 °C; IR (KBr, ν cm^–1): 3449, 2364, 1653, 1490, 1254, 751, 667; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 7.2 Hz, 1H), 7.43–7.28 (m, 8H), 4.71 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 15.6 Hz, 1H), 1.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 137.9, 136.0, 134.8, 130.2, 128.5, 127.6, 127.2, 126.9, 124.6, 123.2, 119.7, 61.1, 51.6, 28.8. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₇H₁₄N₂S: 279.0950; found: 279.0958.

3-Cyano-3-methyl-2-(isopropyl)iminobenzo[b]thiolane (1i)

Reaction time: 6 h; yield: 73% (0.084 g); brown viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3547, 2934, 2238, 1651, 1130, 987, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 7.2 Hz, 1H), 7.38–7.27 (m, 3H), 3.40–3.34 (m, 1H), 1.90 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 160.8, 135.9, 135.2, 130.0, 126.6, 124.5, 123.1, 119.9, 59.7, 51.2, 28.8, 22.5, 22.4. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₃H₁₄N₂S: 231.0950; found: 231.0944.

3-Cyano-3-methyl-2-(ethyl)iminobenzo[b]thiolane (1j)

Reaction time: 12 h; yield: 79% (0.084 g); yellow viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3452, 2979, 2349, 1656, 1470, 982, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.0 Hz, 1H), 7.38–7.28 (m, 3H), 3.52–3.34 (m, 2H), 1.91 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 136.0, 135.0, 130.1, 126.7, 124.5, 123.2, 119.8, 52.8, 51.3, 28.8, 14.7. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₂H₁₂N₂S: 217.0794; found: 217.0805.

3-Cyano-3-methyl-2-(tert-butyl)iminobenzo[b]thiolane (1k)

Reaction time: 6.5 h; yield: 77% (0.094 g); yellow viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3452, 2979, 2336, 1656, 1512, 1470, 982, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.34–7.24 (m, 2H), 1.86 (s, 3H), 1.38 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 155.3, 136.7, 135.3, 129.9, 126.4, 124.4, 122.6, 120.3, 57.2, 53.6, 29.3, 28.1. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₄H₁₆N₂S: 245.1107; found: 245.1109.

3-Cyano-3-methyl-2-phenylimino-5,6-dimethoxybenzo[b]thiolane (1l)

Reaction time: 1 h; yield: 96% (0.155 g); brown viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2946, 2365, 2237, 1265, 1012, 810, 657; ¹H NMR (400 MHz, CD₃SOCD₃) δ 7.46 (t, J = 7.6 Hz, 2H), 7.39 (s, 1H), 7.25 (t, J = 7.0 Hz, 2H), 7.14 (s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 2.02 (s, 3H); ¹³C NMR (100 MHz, CD₃SOCD₃) δ 169.1, 151.4, 150.5, 149.2, 130.0, 126.8, 126.2, 125.4, 120.2, 119.8, 109.2, 107.4, 56.7, 56.5, 52.2, 27.9. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₈H₁₆N₂O₂S: 325.1005; found: 325.1032.

3-Cyano-3-methyl-2-(phenylimino)-5,6-methylenedioxybenzo[b]thiolane (1m)

Reaction time: 1 h; yield: 92% (0.155 g); pale yellow solid; mp = 121–123 °C; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2952, 2815, 2340, 1628, 1539, 1195, 750, 660; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 6.03 (s, 2H), 2.02 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.4, 150.1, 149.5, 147.5, 129.4, 127.7, 126.9, 125.9, 119.7, 119.4, 105.2, 103.6, 102.0, 52.1, 28.7. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₇H₁₂N₂O₂S: 309.0692; found: 309.0631.

3-Cyano-3-methyl-2-phenylimino-6,7-dimethoxybenzo[b]thiolane (1n)

Reaction time: 2 h; yield: 79% (0.128 g); white solid; mp = 128–130 °C; R_f = 0.30 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2930, 2829, 2339, 1630, 1506, 1239, 826, 700; ¹H NMR (700 MHz, CDCl₃) δ 7.40 (t, J = 7.7 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.10 (s, 3H), 3.88 (s, 3H), 2.08 (s, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 168.0, 151.5, 150.4, 146.7, 129.3, 129.0, 126.3, 125.7, 119.6, 117.6, 114.7, 60.9, 56.2, 51.2, 26.6. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₈H₁₆N₂O₂S: 325.1005; found: 325.1004.

