Benzo[d][1,2]thiazepin-5-one 3-Oxides: An Unexplored Scaffold with Anticancer Activity

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Abstract

Herein, we report a simple and versatile method for the synthesis of previously unknown benzo[d][1,2]thiazepin-5-one 3-oxides through the CSIC (carbanion-mediated sulfonamide intramolecular cyclization) reaction strategy. The starting compounds are readily available methyl 2-(bromomethyl)benzoates and imino((di)methyl)((het)aryl)-λ⁶-sulfanones. The method works well with a wide range of substrates, proving its applicability for the synthesis of benzo- and heteroarene-fused derivatives. It allows for the effortless preparation of target endocyclic keto sulfoximines and easy scale-up without diminishing the yield. The synthetic utility of the target compounds was demonstrated by the preparation of several derivatives, some of them represented two novel heterocyclic systems. In vitro cytotoxicity assay showed selective cytotoxicity of S-phenyl-substituted benzo[d][1,2]thiazepin-5-one 3-oxide against triple-negative breast cancer cell line MDA-MB-231. The molecular docking study confirmed good binding affinity of both enantiomeric forms of endocyclic keto sulfoximines to the cancer-associated receptors, which are the therapeutic targets in cancer treatment.

Key words

sulfoximines - CSIC reaction - cyclization - cytotoxicity - molecular docking

• References and Notes

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• 13 General procedure for the synthesis of o-(sulfanylideneaminomethyl)benzoates 3a,g,h (Method A) The solution of NH-sulfoximine 2a,g,h (1.0 mmol, 1 equiv.) in anhyd DME (5 mL) was added to the dispersion of KH (30% w/w in mineral oil; 150 mg, 1.1 mmol, 1.1 equiv.) in anhyd DME (10 mL). The resulting mixture was stirred at rt for 1 h. Then TBAB (16 mg, 0.05 mmol, 5 mol%) and methyl 2-(bromomethyl)benzoate (1a; 270 mg, 1.2 mmol, 1.2 equiv.) were added and the mixture was stirred at rt for 24 h. After reaction completion (LCMS control), the mixture was poured into water (50 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), and evaporated under reduced pressure. Thus obtained crude product was purified by flash chromatography (silica gel, EtOAc) to give pure 3a,g,h.
• 14 General procedure for the synthesis of o-(sulfanylideneaminomethyl)benzoates 3a–k (Method B) NaH (60% w/w in mineral oil; 150 mg, 3.6 mmol, 1.2 equiv.) was added in one portion to the stirred solution of NH-sulfoximine 2a–i (3.0 mmol, 1 equiv.) in anhyd THF (30 mL) at 0 °C. The resulting mixture was then stirred at rt for 1 h. Then TBAB (100 mg, 0.3 mmol, 0.1 equiv.) and 2-(bromomethyl)(hetero)arene 1a–c (3.6 mmol, 1.2 equiv) were added and the mixture was vigorously stirred at rt for 24–48 h. After reaction completion (LCMS control), the mixture was quenched with sat. aq NH₄Cl (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and evaporated under reduced pressure. Thus obtained crude product was purified by flash chromatography (silica gel, EtOAc) to give pure 3a–k.
