Reaction of Bromoacetyl and Sulfhydryl Groups: Efficient Synthesis of Aromatic Oligoamides Consisting of Benzene-1,3,5-tricarboxamide Units

Abstract

A series of aromatic oligoamides consisting of benzene-1,3,5-tricarboxamide (BTA) residues linked by thioether bonds were designed and synthesized based on the highly efficient and specific reaction between sulfhydryl and bromoacetyl groups. Initial assessment of the folding of these oligoamides with circular dichroism (CD) spectroscopy showed that these oligoamides could fold into a helical conformation.

Key words

benzene-1,3,5-tricarboxamides - bromoacetyl group - sulfhydryl group - oligoamides - circular dichroism - folded conformation

• References and Notes

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• 11 Selected Spectroscopic Data Compound 2-1 ¹H NMR (300 MHz, CDCl₃): δ = 0.87–0.94 (m, 6 H), 1.30–1.41 (m, 8 H), 1.57–1.66 (m, 4 H), 4.08–4.22 (m, 2 H), 4.82–4.87 (m, 1 H), 7.37 (d, J = 6.99 Hz, 1 H), 8.96 (m, 2 H), 9.16 (m, 1 H) ppm. Compound 2: ¹H NMR (300 MHz, CDCl₃): δ = 0.90–0.92 (m, 11 H), 1.25–1.40 (m, 16 H), 1.53 (d, J = 7.5 Hz, 3 H), 1.65–1.72 (m, 6 H), 2.35 (t, J = 7.5 Hz, 4 H), 3.99–4.17 (m, 2 H), 4.67–4.75 (m, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.69 (s, 2 H), 7.78 (s, 2 H), 8.00 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.9, 14.0,18.0, 22.4, 22.9, 23.7, 23.8, 25.2, 28.9, 30.3, 30.4, 31.4, 37.5, 38.8, 38.8, 49.0, 68.0, 113.8, 114.0, 135.0, 139.0, 167.0, 172.2, 173.3 ppm. ESI-HRMS: m/z calcd for C₃₀H₄₉N₃O₅Na [M + Na]⁺: 554.3570; found: 554.3583. Compound 3-1 Compound 3-1 was prepared by controlling the molar ratios of 3-(trithylthio)propanoic acid and diamine 2-2 as 2.4 in 65% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.80–0.84 (m, 6 H), 1.21–1.30 (m, 8 H), 1.39 (d, J = 7.26 Hz, 3 H), 1.52 (m, 1 H), 2.37–2.50 (m, 8 H), 3.91–4.02 (m, 2 H), 4.43 (t, J = 7.08 Hz, 1 H), 7.06–7.34 (m, 30 H), 7.68 (d, J = 0.99 Hz, 2 H), 8.10 (s, 1 H), 8.75 (d, J = 6.78 Hz, 1 H), 10.10 (s, 2 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 10.8, 10.9, 13.9, 16.6, 22.4, 23.1, 23.2, 27.3, 28.3, 29.7, 29.8, 35.1,38.2, 48.5, 66.1, 66.3, 112.7, 113.4, 126.7, 128.0, 129.1, 135.4, 139.2, 144.4, 166.7, 169.3, 172.7 ppm. ESI-HRMS: m/z calcd for C₆₂H₆₅N₃O₅S₂Na [M + Na]⁺: 1018.4263; found: 1018.4263. Compound 4-1 Compound 4-1 was prepared by controlling the molar ratios of 3-(trithylthio)propanoic acid and diamine 2-2 as 1.2 in 50% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.78–0.83 (m, 6 H), 1.20–1.26 (m, 8 H), 1.33 (d, J = 7.26 Hz, 3 H), 1.50 (m, 1 H), 2.29–2.35 (m, 4 H), 3.85–4.02 (m, 2 H), 4.34 (t, J = 7.08 Hz, 1 H), 5.25 (s, 2 H), 6.65 (s, 1 H), 7.00 (s, 1 H), 7.05 (s, 1 H), 7.23–7.32 (m, 15 H), 8.50 (d, J = 6.54 Hz, 1 H), 9.74 (s, 1 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 10.8, 13.9, 16.7, 22.4, 23.1, 27.5, 28.4, 29.8, 30.4, 35.1, 38.2, 48.4, 66.2, 106.7, 107.4, 108.3, 126.7, 128.0, 129.1, 135.5, 139.5, 144.38, 144.47. 