3-Cyano-3-methyl-2-(4-methylphenyl)imino-6,7-dimethoxybenzo[b]thiolane (1o)

Reaction time: 2 h; yield: 80% (0.135 g); pale yellow solid; mp = 124–126 °C; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2949, 2367, 1269, 1016, 811, 667; ¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 8.0 Hz, 2H), 6.96–6.85 (m, 4H), 4.09 (s, 3H), 3.88 (s, 3H), 2.36 (s, 3H), 2.06 (s, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 167.1, 151.4, 147.8, 146.7, 135.4, 129.8, 129.0, 126.5, 119.7, 119.6, 117.5, 114.6, 60.8, 56.2, 51.2, 26.6, 21.0. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₉H₁₈N₂O₂S: 339.1162; found: 339.1161.

3-Cyano-3-methyl-2-phenylimino-6-chlorobenzo[b]thiolane (1p)

Reaction time: 1 h; yield: 42% (0.062 g); brown viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3442, 2362, 1641, 1252, 970, 670; ¹H NMR (400 MHz, CDCl₃) δ 7.49–7.43 (m, 3H), 7.32–7.24 (m, 3H), 7.06 (d, J = 7.6 Hz, 2H), 2.05(s, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 165.6, 149.8, 137.2, 136.2, 129.5, 127.3, 126.1, 125.5, 123.1, 119.6, 118.9, 51.5, 28.7. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₁ClN₂S: 299.0404; found: 299.0393.

3-Cyano-3-methyl-2-phenylimino-6-fluorobenzo[b]thiolane (1q)

Reaction time: 1 h; yield: 35% (0.049 g); white solid; mp = 106–108 °C; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3427, 2359, 1656, 1222, 670; ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.48 (m, 1H), 7.43–7.39 (m, 2H), 7.25–7.21 (m, 1H), 7.04–7.00 (m, 3H), 6.99–6.95 (m, 1H), 2.02 (s, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 165.4 (d, J = 234 Hz), 162.3, 149.9, 137.4 (d, J = 16.9 Hz), 131.5 (d, J = 8.0 Hz), 129.5, 126.2, 126.0 (d, J = 16.1 Hz), 119.7, 119.2, 114.3 (d, J = 40 Hz), 110.8 (d, J = 45.1 Hz), 51.3, 28.9; ¹⁹F NMR (376 Hz, CDCl₃) δ −109.43. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₁FN₂S: 283.0700; found: 283.0678.

3-Cyano-3-methyl-2-phenylimino-4,6-di-tertbutylbenzo[b]thiolane (1r)

Reaction time: 3 h; yield: 92%; pale yellow solid; mp = 192–194 °C; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2964, 2341, 1635, 1538, 1436, 1145, 1071, 743, 502, 442; ¹H NMR (700 MHz, CDCl₃) δ 7.44–7.42 (m, 4H), 7.22 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 2.04 (s, 3H), 1.36 (s, 9H), 1.35(s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 150.4, 144.9, 136.7, 129.3, 129.2, 125.6, 124.7, 120.0, 119.9, 119.2, 51.7, 35.8, 34.9, 31.3, 29.4, 29.3. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₂₄H₂₈N₂S: 377.2046; found: 377.2050.

3-Cyano-3-ethyl-2-phenyliminobenzo[b]thiolane (1s)

Reaction time: 2.5 h; yield: 95%; pale yellow solid; R_f: 0.6 in 30% EtOAc in hexane; mp = 85–86 °C; IR (KBr, ν cm^–1) = 3738, 3006, 2989, 2849, 2253, 1763, 1279, 1264, 763, 656. ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.48 (m, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.37–7.28 (m, 2H), 7.24–7.19 (m, 2H), 7.04–7.01 (m, 2H), 2.51–2.41 (m, 1H), 2.39–2.32 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 150.4, 136.4, 134.2, 130.2, 129.5, 126.8, 125.9, 125.0, 123.1, 119.7, 119.0, 56.6, 35.9, 8.1. HR-MS (ESI-TOF), m/z [M + H]⁺ cal. for C₁₇H₁₄N₂S: 279.0950; found: 279.0954.

