An Efficient Synthesis of a Highly Functionalized Dihydrobenzo­thiophene Derivative: A Ring-Contracted Analogue of the Anti-inflammatory Drug Propoxicam

Abstract

A five-step route to a ring-contracted analogue of the oxicam derivative propoxicam from thiosalicylic acid, sarcosine and N,N-dimethyl-1,3-propanediamine is described. The route has as key steps the base-promoted cross-Claisen coupling of protected sarcosine and thiosalicylic acid derivatives, the installation of a β-ketoamide moiety and a final Hg(II)-induced cyclization that creates the C–S bond of the benzothiophen-3-one core.

Key words

oxicam - benzotriazole activation - cross-Claisen coupling - β-ketoamide synthesis - benzothiophene synthesis - domino reactions

• References and Notes

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• 7 2-((4-Methoxybenzyl)thio)benzoic Acid (4) A solution of 4-methoxy-α-toluenethiol (3) (170 mg, 1.1 mmol) in anhydrous THF (2 mL) was placed in a two-necked flask equipped with a condenser under an argon atmosphere. The flask was cooled in an ice bath prior to the dropwise addition of LDA (0.6 mL, 2 M solution in THF, 1.2 mmol). In another flask, 2-fluorobenzoic acid (2) (140 mg, 1 mmol) was dissolved in anhydrous THF (2 mL) under an argon atmosphere and, after cooling in an ice bath, LDA (0.6 mL, 2 M solution in THF, 1.2 mmol) was added dropwise. The two reactions were allowed to warm to room temperature and stirred for 30 min. After this time, the benzoic acid solution was added slowly to the two-necked flask, and the resulting reaction mixture was stirred at reflux for 16 h. The reaction was then cooled to room temperature, poured onto ice and the mixture was acidified with aqueous 2 M HCl solution. The solid obtained was washed with cold water and dried to afford 4 as a white solid (235 mg, 86%). ¹H NMR (250 MHz, DMSO-d ₆): δ = 7.87 (d, J = 7.3 Hz, 1 H), 7.47 (br s, 2 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.24–7.15 (m, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 4.13 (s, 2 H), 3.73 (s, 3 H). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 167.47 (C_q), 158.45 (C_q), 141.55 (C_q), 132.37 (CH), 130.96 (CH), 130.38 (2 × CH), 128.21 (C_q), 127.59 (C_q), 125.71 (CH), 123.92 (CH), 113.93 (2 × CH), 55.10 (OCH₃), 35.09 (CH₂). These data correspond with those reported in the literature, see: Reference 17.
• 8 (Benzo[d][1,2,3]triazol-1-yl)(2-((4-methoxybenzyl)thio)phenyl)methanone (5) SOCl₂ (0.22 mL, 3 mmol) was added to a stirred solution of benzotriazole (0.953 g, 8 mmol) in anhydrous CH₂Cl₂ (25 mL). Stirring was continued for 30 min. Compound 4 (0.549 g, 2 mmol) was then added to the reaction mixture and stirring was continued for another 16 h. The resulting white precipitate was filtered off and washed with CH₂Cl₂. The combined filtrate was washed with 10% NaOH aqueous solution and brine, dried over MgSO₄, and concentrated to give a pale yellow solid. Flash chromatography over silica gel, using n-hexane/ethyl acetate from 100:0 to 90:10, gave compound 5 (0.675 g, 90%) as an off-white powder. Mp 99–101 °C. IR (film): 2959, 2931, 2836, 1705, 1606, 1581, 1508, 1451, 1361 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 8.41 (d, J = 8.2 Hz, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 7.85–7.34 (m, 6 H), 7.11 (d, J = 8.7 Hz, 2 H), 6.74 (d, J = 8.7 Hz, 2 H), 4.04 (s, 2 H), 3.76 (s, 3 H). ¹³C NMR (63 MHz, CDCl₃): δ = 167.18 (C_q), 158.92 (C_q), 146.24 (C_q), 136.56 (C_q), 135.23 (C_q), 132.05 (CH), 131.85 (CH), 131.68 (C_q), 130.57 (CH), 130.23 (2 × CH), 129.92 (CH), 128.50 (C_q), 126.55 (2 × CH), 120.33 (CH), 114.70 (CH), 113.96 (2 × CH), 55.31 (OCH₃), 39.58 (CH₂). Anal Calcd for C₂₁H₁₇N₃O₂S: C, 67.18; H, 4.56; N, 11.19; S, 8.54. Found: C, 66.81; H, 4.52; N, 11.20; S, 8.46.