• 15 Methyl 2-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}methyl)benzoate (3c) was obtained from 2-(bromomethyl)benzoate 1a (3.3 g, 14.4 mmol) and NH-sulfoximine 2c (1.86 g 12 mmol) following Method B (reaction time 48 h); yield: 1.64 g (5.4 mmol, 45%); beige solid. The scale of the general procedure was then increased 80-fold without affecting the yield. ¹H NMR (400 MHz, CDCl₃): δ = 3.16 (s, 3 H), 3.82 (s, 3 H), 4.45 (d, J = 16.4 Hz, 1 H), 4.58 (d, J = 16.4 Hz, 1 H), 7.27 (t, J = 7.6 Hz, 1 H), 7.48–7.57 (m, 3 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.88–7.97 (m, 3 H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 45.4, 45.5, 52.0, 126.3, 128.6, 128.7 (2 C), 128.9, 129.5 (2 C), 130.3, 132.3, 133.0, 139.7, 143.3, 168.0. LCMS (CI): m/z = 304 [M + H]⁺. Anal. Calcd for C₁₆H₁₇NO₃S: C, 63.35; H, 5.65; N, 4.62; S, 10.57. Found: C, 63.13; H, 5.74; N, 4.80; S, 10.79.
• 16 General procedure for the synthesis of endocyclic keto sulfoximines 4a–k The solution of (sulfanylideneaminomethyl)carboxylate 3a–k (1 mmol, 1 equiv) in anhyd THF (5 mL) was added dropwise to the stirred solution of t-BuOK (340 mg, 3 mmol, 3 equiv) in anhyd THF (10 mL) at 0 °C. The resulting mixture was then stirred at rt for 2 h whereupon diluted with water (30 mL), acidified with sat. aq NaHSO₄ to pH 4, and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (40 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give 4a–k.
• 17 3-Phenyl-1,4-dihydro-5H-3λ⁶,2-benzothiazepin-5-one 3-oxide (4c) was obtained from linear sulfoximine 3c (1.52 g, 5.0 mmol); yield: 1.22 g (4.5 mmol, 90%); beige solid. The scale of the general procedure was increased 5-fold without affecting the yield. ¹H NMR (500 MHz, DMSO-d ₆): δ = 4.52 (d, J = 16.7 Hz, 1 H), 4.67 (d, J = 13.8 Hz, 1 H), 5.28 (d, J = 16.7 Hz, 1 H), 5.97 (d, J = 13.8 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 2 H), 7.70–7.77 (m, 2 H), 7.86 (d, J = 7.8 Hz, 2 H). ¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 47.8, 66.6, 127.3, 128.9, 129.2 (4 C), 129.9, 132.6, 134.0, 136.2, 136.4, 145.9, 188.4. LCMS (CI): m/z = 272 [M + H]⁺. Anal. Calcd for C₁₅H₁₃NO₂S: C, 66.40; H, 4.83; N, 5.16; S, 11.82. Found: C, 66.57; H, 4.96; N, 5.02; S, 11.69.
• 18 CCDC 2431450 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
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• 20 4-[(Dimethylamino)methylene]-3-phenyl-1,4-dihydro-5H-3λ⁶,2-benzothiazepin-5-one 3-oxide (5) The stirred solution of keto sulfoximine 4c (540 mg, 2 mmol, 1 equiv) and DMF-DMA (0.72 g, 0.8 mL, 6 mmol, 3 equiv) in toluene (25 mL) was refluxed for 2 h. After the scheduled time the mixture was evaporated under reduced pressure and the residue was dissolved in EtOAc (50 mL). The organic layer was sequentially washed with water (2 × 25 mL) and brine (1 × 25 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give crude 5. Thus obtained product was used in the next step without purification; yield: 580 mg (1.8 mmol, 89%); viscous brown oil. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.61 (br s, 3 H), 3.36 (br s, 3 H), 4.15 (d, J = 14.4 Hz, 1 H), 4.89 (d, J = 14.4 Hz, 1 H), 7.34–7.42 (m, 4 H), 7.45–7.52 (m, 2 H), 7.55 (d, J = 8.0 Hz, 2 H), 7.83 (s, 1 H), 7.94 (d, J = 8.1 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 42.7, 46.8, 47.3, 106.1, 127.0 (3 C), 128.1, 128.7 (2 C), 130.2, 131.4, 132.0, 136.8, 144.3, 146.5, 157.4, 181.8. LCMS (CI): m/z = 327 [M + H]⁺. Anal. Calcd for C₁₈H₁₈N₂O₂S: C, 66.23; H, 5.56; N, 8.58; S, 9.82. Found: C, 66.01; H, 5.64; N, 8.49; S, 9.70.