3-Cyano-3-benzyl-2-phenyliminobenzo[b]thiolane (1t)

Reaction time: 2.5 h; yield: 85%; white solid; R_f: 0.7 in 30% EtOAc in hexanes; mp = 145–147 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (t, J = 7.6 Hz, 2H), 7.25–7.14 (m, 7H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 3.60–3.51 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 150.1, 136.5, 133.3, 132.5, 130.7, 130.3, 129.4, 128.2, 128.0, 126.3, 125.95, 125.86, 122.9, 119.8, 118.5, 57.1, 48.0. HR-MS (ESI-TOF), m/z [M + H]⁺ cal. for C₂₂H₁₆N₂S: 341.1107; found: 341.1092.

3-Cyano-3-allyl-2-phenyliminobenzo[b]thiolane (1u)

Reaction time: 6 h; yield: 52% (0.075 g); viscous liquid; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3447, 2956, 2248, 1652, 1465, 960, 742, 656; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 8.0 Hz, 4H), 7.44 (t, J = 7.8 Hz, 2H), 7.39–7.31 (m, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.81–5.70 (m, 1H), 5.24 (t, J = 15.2 Hz, 2H), 3.13 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 150.3, 136.1, 133.7, 130.2, 129.4, 129.1, 126.6, 125.9, 125.3, 123.0, 121.9, 119.7, 118.5, 55.7, 46.3. HR-MS (ESI-TOF), m/z: [M + Na]⁺ cal. for C₁₈H₁₄N₂S: 313.0770; found: 313.0803.

3-Methyl ester-3-methyl-2-phenyliminobenzo[b]thiolane (1v)

Reaction time: 3.5 h; yield: 89% (0.132 g); brown viscous compound; R_f = 0.28 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2954, 2280, 1745, 1487, 1237, 959, 697; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 7.6 Hz, 1H), 7.37–7.27 (m, 4H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.04(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 164.7, 157.8, 142.9, 136.6, 135.5, 130.2, 126.9, 124.6, 123.1, 121.6, 119.6, 144.5, 55.5, 52.2, 28.9. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₇H₁₅N₂OS: 298.0896; found: 298.0905.

3-Cyano-3-methyl-2-(1-phenylethyl)iminobenzo[b]thiolane (1w)

Reaction time: 1.5 h; yield: 75% (0.109 g); viscous liquid; R_f = 0.29 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 3061, 2972, 2850, 2240, 1651, 1352, 1026, 884, 578; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.45 (m, 3H), 7.41–7.35 (m, 3H), 7.32–7.28 (m, 3H), 4.44–4.38 (m, 1H), 2.00 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 162.8, 143.7, 135.9, 135.1, 130.1, 128.5, 127.2, 126.8, 126.4, 124.6, 123.2, 119.7, 66.9, 51.5, 29.1, 23.9. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₈H₁₆N₂S: 293.1107; found: 293.1135.

3-Cyano-3-methyl-2-(1-phenylethyl)imino-5,6-methylenedioxybenzo[b]thiolane (1x)

Reaction time: 2 h; yield: 75% (0.132 g); viscous liquid; R_f = 0.32 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2967, 2359, 1653, 1497, 1277, 1175, 1032, 699, 435; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.28 (m, 5H), 6.99 (s, 1H), 6.76 (s, 1H), 4.36–4.33 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 1.96 (s, 3H), 1.62 (d, J = 5.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.7, 150.9, 149.6, 143.7, 128.5, 127.2, 125.9, 120.1, 114.0, 107.5, 105.9, 67.3, 56.3, 51.9, 29.7, 29.0, 23.9. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₂₀H₂₀N₂O₂S: 353.1318; found: 353.1301.

3-Cyano-3-methyl-2-(1-phenylethyl)imino-5,6-dimethoxybenzo[b]thiolane (1y)

Reaction time: 2.5 h; yield: 66% (0.126 g); viscous liquid; R_f = 0.30 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2958, 2365, 1637, 1285, 1167, 1022, 720, 585; diastereoselectivity ratio: 1:1 (only one diastereomer is given); ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.28 (m, 5H), 6.79 (s, 1H), 6.74 (s, 1H), 6.01 (s, 2H), 4.36–4.33 (m, 1H), 1.95 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 155.9, 142.7, 136.6, 132.9, 132.4, 128.59, 128.58, 127.9, 127.7, 126.7, 126.2, 114.0, 113.9, 50.2, 50.1, 40.1, 34.2. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₉H₁₆N₂O₂S: 337.1005; found: 337.1000.

