A New Simple Procedure for the Synthesis of Heptamethyl Cyclohepta-1,3,5-triene-1,2,3,4,5,6,7-heptacarboxylate

Abstract

A new and simple procedure for the synthesis of heptamethyl cyclohepta-1,3,5-triene-1,2,3,4,5,6,7-heptacarboxylate in a 51% yield is presented. An optimization of the reaction conditions was performed, and a convenient protocol for the isolation of the reaction product was developed. The structure of the key electrophilic intermediate was determined by means of NMR spectroscopy, and a plausible reaction mechanism is proposed.

Key words

cascade reactions - cycloheptatrienes - cycloheptatrieneheptacarboxylate - ylides - organocatalysis

• References and Notes

• 1 Tomilov YuV. Platonov DN. Salikov RF. Okonnishnikova GP. Tetrahedron 2008; 64: 10201
• 2a Tomilov YuV. Platonov DN. Okonnishnikova GP. Tetrahedron Lett. 2009; 50: 5605
• 2b Platonov DN. Okonnishnikova GP. Tomilov YuV. Mendeleev Commun. 2010; 20: 83
• 2c Tomilov YuV. Platonov DN. Shulishov EV. Okonnishnikova GP. Levina AA. Tetrahedron 2015; 71: 1403
• 2d Platonov DN. Okonnishnikova GP. Novikov RA. Suponitsky KYu. Tomilov YuV. Tetrahedron Lett. 2014; 55: 2381
• 2e Tomilov YuV. Platonov DN. Okonnishnikova GP. Nefedov OM. Russ. Chem. Bull. 2010; 59: 1387
• 2f Tomilov YV. Platonov DN. Shulishov EV. Okonnishnikova GP. Tetrahedron 2015; 69: 6855
• 3 HMCH: General Procedure To a suspension of 1-(2-methoxy-2-oxoethyl)pyridinium bromide (3; 1.65 g, 7.1 mmol) and dimethyl bromomaleate (1; 5 g, 22.4 mmol) in the requisite volume of solvent (see Table 1) was added the requisite amount of pyridine, and the mixture was stirred for 72 h. In Method A (Table 1), the mixture was diluted with H₂O (50 mL) and extracted with CHCl₃ (3 × 25 mL). The combined organic phases were washed with 1 M NaHSO₄ and brine, then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography [silica gel, EtOAc–CHCl₃ (1:4)]. In Method B, the mixture was poured into H₂O (100 mL) with vigorous stirring. The mixture was filtered and the collected solid was washed with H₂O and Et₂O then dried in air.
• 4 HMCH; Optimized Procedure To a suspension of 1-(2-methoxy-2-oxoethyl)pyridinium bromide (3; 16.4 g, 71 mmol) in DMF (36 mL) were added dimethyl 2,3-dibromosuccinate (64.4 g, 213 mmol) and pyridine (35.3g, 450 mmol), and the mixture was stirred for 72 h. The mixture was then poured into H₂O (750 mL) with vigorous stirring and filtered. The collected solid was washed with H₂O and Et₂O, then dried in air to give a pale-purple powder; yield: 17.46 g (49%); mp 136–137 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.19 (s, 1 H), 3.84 (s, 6 H), 3.81 (s, 6 H), 3.80 (s, 6 H), 3.63 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 166.8 (2COO), 164.6 (COO), 164.5, 164.0 (2 × 2COO), 136.8, 133.7, 132.2 (3 × 2C), 53.4, 53.3 (2 × 2OCH₃), 53.1 (OCH₃), 53.0 (2OCH₃), 43.4 (CH).
