Simple Procedures for the Preparation of 1,3,5-Substituted 2,4,6-Trimethoxybenzenes

Abstract

We describe straightforward protocols for the preparation of a number of 1,3,5-substituted 2,4,6-trimethoxybenzenes. A two-step procedure for the preparation of a 1,3,5-tris-methylamino-2,4,6-trimethoxybenzene and further synthetic elaboration of this key substrate to yield a triamide, a tricarbamate and three different triureas is described. We also present a computational (DFT) study that investigates the different possible conformations of the overcrowded benzene substrate and a single-crystal X-ray structure of one of the key intermediates.

Key words

supramolecular chemistry - tripodal receptors - ureas - amides - overcrowded aromatics

• References and Notes

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• 7 1,3,5-Tris(bromomethyl)-2,4,6-trimethoxybenzene (2): 1,3,5-Trimethoxybenzene (10.0 g, 59.5 mmol) and paraformaldehyde (11.0 g, 366 mmol) were suspended in 33% HBr in AcOH (85 mL) in a sealed stainless steel reaction vessel. The mixture was stirred for 3 h at 85 °C. After cooling to 25 °C CH₂Cl₂ (200 mL) was added, the phases were separated, and the organic phase was washed with H₂O (3 × 75 mL). The CH₂Cl₂ phase was filtered through silica (Ø = 50 mm, h = 60 mm) and the column was flushed with further CH₂Cl₂ (2 × 150 mL). The solvent was removed in vacuo, and the resulting yellow oil was dissolved in a mixture of 2-propanol (100 mL) and CH₂Cl₂ (100 mL). White crystals were obtained by reducing the volume of the solution to 50 mL and the precipitates were filtered off and washed with 2-propanol. Yield: 13.0 g (49%); mp 125–126 °C. ¹H NMR (500 MHz, CDCl₃): δ = 4.60 (s, 6 H), 4.14 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.3, 123.5, 62.9, 22.7. HRMS: m/z [M + NH₄]⁺ calcd for C₁₂H₁₉O₃NBr₃ ⁺: 461.8910; found: 461.8924.
• 8 (2,4,6-Trimethoxybenzene-1,3,5-triyl)trimethanamine Hydrobromide (3): 1,3,5-Tris(bromomethyl)-2,4,6-trimethoxybenzene (401 mg, 0.898 mmol) and liquid NH₃ (160 mL) were stirred at 25 °C for 18 h in a sealed reaction vessel. The ammonia was removed by evaporation, and the residue was dissolved in H₂O (30 mL) and filtered. Concentration in vacuo gave a colorless solid. Yield: 437 mg (98%); mp 176 °C (dec.). ¹H NMR (500 MHz, D₂O): δ = 4.33 (s, 6 H), 3.92 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.3, 118.1, 63.0, 33.2. HRMS: m/z [2 M + H] calcd for C₂₄H₄₃ N₆O₆ ⁺: 511.3239; found: 511.3239.
• 9 Tri-tert-butyl [(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tricarbamate (4): The tribromide 2 (1.80 g, 4.02 mmol) was dissolved in THF–EtOH (100 mL; 1:1) and concentrated aq NH₃ (80 mL) was added. The reaction mixture was stirred for 14 h whereafter the solvent was removed in vacuo. The residue was dissolved in dioxane–H₂O (70 mL, 1:1) and NaOH (0.80 g, 20 mmol) was added. Boc₂O (5.76 g, 26 mmol) in dioxane (20 mL) was slowly added at 0 °C and the reaction was stirred for an hour at 0 °C and 5 h at 25 °C. H₂O was added and the solution was extracted with CH₂Cl₂ (3 × 60 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The product was further purified by dry column chromatography (Ø = 60 mm, h = 50 mm, heptane with 0.1% Et₃N to EtOAc with 0.1% Et₃N with 5% gradient), followed by recrystallization from heptane. Yield: 0.517 g (23%); mp 93.5–95 °C. ¹H NMR (500 MHz, CDCl₃): δ = 5.12 (s, 3 H), 4.39 (d, 6 H), 3.81 (s, 9 H), 1.44 (s, 27 H). ¹³C NMR (125 MHz, CDCl₃): δ = 158.5, 155.1, 122.6, 79.1, 62.4, 34.8, 28.6. HRMS: m/z [M + Na]⁺ calcd for C₂₇H₄₅N₃O₉Na⁺: 578.3048; found: 578.3069.