• 9 Methyl 2-((tert-Butoxycarbonyl)(methyl)amino)-3-(2-((4-methoxybenzyl)thio)phenyl)-3-oxopropanoate (7) Sodium hexamethyldisilazide (1.0 mL, 1 M solution in THF, 1 mmol) was slowly added to a cold (–20 °C) solution of N-Boc-sarcosine methyl ester 6 (0.102 g, 0.5 mmol) in anhydrous THF (2 mL) under an argon atmosphere. After stirring for 2 h, a solution of compound 5 (0.188 g, 0.5 mmol) in anhydrous THF (3 mL) was added. The reaction mixture was then allowed to warm to 0 °C and stirred for 16 h. After completion of the reaction (as monitored by TLC), a saturated solution of NH₄Cl (10 mL) was added and the aqueous mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel, using a gradient of n-hexane/ethyl acetate from 100:0 to 80:20, to give 7 as a pale yellow solid (0.140 g, 61%), comprised of a mixture of the target β-ketoester and its tautomeric enol and carbamate rotamers, as reported below. Mp 104–106 °C. IR (film): 2960, 2920, 2850, 1751, 1680, 1608, 1583, 1509, 1436, 1377, 1322 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 12.30 and 12.14 (s, 1 H, enol), 7.88 (d, J = 7.9 Hz, 1 H, β-ketoester) and 7.71 (d, J = 8.1 Hz, 1 H, β-ketoester), 7.47–7.41 (m, 1 H, enol + β-ketoester), 7.36–7.14 (m, 5 H, enol + β-ketoester), 6.81 (t, J = 8.4 Hz, 2 H, enol + β-ketoester), 6.45 and 6.10 (s, 1 H, β-ketoester), 4.10 (s, 2 H, enol + β-ketoester), 3.84, 3.80, 3.78 and 3.77 (s, 6 H, enol + β-ketoester), 2.82, 2.79, 2.60 and 2.58 (s, 3 H, enol + β-ketoester), 1.45, 1.42 and 1.37 (s, 9 H, enol + β-ketoester). ¹³C NMR (63 MHz, CDCl₃): δ = 194.50 (C_q), 193.78 (C_q), 172.04 (C_q), 171.62 (C_q), 170.35 (C_q), 168.82 (C_q), 168.38 (C_q), 159.03 (C_q), 158.96 (C_q), 155.82 (C_q), 155.65 (C_q), 154.49 (C_q), 143.04 (C_q), 135.19 (C_q), 134.79 (C_q), 134.30 (C_q), 133.67 (C_q), 133.12 (CH), 132.91 (CH), 132.26 (C_q), 131.11 (CH), 130.52 (CH), 130.34 (CH), 130.28 (CH), 130.25 (CH), 130.17 (CH), 130.09 (CH), 130.04 (CH), 129.09 (C_q), 128.85 (C_q), 128.69 (CH), 128.37 (CH), 128.00 (CH), 127.81 (C_q), 126.89 (CH), 126.08 (CH), 124.59 (CH), 124.25 (CH), 114.12 (CH), 113.99 (CH), 109.76 (C_q), 109.54 (C_q), 81.56 (C_q), 81.18 (C_q), 80.07 (C_q), 65.87 (OCH₃), 63.81 (OCH₃), 55.40 (OCH₃), 55.37 (OCH₃), 52.64 (OCH₃), 52.57 (OCH₃), 52.40 (OCH₃), 52.17 (OCH₃), 38.95 (CH₂), 38.59 (CH₂), 37.60 (CH₂), 37.10 (CH₂), 36.22 (CH₃), 32.45 (CH₃), 32.27 (CH₃), 31.09 (CH₃), 28.49 (CH₃), 28.34 (CH₃). HRMS (ESI-negative): m/z [M – H]^– calcd for C₂₄H₂₈NO₆S: 458.16428; found: 458.16287. Anal. Calcd for C₂₄H₂₉NO₆S: C, 62.73; H, 6.36; N, 3.05; S, 6.98. Found: C, 62.73; H, 6.25; N, 3.17; S, 7.00.