148.9, 167.4, 168.9, 172.8 ppm. ESI-HRMS: m/z calcd for C₄₀H₄₇N₃O₄SNa [M + Na]⁺: 688.3185; found: 688.3179. Compound 4 ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.80–0.84 (m, 6 H), 1.21–1.30 (m, 8 H), 1.38 (d, J = 7.26 Hz, 3 H), 1.50–1.52 (m, 1 H), 2.34–2.42 (m, 4 H), 3.92–4.04 (m, 4 H), 4.41 (m, 1 H), 7.23–7.37 (m, 15 H), 7.68 (s, 2 H), 8.09 (s, 1 H), 8.79 (d, J = 6.90 Hz, 1 H), 10.13 (s, 1 H), 10.54 (s, 1 H) ppm. ¹³C NMR (75MHz, DMSO-d ₆): δ = 10.8, 13.9, 16.6, 22.4, 23.1, 27.3, 28.3, 29.8, 38.2, 40.1, 48.5, 66.1, 66.3, 112.9, 113.5, 130.0, 126.7, 128.0, 129.1, 135.5, 138.7, 144.4, 164.8, 166.5, 169.3, 172.6 ppm. ESI-HRMS: m/z calcd for C₄₂H₄₈BrN₃O₅SNa [M + Na]⁺: 808.2396; found: 808.2374. Oligoamide 1a Light yellow powder (540 mg) in 70% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.80–0.84 (m, 18 H), 1.21–1.30 (m, 24 H), 1.38 (d, J = 7.17 Hz, 9 H), 1.50–1.52 (m, 3 H), 2.35–2.42 (m, 8 H), 2.69–2.71 (m, 4 H), 2.92–2.94 (m, 4 H), 3.38 (s, 4 H), 3.92–4.01 (m, 6 H), 4.39–4.44 (m, 3 H), 7.24–7.33 (m, 30 H), 7.68–7.70 (m, 6 H), 8.11–8.13 (m, 3 H), 8.75–8.77 (m, 3 H), 10.10 (s, 2 H), 10.16 (s, 2 H), 10.26 (s, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 10.9, 13.9, 16.7, 22.4, 23.2, 27.4, 27.7, 28.3,29.8, 29.9, 35.1, 36.3, 38.3, 48.6, 66.2, 66.3, 112.7, 113.4, 126.8, 128.0, 129.1, 135.5, 139.3, 144.4, 166.7, 168.2, 169.3, 169.6, 172.7 ppm. ESI-HRMS: m/z calcd for C₁₀₈H₁₃₀N₉O₁₅S₄Na [M + Na]⁺: 1943.8467; found: 1943.8134. Oligoamide 1b Using 1a′ as starting material, light yellow powder (502 mg) in 85% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.79–0.84 (m, 30 H), 1.21–1.30 (m, 40 H), 1.37 (d, J = 7.41 Hz, 15 H), 1.52 (m, 5 H), 2.34–2.39 (m, 8 H), 2.66–2.70 (m, 8 H), 2.91–2.93 (m, 8 H), 3.34 (s, 8 H), 3.99–4.01 (m, 10 H), 4.41–4.43 (m, 5 H), 7.22–7.34 (m, 30 H), 7.67–7.70 (m, 10 H), 8.10–8.13 (m, 5 H), 8.73–8.75 (m, 5 H), 10.08–10.25 (m, 10 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 10.8, 10.9, 13.9, 16.7, 22.4, 23.2, 27.6, 28.3, 29.8, 29.9, 36.2, 38.3, 48.5, 66.2, 66.3, 112.7, 113.4, 113.6, 126.7, 128.0, 129.1, 135.5, 139.2, 139.3, 144.4, 166.7, 168,2, 169.3, 169.6, 169.7, 172.7 ppm. ESI-HRMS: m/z calcd for C₁₅₄H₁₉₆N₁₅O₂₅S₆Na₂ [M + 2Na – H]⁺: 2893.2646; found: 2893.2623. Oligoamide 1c Using 1b′ as starting material, light yellow powder (301 mg) in 63% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.80–0.84 (m, 42 H), 1.12–1.30 (m, 56 H), 1.38 (d, J = 7.20 Hz, 21 H), 1.51 (m, 7 H), 2.34–2.40 (m, 8 H), 2.66–2.71 (m, 12 H), 2.91–2.96 (m, 12 H), 3.35 (s, 12 H), 