Procedure for (Z)-3-Methyl-2-(phenylimino)-2,3-dihydrobenzo[b]thiophene-3-carboxamide (7a)

An oven-dried 8 mL reaction vial was charged with 1a (0.50 mmol) and TfOH (5 mmol) in 2.0 mL of DCE solvent, which was stirred at 60 °C for 2 h. The reaction mixture was monitored by TLC. After the starting material was completely consumed, the reaction mixture was quenched with saturated NaHCO₃ solution and extracted with EtOAc. The combined organic layer was washed with water (3 × 25 mL), dried over anhydrous Na₂SO₄, and concentrated under a reduced pressure. The crude product was purified by flash chromatography using hexane and EtOAc as the eluents.

Reaction time: 2 h; yield: 77% (0.108 g); pale yellow solid; R_f = 0.28 in 30% EtOAc in hexane; mp = 121–123 °C; IR (KBr, ν cm^–1): 2958, 2365, 1637, 1285, 1167, 1022, 720, 585; ¹H NMR (400 MHz, CDCl₃) δ 7.65–7.31 (m, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.30–7.24 (m, 4H), 7.04 (d, J = 7.2 Hz, 2H), 5.64 (s, 1H), 1.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 174.5, 172.3, 151.2, 139.4, 135.0, 129.5, 129.0, 127.0, 126.2, 125.6, 122.3, 119.8, 63.5, 28.4. HR-MS (ESI-TOF), m/z: [M + Na]⁺ cal. for C₁₆H₁₄N₂OS: 305.0719; found: 305.0725.

Procedure for 2-(2-Mercaptophenyl)-2-methyl-N-phenylmalonamide (8a)

In an oven-dried round-bottom flask, 1a (0.5 mmol) was taken. To it, conc. H₂SO₄ was added (10 mL). Then, it was stirred at room temperature for 2 h (in the case of HCl, 1a was dissolved in EtOH (12 mL). To it, conc. HCl (1.5 mmol) was added. Then, it was stirred at 60 °C for 3 h). After the starting material (monitored by TLC) was completely consumed, the reaction was quenched with cold NaHCO₃ solution and extracted with EtOAc. The combined organic layer was washed with water (3 × 25 mL), dried over anhydrous Na₂SO₄, and concentrated under a reduced pressure. The crude product was purified by flash chromatography using hexane and EtOAc as eluents.

Reaction time: 2 h; yield: 99% (0.148 g) [68% (0.102 g)]; viscous liquid; R_f = 0.25 in 30% EtOAc in hexane; IR (KBr, ν cm^–1): 2960, 2100, 1549, 1290, 1158, 1122, 720, 585; ¹H NMR (400 MHz, CDCl₃) δ 7.66–7.65 (m, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.32–7.23 (m, 4H), 7.06 (d, J = 7.2 Hz, 2H), 5.83 (s, 1H), 1.99 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 174.5, 172.0, 151.0, 139.2, 134.9, 129.4, 128.9, 126.9, 126.1, 125.5, 122.2, 119.7, 63.4, 28. HR-MS (ESI-TOF), m/z: [M + H]⁺ cal. for C₁₆H₁₆N₂O₂S: 301.1000; found: 301.1010.

Crystal data for 1a in CH₂Cl₂/n-hexane: C₁₆H₁₂N₂S, M_w = 264.34, triclinic, space group P-1, a = 8.1526(2) Å, b = 9.0963(2) Å, c = 10.4069(2) Å, α = 106.308(2)°, β = 104.374(2)°, γ = 103.637(2)°, V = 677.69(3) Å³, Z = 2, D_calc = 1.295 g/cm³, T = 291 K, R1 = 0.0408(2645), wR2 = 0.1105(2813), and GOF = 1.046.

Crystal data for 7a in CH₂Cl₂/n-hexane: C₁₆H₁₄N₂OS, M_w = 282.35, monoclinic, space group C 2/c, a = 18.6061(13) Å, b = 6.3779(3) Å, c = 24.5520(12) Å, α = 90°, β = 103.547(4)°, γ = 90°, V = 2832.5(3) Å³, Z = 8, D_calc = 1.324 g/cm³, T = 293 K, R1 = 0.0149(2945), wR2 = 0.0276(3228), and GOF = 1.092.