• 10 tert-Butyl (1-((3-(Dimethylamino)propyl)amino)-3-(2-((4-methoxybenzyl)thio)phenyl)-1,3-dioxopropan-2-yl)(methyl)carbamate (8) To a solution of compound 7 (460 mg, 1.0 mmol), N,N-dimethyl-1,3-propanediamine (102 mg, 1.0 mmol) and DMAP (18 mg, 0.15 mmol) in toluene (3 mL), placed in a sealed tube equipped with a stirring bar, were added 4 Å MS (100 mg) and the suspension was heated at 130 °C for 16 h. After completion, the reaction mixture was cooled to room temperature and the suspension was filtered through a short pad of Celite, which was thoroughly rinsed with toluene and ethyl acetate. The solvents were removed under reduced pressure and the crude mixture was purified by flash chromatography over silica gel, using dichloromethane/methanol from 100:0 to 90:10, to give 8 as a yellow solid (440 mg, 83%), comprised of a mixture of two different carbamate rotamers that are reported below. Mp 128–130 °C. IR (film): 3374, 2929, 2820, 2770, 1690, 1605, 1507, 1458, 1435, 1346 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 14.49 (s, 1 H), 8.08 (s, 1 H), 7.51–7.02 (m, 6 H), 6.79 (d, J = 8.7 Hz, 2 H), 4.11 and 4.07 (s, 2 H), 3.77 (s, 3 H), 3.52–3.34 (m, 2 H), 2.88, 2.60 and 2.59 (s, 3 H), 2.43 (t, J = 5.7 Hz, 2 H), 2.24, 2.20 and 2.17 (s, 6 H), 1.74–1.66 (m, 2 H), 1.44, 1.41 and 1.34 (s, 9 H). ¹³C NMR (63 MHz, CDCl₃): δ = 170.34 (C_q), 168.20 (C_q), 158.90 (C_q), 155.16 (C_q), 135.39 (C_q), 135.19 (C_q), 130.64 (CH), 130.31 (CH), 130.22 (CH), 129.82 (CH), 129.62 (CH), 129.34 (C_q), 129.08 (C_q), 128.58 (CH), 128.09 (CH), 126.19 (CH), 126.09 (CH), 114.08 (CH), 113.95 (CH), 110.17 (C_q), 80.32 (C_q), 59.83 (CH₂), 55.38 (CH₃), 45.76 (CH₃), 45.55 (CH₃), 40.51 (CH₂), 38.98 (CH₂), 38.62 (CH₂), 37.24 (CH₃), 36.15 (CH₃), 28.59 (CH₃), 28.45 (CH₃), 28.37 (CH₃), 24.91 (CH₂), 24.76 (CH₂). HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₂₈H₄₀N₃O₅S: 530.2683; found: 530.2476. Anal. Calcd for C₂₈H₃₉N₃O₅S: C, 63.49; H, 7.42; N, 7.93; S, 6.05. Found: C, 63.16; H, 7.23; N, 7.80; S, 5.93.
• 11 3-(3-(2-((4-Methoxybenzyl)thio)phenyl)-2-(methylamino)-3-oxopropanamido)-N,N-dimethylpropan-1-ammonium Chloride (9) To a stirred solution of 8 (106 mg, 0.2 mmol) in AcOEt (2 mL) was added fuming SnCl₄ (130 mg, 0.5 mmol) at room temperature. CAUTION! SnCl₄ irritates the respiratory system. The resulting clear solution was stirred until TLC analysis indicated complete consumption of the starting material (2 h). The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography over silica gel, using dichloromethane/methanol from 100:0 to 70:30, to give 9 as a pale yellow solid (55 mg, 58%). ¹H NMR (250 MHz, DMSO-d ₆): δ = 10.44 (s, 1 H), 9.82 (s, 1 H), 9.60 (s, 1 H), 8.37 (d, J = 7.7 Hz, 1 H), 7.61 (s, 2 H), 7.33 (d, J = 7.9 Hz, 3 H), 6.89 (d, J = 7.7 Hz, 2 H), 6.01 (s, 1 H), 4.19 (dd, J = 28.8, 12.4 Hz, 2 H), 3.73 (s, 3 H), 3.26–3.01 (m, 2 H), 2.92 (t, J = 7.6 Hz, 2 H), 2.65 (s, 6 H), 2.56 (s, 3 H), 1.90–1.65 (m, 2 H). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 188.85 (C_q), 161.76 (C_q), 158.50 (C_q), 142.95 (C_q), 134.04 (CH), 131.87 (CH), 130.40 (2 × CH), 129.61 (C_q), 127.80 (C_q), 126.71 (CH), 124.14 (CH), 113.98 (2 × CH), 66.58 (CH₃), 55.13 (CH), 54.09 (CH₂), 41.92 (CH₃), 36.37 (CH₂), 35.31 (CH₂), 31.28 (CH₃), 23.43 (CH₂). Anal. Calcd for C₂₃H₃₂ClN₃O₃S: C, 59.28; H, 6.92; N, 9.02; S, 6.88. Found: C, 59.06; H, 7.13; N, 8.80; S, 6.63.
