Synlett 2013; 24(18): 2437-2442
DOI: 10.1055/s-0033-1339639
letter
© Georg Thieme Verlag Stuttgart · New York

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

Bjarne E. Nielsen
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark   Fax: +4535320212   Email: pittel@kiku.dk
,
Henrik Gotfredsen
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark   Fax: +4535320212   Email: pittel@kiku.dk
,
Brian Rasmussen
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark   Fax: +4535320212   Email: pittel@kiku.dk
,
Christian G. Tortzen
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark   Fax: +4535320212   Email: pittel@kiku.dk
,
Michael Pittelkow*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark   Fax: +4535320212   Email: pittel@kiku.dk
› Author Affiliations
Further Information

Publication History

Received: 09 July 2013

Accepted after revision: 23 July 2013

Publication Date:
27 August 2013 (online)


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.

Supporting Information

 
  • 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 C27H49N6O6 +: 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 C51H67N6O15 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) Å3; T = 122 K; space group P21/c; Z = 8; μ(Mo–Kα) = 0.07 mm–1; 94511 reflections measured, 11105 independent reflections (Rint = 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.