3.92–4.01 (m, 14 H), 4.39–4.41 (m, 7 H), 7.22–7.36 (m, 30 H), 7.67–7.70 (m, 14 H), 8.10–8.13 (m, 7 H), 8.75–8.78 (m, 7 H), 10.09–10.26 (m, 14 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 10.8, 10.9, 13.9, 16.7, 22.4, 23.2, 23.3, 27.3, 27.6, 28.4, 29.8, 29.9, 35.1, 35.4, 36.2, 38.2, 38.3, 48.6, 66.2, 66.3, 112.7, 113.4, 113.6, 126.8, 128.1, 129.1, 135.5, 139.2, 139.3, 144.4, 166.8, 168,3, 169.3, 169.6, 169.7, 172.7 ppm. ESI-HRMS: m/z calcd for C₂₀₀H₂₆₂N₂₁O₃₅S₈KNa [M + Na + K – H]⁺: m/z 3835.6668; found: 3835.6474. Oligoamide 1d Using 1c′ as starting material, light yellow powder (43 mg) in 77% yield. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.80–0.84 (m, 54 H), 1.12–1.30 (m, 72 H), 1.38 (d, J = 7.23 Hz, 27 H), 1.50–1.52 (m, 9 H), 2.34–2.40 (m, 8 H), 2.66–2.71 (m, 16 H), 2.92–2.96 (m, 16 H), 3.35 (s, 16 H), 3.92–4.01 (m, 18 H), 4.39–4.44 (m, 9 H), 7.24–7.37 (m, 30 H), 7.67–7.71 (m, 18 H), 8.10–8.13 (m, 9 H), 8.75–8.78 (m, 9 H), 10.1–10.3 (m, 18 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 11.2, 11.3, 14.3, 17.1, 22.8, 23.6, 23.7, 27.7, 28.1, 28.7, 28.8, 30.2, 30.3, 35.6, 35.8, 36.7, 38.6, 38.7, 49.0, 66.6, 66.8, 113.2, 113.8, 114.1, 127.2, 128.5, 129.5, 135.9, 139.6, 139.7, 144.9, 167.2, 168.6, 169.7, 170.1, 173.1 ppm. ESI-HRMS: m/z calcd for C₂₄₇H₃₂₉Cl₂N₂₇O₄₅S₁₀ [M + CH₂Cl₂ – 2H]^2–: 2392.555; found: 2392.8. Representative Procedure for the Preparation of Oligoamide 1a The solution of compound 4 (802 mg, 1.02 mmol) dissolved in CH₂Cl₂ (10 mL) was added dropwise to the ice-cold mixture of compound 3 (209 mg, 0.409 mmol) and Et₃N(0.14 mL, 1.02 mmol) in CH₂Cl₂ (20 mL). The mixture was allowed to warm to r.t. and kept at this temperature overnight. The resulting mixture was washed with 1 M HCl solution (30 mL), brine (30 mL), and then dried over anhydrous Na₂SO₄. After filtration and concentration the crude product was purified by column chromatography (3 vol% MeOH in CH₂Cl₂, R_f = 0.1) to afford pure compound 1a. Oligoamides 1b–d could be prepared using the same method described as 1a. Representative Procedure for the Preparation of Oligoamide 1a′ The solution of TFA (0.31 mL, 4.16 mmol) in CH₂Cl₂ (10 mL) was added dropwise to the ice-cold mixture of compound 1a (400 mg, 0.208 mmol) and triethylsilane (0.33 mL, 2.08 mmol) in CH₂Cl₂ (20 mL) over 15 min. The mixture was allowed to warm to r.t. and kept at this temperature for 1 h. After concentration, the crude mixture was purified by flash column chromatography (5% v/v MeOH in CH₂Cl₂, R_f = 0.2) to give compound 1a′. Oligoamides 1b′ and 1c′ could be prepared using the same method described as 1a′. Oligoamide 1a′ White solid; yield: 293 mg (98%). Oligoamide 1b′ White solid; yield: 289 mg (97%). Oligoamide 1c′ White solid; yield: 38 mg (97%).