Acknowledgments

The Department of Atomic Energy supported this work. We thank the Science and Engineering Research Board (SERB), New Delhi (Grant EMR/2017/005521) for the financial support. We thank Dr. Krishnan Venkatasubbaiah for solving one of the X-ray crystal data.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c03410.

¹H NMR and ¹³C NMR spectra of all of the compounds, synthesis of α-trisubstituted thioamides, and HPLC data of 1w–y and 3w–y (PDF)
X-ray crystallographic data for compounds 4a and 7a (CIF)
X-ray data were also deposited at the CCDC (entries 2082713 and 2082714) (CIF)

The authors declare no competing financial interest.

Supplementary Material

ao1c03410_si_001.pdf^{(8.2MB, pdf)}

ao1c03410_si_002.cif^{(327KB, cif)}

ao1c03410_si_003.cif^{(334.7KB, cif)}

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Associated Data

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Supplementary Materials

ao1c03410_si_001.pdf^{(8.2MB, pdf)}

ao1c03410_si_002.cif^{(327KB, cif)}

ao1c03410_si_003.cif^{(334.7KB, cif)}

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[ref23] 1a was treated with LAH affording an intractable mixture of compounds, which could not characterized, whereas in NaBH₄ in TFA, 1a was recovered completely.

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PERMALINK

Chemoselective Ullmann Reaction of α-Trisubstituted Thioamides: Synthesis of Novel 2-Iminobenzothiolanes

Anwesha Bhattacharya

Annaram Thirupathi

Pradeep Natarajan

Saravanan Peruncheralathan

Abstract

Introduction

Figure 1.

Results and Discussion

Table 1. Optimization of S-Arylation of α-Trisubstituted Thioamide 3.

Table 2. Scope of the Copper-Catalyzed S-Arylation of α-Trisubstituted Thioamides 3b–ya.

Scheme 1. Hydrolysis of Benzo[b]thiolane 1a.

Scheme 2. Plausible Mechanism for the Formation of Benzo[b]thiolane 1.

Conclusions

Experimental Section

General Information

General Procedure for the Synthesis of Thioamides 3a–aa

2-(2-Bromophenyl)-2-cyano-N-phenylpropanethioamide (3a)

2-(2-Bromophenyl)-2-cyano-N-(4-methoxyphenyl)propanethioamide (3b)

2-(2-Bromophenyl)-2-cyano-N-(p-tolyl)propanethioamide (3c)

2-(2-Bromophenyl)-2-cyano-N-(4-fluorophenyl)propanethioamide (3d)

2-(2-Bromophenyl)-2-cyano-N-(4-nitrophenyl)propanethioamide (3e)

2-(2-Bromophenyl)-2-cyano-N-(2-methoxyphenyl)propanethioamide (3f)

2-(2-Bromophenyl)-2-cyano-N-(2-(trifluoromethyl)phenyl)propanethioamide (3g)

N-Benzyl-2-(2-bromophenyl)-2-cyanopropanethioamide (3h)

2-(2-Bromophenyl)-2-cyano-N-isopropylpropanethioamide (3i)

2-(2-Bromophenyl)-2-cyano-N-ethylpropanethioamide (3j)

2-(2-Bromophenyl)-N-(tert-butyl)-2-cyanopropanethioamide (3k)

2-(2-Bromo-4,5-dimethoxyphenyl)-2-cyano-N-phenylpropanethioamide (3l)

2-(6-Bromo-3,4-methylenedioxyphenyl)-2-cyano-N-phenylpropanethioamide (3m)

2-(6-Bromo-2,3-dimethoxyphenyl)-2-cyano-N-phenylpropanethioamide (3n)

2-(6-Bromo-2,3-dimethoxyphenyl)-2-cyano-N-(p-tolyl)propanethioamide (3o)

2-(2-Bromo-4-chlorophenyl)-2-cyano-N-phenylpropanethioamide (3p)

2-(2-Bromo-4-fluorophenyl)-2-cyano-N-phenylpropanethioamide (3q)