• 5 1-[3-Methoxy-1-(methoxycarbonyl)-3-oxoprop-1-en-1-yl]pyridinium Bromide (4) The experiments were carried out in an NMR tube. (A) Pyridine (17 mg, 0.22 mmol) was added to a solution of dimethyl bromomaleate (1; 50 mg, 0.22 mmol) in DMSO-d ₆ (0.5 mL), and the mixture was kept at rt. After 2 weeks, the conversion was 26%. (B) DMAD (44 mg, 0.31 mmol) was added to a solution of pyridine hydrobromide (50 mg, 0.31 mmol) in DMSO-d ₆ (0.5mL), and the mixture was allowed to stand overnight. The yield was estimated to be ~90%. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.25 (dd, J = 6.7, 1.4 Hz, 2 H), 8.88 (tt, J = 7.9, 1.4 Hz, 1 H), 8.40–8.32 (m, 2 H), 7.48 (s, 1 H), 3.84 (s, 3 H), 3.61 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 162.3, 160.8, 149.3, 146.3, 139.9, 128.8, 128.2, 54.7, 53.4.
• 6 4-Methoxy-1-(2-methoxy-2-oxoethyl)pyridinium Bromide (9a) Methyl bromoacetate (1.4 g, 9.17 mmol) was added to a solution of 4-methoxypyridine (1.0 g, 9.17 mmol) in acetone (4 mL). The mixture was stirred at rt for 24 h then filtered, washed with Et₂O, and dried under reduced pressure to give a white solid; yield: 1.92 g (80%); mp 120–122 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.92 (d, J = 7.3 Hz, 2 H), 7.74 (d, J = 7.4 Hz, 2 H), 5.61 (s, 2 H), 4.12 (s, 3 H), 3.74 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 171.7, 167.8, 147.9, 113.7, 58.9, 58.8, 53.5. HRMS (ESI+): m/z [M – Br]⁺ calcd for C₉H₁₂NO₃: 182.0812; found: 182.0819.
• 7 4-(2-Methoxy-2-oxoethyl)-1-methyl-1H-1,2,4-triazol-4-ium bromide (9b) Methyl bromoacetate (9.21 g, 60.2 mmol) was added to 1-methyl-1,2,4-triazole (9.21 g, 60.2 mmol), and the mixture was left for 3 d to give a white solid: yield: quant; mp 111–113 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.22 (s, 1 H), 9.28 (s, 1 H), 5.46 (s, 2 H, CH₂), 4.18 (s, 3 H, NMe), 3.79 (s, 3 H, COOMe). ¹³C NMR (75.5 MHz, CDCl₃): δ = 166.1, 144.8, 143.1, 52.6, 47.6, 38.4. HRMS (ESI+): m/z [M – Br]⁺ calcd for C₆H₁₀N₃O₂: 156.0768; found: 156.0773.
• 8 2-(2-Methoxy-2-oxoethyl)-1-methyl-1H-pyrazol-2-ium Bromide (9c) Methyl bromoacetate (10.7g, 65.7 mmol) was added to 1-methyl-1H-pyrazole (5.0 g, 65.7 mmol), and the mixture was left for 2 weeks to give a white solid; yield: quant; mp 104–107 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.75 (d, ³ J = 1.2 Hz, 1 H), 8.66 (d, ³ J = 1.35 Hz, 1 H), 6.97 (dd, ³ J = 1.2, 1.35 Hz, 1 H), 5.82 (s, 2 H, CH₂), 4.17 (s, 3 H, NMe), 3.79 (s, 3 H, COOMe). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 165.4 (COO), 138.5 (CH), 138.4 (CH), 107.0 (CH), 52.7, 49.5, 36.3. HRMS (ESI +): m/z [M – Br]⁺ calcd for C₇H₁₁N₂O₂: 155.0815; found: 155.0812
• 9 1-(2-Oxopropyl)pyridinium bromide (10c), 1-(2-oxo-2-phenylethyl)pyridinium bromide (10b), 1-(2 methoxy-2-oxoethyl)pyridinium bromide (3)¹⁰, (cyanomethyl)(triethyl)ammonium chloride (10e)¹¹, and 3-(2-methoxy-2-oxoethyl)-1-methyl-1H-imidazol-3-ium bromide (10f)¹² were prepared according to the reported methods.
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• 13 Platonov DN. Belyy AYu. Ananyev IV. Tomilov YuV. Eur. J. Org. Chem. 2016; 4105