• 10 Trimethyl 4,4′,4′′-[{[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tri-benzoate (5): Iodine (458 mg, 1.81 mmol) was added to an ice-cooled solution of trimethyl phosphite (0.213 mL, 1.81 mmol) in CH₂Cl₂ (40 mL). When all the iodine had dissolved, terephthalic acid monomethyl ester (325 mg, 1.81 mmol) and Et₃N (1.12 mL, 8.03 mmol) were added and the solution was stirred for 20 min under continued cooling. The triamide 3 (200 mg, 0.401 mmol) was added and the mixture was stirred for 10 min at 0 °C and for 3 h at 25 °C. Sat. NaHCO₃ was added and the aqueous phase was extracted with CH₂Cl₂ (50 mL). The organic phase was washed with 2 M HCl (2 × 50 mL) and brine (50 mL), dried over Na₂SO₄, and filtered. The product was further purified by dry column chromatography (Ø = 40 mm, h = 40 mm, CH₂Cl₂ to 12% MeOH in CH₂Cl₂ with 1.5% gradient). Yield: 0.31 g (66%); mp 212–213 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.60 (t, J = 4.8 Hz, 3 H), 7.94–8.02 (m, 12 H), 4.58 (d, J = 4.8 Hz, 6 H), 3.88 (s, 9 H), 3.83 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 165.69, 165.21, 158.98, 138.58, 131.60, 128.98, 127.75, 121.01, 62.17, 52.33, 33.92. HRMS: m/z [M + H]⁺ calcd for C₃₉H₄₀N₃O₁₂ ⁺: 742.2607; found: 742.2613.
• 11 2,2′,2′′-[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris(isoindoline-1,3-dione) (6): 1,3,5-Trimethoxybenzene (500 mg, 2.97 mmol) and N-hydroxymethylphthalimide (1.65 g, 9.31 mmol) were dissolved in boron triflouride etherate (25 mL) by gentle heating. Afterwards the solution was stirred at 25 °C for 3 h. The reaction mixture was poured into an ice–sodium acetate mixture (100 g/15 g) and stirred for an hour. The aqueous phase was extracted with CH₂Cl₂ (3 × 50 mL) and the combined organic phase was washed with H₂O (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The product was further purified by dry column chromatography (Ø = 40 mm, h = 40 mm, toluene to 15% MeCN in toluene with 3% gradient). Yield: 0.31 g (16%); mp 223–224 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.65–7.78 (m, 12 H), 4.77 (s, 6 H), 3.73 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 167.24, 158.18, 134.22, 131.30, 122.73, 119.02, 61.82, 32.27. HRMS: m/z [M + H]⁺ calcd for C₃₆H₂₈N₃O₉ ⁺: 646.1820; found: 646.1794.
• 12 Gali H, Prabhu KR, Karra SR, Katti KV. J. Org. Chem. 2000; 65: 676
• 13 1,1′,1′′-[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris[3-(tert-butyl)urea] (7): The triamine 3 (200 mg, 0.402 mmol) was suspended in CH₂Cl₂–Et₃N (50 mL, 9:1) and tert-butylisocyanate (318 mg, 3.21 mmol) was added. The reaction mixture was stirred for 3 d at 25 °C. The volatiles were removed in vacuo and the residues were redissolved in CH₂Cl₂ (75 mL) and washed with 1 M hydrochloric acid (2 × 30 mL) and brine. The product was further purified by preparative HPLC, to yield 58% yield of a white solid; mp 275 °C (dec.). ¹H NMR (500 MHz, DMSO-d ₆): δ = 5.83 (s, 3 H), 5.71 (t, J = 5.3 Hz, 3 H), 4.20 (d, J = 5.3 Hz, 6 H), 3.73 (s, 9 H), 1.20 (s, 27 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 157.80, 156.82, 122.90, 62.00, 48.93, 32.64, 29.31. HRMS: m/z [M + H]⁺ calcd for C₂₇H₄₉N_6O6 ⁺: 553.3708; found: 553.3717.
• 14 Diness F, Beyer J, Meldal M. QSAR Comb. Sci. 2004; 23: 117
• 15 2,2′,2′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-(azanediyl)}tris[3-(tritylthio)propanoic Acid] (8): The triamine 3 (100 mg, 0.200 mmol) was dissolved in DMF (10 mL) and a solution of 1,1′-carbonyldiimidazole (100.9 mg, 0.622 mmol) in MeCN (10 mL) was added. The reaction mixture was stirred for an hour and S-tritylcysteine (233.5 mg, 0.643 mmol) and Et₃N (0.142 mL, 1 mmol) were added. The reaction mixture was stirred overnight whereafter the volatiles were removed. The residue was redissolved in CHCl₃ and washed with 0.5 M HCl (3 × 50 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The product was further purified by preparative HPLC