2-(2-Bromo-3,5-di-tert-butylphenyl)-2-cyano-N-phenylpropanethioamide (3r)

2-(2-Bromophenyl)-2-cyano-N-phenylpent-4-enethioamide (3s)

2-(2-Bromophenyl)-2-cyano-N-3-diphenylpropanethioamide (3t)

2-(2-Bromophenyl)-2-cyano-N-phenylpent-4-enethioamide (3u)

Methyl 2-(2-bromophenyl)-2-methyl-3-(phenylamino)-3-thioxopropanoate (3v)

2-(2-Bromophenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3w)

2-(2-Bromo-4,5-dimethoxyphenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3x)

2-(6-Bromo-3,4-methylenedioxyphenyl)-2-cyano-N-(1-phenylethyl)propanethioamide (3y)

2-(2-Chlorophenyl)-2-cyano-N-phenylpropanethioamide (3z)

2-(2-Iodophenyl)-2-cyano-N-phenylpropanethioamide (3aa)

Procedure for Optimization of Benzo[b]thiolane 1a

General Procedure for the Synthesis of Benzo[b]thiolanes 1

3-Cyano-3-methyl-2-phenyliminobenzo[b]thiolane (1a)

3-Cyano-3-methyl-2-(4-methoxyphenyl)iminobenzo[b]thiolane (1b)

3-Cyano-3-methyl-2-(4-methylphenyl)iminobenzo[b]thiolane (1c)

3-Cyano-3-methyl-2-(4-fluorophenyl)iminobenzo[b]thiolane (1d)

3-Cyano-3-methyl-2-(4-nitrophenyl)iminobenzo[b]thiolane (1e)

3-Cyano-3-methyl-2-(2-methoxyphenyl)iminobenzo[b]thiolane (1f)

3-Cyano-3-methyl-2-(2-trifluoromethylphenyl)iminobenzo[b]thiolane (1g)

3-Cyano-3-methyl-2-(benzyl)iminobenzo[b]thiolane (1h)

3-Cyano-3-methyl-2-(isopropyl)iminobenzo[b]thiolane (1i)

3-Cyano-3-methyl-2-(ethyl)iminobenzo[b]thiolane (1j)

3-Cyano-3-methyl-2-(tert-butyl)iminobenzo[b]thiolane (1k)

3-Cyano-3-methyl-2-phenylimino-5,6-dimethoxybenzo[b]thiolane (1l)

3-Cyano-3-methyl-2-(phenylimino)-5,6-methylenedioxybenzo[b]thiolane (1m)

3-Cyano-3-methyl-2-phenylimino-6,7-dimethoxybenzo[b]thiolane (1n)

3-Cyano-3-methyl-2-(4-methylphenyl)imino-6,7-dimethoxybenzo[b]thiolane (1o)

3-Cyano-3-methyl-2-phenylimino-6-chlorobenzo[b]thiolane (1p)

3-Cyano-3-methyl-2-phenylimino-6-fluorobenzo[b]thiolane (1q)

3-Cyano-3-methyl-2-phenylimino-4,6-di-tertbutylbenzo[b]thiolane (1r)

3-Cyano-3-ethyl-2-phenyliminobenzo[b]thiolane (1s)

3-Cyano-3-benzyl-2-phenyliminobenzo[b]thiolane (1t)

3-Cyano-3-allyl-2-phenyliminobenzo[b]thiolane (1u)

3-Methyl ester-3-methyl-2-phenyliminobenzo[b]thiolane (1v)

3-Cyano-3-methyl-2-(1-phenylethyl)iminobenzo[b]thiolane (1w)

3-Cyano-3-methyl-2-(1-phenylethyl)imino-5,6-methylenedioxybenzo[b]thiolane (1x)

3-Cyano-3-methyl-2-(1-phenylethyl)imino-5,6-dimethoxybenzo[b]thiolane (1y)

Procedure for (Z)-3-Methyl-2-(phenylimino)-2,3-dihydrobenzo[b]thiophene-3-carboxamide (7a)

Procedure for 2-(2-Mercaptophenyl)-2-methyl-N-phenylmalonamide (8a)

Acknowledgments

Supporting Information Available

Supplementary Material

References

Associated Data

Supplementary Materials

Table 2. Scope of the Copper-Catalyzed S-Arylation of α-Trisubstituted Thioamides 3b–y^a.