• 12 4-Hydroxy-3-(methylamino)-2H-thiochromen-2-one (11) A solution of 8 (106 mg, 0.2 mmol), anisole (65 mg, 0.6 mmol) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 h. After completion of the reaction (as monitored by TLC), the pH was adjusted to 7 by employing an aqueous saturated solution of NaHCO₃ and the aqueous solution was extracted with ethyl acetate (3 × 10 mL). The combined extracts were dried and evaporated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel, eluting with dichloromethane/methanol from 100:0 to 95:5, to give compound 11 as an off-white solid (29 mg, 71%). Mp 227–229 °C. IR (film): 3017, 2787, 1567, 1538, 1480, 1434, 1378, 1312 cm^–1. ¹H NMR (250 MHz, DMSO-d ₆): δ = 9.31 (s, 1 H), 8.19 (d, J = 7.9 Hz, 1 H), 7.63–7.21 (m, 3 H), 2.68 (s, 3 H). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 170.98 (C_q), 170.84 (C_q), 134.53 (C_q), 130.28 (CH), 129.95 (C_q), 127.65 (CH), 125.48 (CH), 125.25 (CH), 111.49 (C_q), 34.17 (CH₃). HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₁₀H₁₀NO₂S: 208.0427; found, 208.0389.
• 13 Nishimura O, Kitada C, Fujino M. Chem. Pharm. Bull. 1978; 26: 1576
• 14 tert-Butyl (4-Hydroxy-2-oxo-2H-thiochromen-3-yl)(methyl)carbamate (12) A solution of compound 8 (104 mg, 0.2 mmol), mercury(II) trifluoroacetate (111 mg, 0.26 mmol) and aqueous acetic acid (80% by weight, 3 mL) was stirred at room temperature for 2 h and then 2-mercaptoethanol (31 mg, 0.4 mmol) was added. The resulting mixture was stirred for 2 h and then filtered through a pad of silica gel. The silica gel was rinsed with Et₂O (3 × 15 mL) and then water (20 mL) was added to the filtrate. The organic layer was separated and washed with brine, dried over MgSO₄, filtered and concentrated. The crude residue was purified by flash chromatography over silica gel, using dichloromethane/ethyl acetate from 100:0 to 90:10, to give compound 12 as a white solid (48 mg, 79%), comprised of a mixture of two carbamate rotamers. ¹H NMR (250 MHz, MeOD): δ = 8.26 (d, J = 8.1 Hz, 1 H), 7.72–7.42 (m, 3 H), 3.03 and 2.99 (s, 3 H), 1.53 and 1.35 (s, 9 H). ¹³C NMR (63 MHz, MeOD): δ = 182.75 (C_q), 163.33 (C_q), 157.74 (C_q), 136.46 and 136.19 (C_q), 132.10 and 132.04 (CH), 128.29 and 128.23 (CH), 127.66 and 127.61 (CH), 126.50 (CH), 125.74 and 125.67 (C_q), 121.12 (C_q), 82.46 and 81.67 (C_q), 36.76 and 35.53 (CH₃), 28.56 and 28.36 (CH₃). Anal. Calcd for C₁₅H₁₇NO₄S: C, 58.61; H, 5.57; N, 4.56; S, 10.43. Found: C, 58.38; H, 5.70; N, 4.57; S, 10.27.
• 15 N-(3-(Dimethylamino)propyl)-2-(methylamino)-3-oxo-2,3-dihydrobenzo[b]thiophene-2-carboxamide (1) A solution of compound 8 (233 mg, 0.5 mmol), mercury(II) trifluoroacetate (320 mg, 0.75 mmol), anisole (162 mg, 1.5 mmol) and trifluoroacetic acid (0.75 mL) was stirred at 0 °C for 2 h. The trifluoroacetic acid solvent was removed in vacuo, whereupon MeOH (1.0 mL) and 2-mercaptoethanol (195 mg, 2.5 mmol) were added at 0 °C. The resulting mixture was stirred at the same temperature for 2 h and then the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography on silica gel, using dichloromethane/methanol/NH₄OH from 100:0:0 to 92:7:1, to give 1 as a pale yellow syrup (110 mg, 72%). IR (neat): 3330, 2945, 2862, 1702, 1671, 1589, 1447 cm^–1. ¹H NMR (250 MHz, acetone-d ₆): δ = 8.23 (s, 1 H), 7.83–7.57 (m, 2 H), 7.52 (dt, J = 7.8, 0.9 Hz, 1 H), 7.40–7.13 (m, 1 H), 3.34–3.17 (m, 3 H), 2.34–2.26 (m, 5 H), 2.01 (s, 6 H), 1.65–1.52 (m, 2 H). ¹³C NMR (63 MHz, acetone-d ₆): δ = 199.23 (C_q), 166.84 (C_q), 153.26 (C_q), 137.42 (CH), 130.70 (C_q), 127.58 (CH), 125.77 (CH), 125.47 (CH), 88.63 (C_q), 59.00 (CH₂), 45.28 (CH₃), 40.48 (CH₂), 30.42 (CH₃), 26.19 (CH₂). HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₁₅H₂₂N₃O₂S: 308.14272; found: 308.14310. Anal. Calcd for C₁₅H₂₁N₃O₂S: C, 58.61; H, 6.89; N, 13.67; S, 10.43. Found: C, 58.31; H, 6.92; N, 13.62; S, 10.08.
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