• 21 4-Phenyl-2,6-dihydro-4λ⁶-pyrazolo[4,3-d][3,2]benzothiazepine 4-oxide (6) The stirred solution of (dimethylamino)methylene keto sulfoximine 5 (200 mg, 0.6 mmol, 1 equiv) and N₂H₄·H₂O (150 mg, 145 μL, 3 mmol, 5 equiv) in 1,4-dioxane (20 mL) was refluxed for 1 h. After the scheduled time the mixture was evaporated under reduced pressure, triturated with water (50 mL), and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 25 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give pure 6; yield: 145 mg (0.5 mmol, 82%); yellowish solid. ¹H NMR (500 MHz, DMSO-d ₆): δ = 4.28 (d, J = 14.1 Hz, 1 H), 4.39 (d, J = 14.1 Hz, 1 H), 7.42–7.49 (m, 4 H), 7.50–7.57 (m, 2 H), 7.73 (d, J = 7.8 Hz, 2 H), 7.85–7.92 (m, 1 H), 8.32 (s, 1 H), 13.81 (br s, 1 H). ¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 46.6, 120.2, 127.6 (3 C), 128.3, 128.7, 129.2 (2 C), 130.0, 132.6, 134.4, 141.4–142.2 (3 C), 147.0. LCMS (CI): m/z = 296 [M + H]⁺. Anal. Calcd for C₁₆H₁₃N₃OS: C, 65.07; H, 4.44; N, 14.23; S, 10.85. Found: C, 64.93; H, 4.60; N, 14.08; S, 10.97.
• 22 5-Phenyl-7H-λ⁶-pyrimido[5,4-d][3,2]benzothiazepin-2-amine 5-oxide (7) Guanidine hydrochloride (115 mg, 1.2 mmol, 2 equiv) and (dimethylamino)methylene keto sulfoximine 5 (200 mg, 0.6 mmol, 1 equiv) were sequentially added to the stirred solution of MeONa (65 mg, 2 mmol, 2 equiv) in MeOH (20 mL) and the resulting mixture was stirred at rt for 6 h. Then it was evaporated under reduced pressure, the residue was diluted with water (20 mL), acidified with 2 M aq HCl to pH 7, and filtered. Thus obtained crude product was recrystallized (EtOH) to give pure 7; yield: 180 mg (0.56 mmol, 91%); white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.24 (d, J = 13.8 Hz, 1 H), 4.49 (d, J = 13.8 Hz, 1 H), 7.48 (m, 8 H), 7.76 (s, 2 H), 7.97 (d, J = 7.7 Hz, 1 H), 8.85 (s, 1 H). ¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 46.7, 121.7, 127.2, 127.4, 127.6 (2 C), 129.2 (2 C), 130.7, 131.4, 132.7, 134.9, 142.8, 144.7, 162.3, 162.4, 164.1. LCMS (CI): m/z = 323 [M + H]⁺. Anal. Calcd for C₁₇H₁₄N₄OS: C, 63.34; H, 4.38; N, 17.38; S, 9.94. Found: C, 63.52; H, 4.25; N, 17.55; S, 9.78.
• 23 3-Phenyl-4,5-dihydro-1H-3λ⁶,2-benzothiazepin-5-ol 3-oxide (8) NaBH₄ (28 mg, 0.74 mmol, 1 equiv) was added portionwise to cold (0 °C) stirred solution of keto sulfoximine 4c (200 mg, 0.74 mmol, 1 equiv) in MeOH (20 mL). After the addition was complete the mixture was left to stir at rt overnight and then evaporated under reduced pressure. The residue was triturated with water (50 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 25 mL), dried (Na₂SO₄), and evaporated under reduced pressure. Thus obtained crude product was purified by recrystallization (EtOH) to give 8 as a mixture of diastereomers (dr 15:85); yield: 170 mg (0.63 mmol, 86%); white solid. ¹H NMR (400 MHz, DMSO-d ₆), major diastereomer: δ = 2.92 (t, J = 11.4 Hz, 1 H), 3.76 (d, J = 11.4 Hz, 1 H), 4.07 (d, J = 14.2 Hz, 1 H), 4.68 (d, J = 14.2 Hz, 1 H), 5.60 (dd, J = 11.4, 4.9 Hz, 1 H), 6.19 (d, J = 4.9 Hz, 1 H), 7.25 (t, J = 7.4 Hz, 1 H), 7.30–7.37 (m, 2 H), 7.54–7.64 (m, 3 H), 7.68 (t, J = 7.4 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 2 H). ¹³C{¹H} NMR (101 MHz, DMSO-d ₆), major diastereomer: δ = 45.4, 63.1, 63.4, 124.5, 127.0, 127.2, 127.4 (2 C), 128.8, 129.3 (2 C), 133.4, 137.7, 139.1, 143.4. LCMS (CI): m/z = 274 [M + H]⁺. Anal. Calcd. for C₁₅H₁₅NO₂S: C, 65.91; H, 5.53; N, 5.12; S, 11.73. Found: C, 65.68; H, 5.61; N, 5.22; S, 11.51.
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