to give a white solid material. Yield: 121 mg (45%); mp 177–179 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 12.70 (s, 3 H), 7.17–7.40 (m, 45 H), 6.42 (d, J = 8.3 Hz, 3 H), 6.30 (t, J = 5.4 Hz, 3 H), 4.25 (d, J = 5.4 Hz, 6 H), 4.20 (ddd, J = 8.3, 6.8, 5.1 Hz, 3 H), 3.72 (s, 9 H), 2.41 (dd, J = 11.7, 6.8 Hz, 3 H), 2.33 (dd, J = 11.7, 5.1 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 172.60, 158.04, 156.69, 144.16, 129.00, 128.03, 126.78, 122.54, 65.80, 62.13, 51.60, 34.31, 33.03. HRMS: m/z [M + H]⁺ calcd for C₈₁H₇₉N₆O₁₂S₃ ⁺: 1423.4913; found: 1423.4884.
• 16 3,3′,3′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-(azanediyl)}tribenzoic Acid (9): The triamine 3 (202 mg, 0.406 mmol) was dissolved in DMF (20 mL) and a solution of 1,1′-carbonyldiimidazole (3.1 equiv, 204 mg, 1.26 mmol) in MeCN (20 mL) was added. The reaction mixture was stirred for an hour at r.t. 3-Aminobenzoic acid (3.2 equiv, 178 mg, 1.30 mmol), Et₃N (21.2 equiv, 1.2 mL, 8.6 mmol) and DMAP (0.1 equiv, 5.1 mg, 0.042 mmol) were added and the reaction mixture was stirred for 3 d. Thereafter, the reaction mixture was poured into an ice-cold solution of 2 M HCl, the precipitate was filtered off and dried in vacuo. Finally, the crude product was washed once with 2 M NaOH (20 mL), reacidified with 2 M HCl, filtered and dried in vacuo. Yield: 62.9 mg (21%). ¹H NMR (500 MHz, DMSO-d ₆): δ = 9.24 (s, 3 H), 8.06 (s, 3 H), 7.58 (d, J = 7.7 Hz, 3 H), 7.44 (d, J = 7.7 Hz, 3 H), 7.31 (t, J = 7.7 Hz, 3 H), 6.57 (s, 3 H), 4.38 (s, 6 H), 3.84 (s, 9 H). ¹³C NMR (125 MHz, DMSO): δ = 167.36, 158.22, 154.79, 140.90, 131.19, 128.78, 122.34, 121.73, 121.48, 118.00, 62.37, 32.98. HRMS: m/z [M + H]⁺ calcd for C₃₆H₃₇ N₆O₁₂ ⁺: 745.2464; found: 745.2489.
• 17 Trimethyl 2,2′,2′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-(azanediyl)}tris{3-[(4-methoxybenzyl)thio]propanoate} (10): The PMB-protected cysteine (234 mg, 0.830 mmol) was dissolved in DMF (20 mL) and a solution of 1,1′-carbonyldiimidazole (143.1 mg, 0.883 mmol) in MeCN (20 mL) was added. The mixture was stirred for 30 min and the triamine 3 (100 mg, 0.201 mmol) and imidazole (136 mg, 2.00 mmol) were added. The reaction mixture was stirred overnight whereafter the volatiles were removed. The residues were redissolved in CH₂Cl₂ (80 mL) and washed with 0.5 M HCl (3 × 50 mL) and brine. The organic phase was dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was further purified by dry column chromatography (Ø = 40 mm, h = 40 mm, CH₂Cl₂ to 5% MeOH in CH₂Cl₂ with 0.5% gradient) to yield a white solid. Yield: 65 mg (28%); mp 195 °C (dec.). ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.19 (d, J = 8.7 Hz, 6 H), 6.86 (d, J = 8.7 Hz, 6 H), 6.52 (d, J = 8.2 Hz, 3 H), 6.32 (t, J = 5.3 Hz, 3 H), 4.38–4.49 (m, 3 H), 4.27 (d, J = 5.3 Hz, 6 H), 3.74 (s, 9 H), 3.72 (s, 9 H), 3.67 (s, 6 H), 3.61 (s, 9 H), 2.71 (dd, J = 13.6, 5.3 Hz, 3 H), 2.65 (dd, J = 13.6, 6.8 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 172.14, 158.16, 158.05, 156.72, 129.95, 129.79, 122.47, 113.73, 62.10, 55.00, 52.41, 51.91, 34.79, 33.07, 33.00. HRMS: m/z [M + H]⁺ calcd for C₅₁H₆₇N_6O15 S₃ ⁺: 1099.3821; found: 1099.3853.
• 18 C₁₂H₁₅Br₃N₃; M = 446.97; monoclinic; a = 9.9840(8) Å, b = 16.845(2) Å, c = 18.806(2) Å, α = 90°, β = 112.224(8)°, γ = 90°; V = 2927.8(5) ų; T = 122 K; space group P2₁/c; Z = 8; μ(Mo–K_α) = 0.07 mm^–1; 94511 reflections measured, 11105 independent reflections (R_int = 0.112). The final R ₁ values were 0.039 [F ² >2σ (F ²)]. The final R ₁ values were 0.0688 (all data). The final wR(F ²) (all data) values were 0.110. The goodness of fit on F ² was 1.163. The structure of the tribromide 2 has been submitted to the Cambridge Crystallographic Data Centre (CCDC) as CCDC 947822.