Selective Metalation of 4,6-Dibromoresorcinol Dimethyl Ether with LiTMP

Abstract

4,6-Dibromoresorcinol dimethyl ether was selectively metalated at C-5 with lithium tetramethylpiperidide (LiTMP). A rationale for the selective metalation is proposed.

Key words

lithium tetramethylpiperidide - metalation - regioselectivity - theory - alkylation

References and Notes

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19

Representative experimental procedure. To a solution of tetramethylpiperidine (326 mg, 0.392 mL, 2.3 mmol) in THF (5 mL) at 0 ˚C was added n-BuLi (2.5 M in hexane, 0.843 mL, 2.1 mmol). After stirring for 20 min, the flask was cooled to -78 ˚C and opened quickly, solid 4,6-dibromo-resorcinol dimethyl ether (1; 297 mg, 1.0 mmol) was added all at once, and the flask was immediately sealed. Compound 1 dissolved to give a homogeneous mixture, which became a white slurry about 30 min after the addition. After stirring at -78 ˚C for a total time of 3 h, a solution of allyl bromide (607 mg, 0.424 mL, 5.0 mmol) in THF (1 mL) was added over 1 min. The resulting mixture was stirred at -78 ˚C for 30 min, and then the ice bath was removed. After warming to r.t., the reaction mixture was poured into saturated NH₄Cl solution and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over MgSO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc-hexane, 1:99) to give 3 (329 mg, 98%) as a white solid. 1,3-Dibromo-2-methyl-4,6-dimethoxybenzene (2): Purification by column chromatography on silica gel (EtOAc-hexane, 1:20) gave the title compound 2 in 96% yield, which crystallized from benzene-hexane (3:1) as white needles; mp 168-169 ˚C (Lit.^¹8 168-169 ˚C). ^¹H NMR (400 MHz, CDCl₃): δ = 6.42 (s, 1 H), 3.91 (s, 6 H), 2.62 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 155.7, 139.2, 105.7, 94.8, 56.5, 24.2. HRMS (EI): m/z calcd for C₉H₁₀Br₂O₂: 309.9027; found: 309.9032. Anal. Calcd for C₉H₁₀Br₂O₂: C, 34.87; H, 3.25. Found: C, 34.85; H, 3.20. 2-Allyl-1,3-dibromo-4,6-dimethoxybenzene (3): Purification by column chromatography on silica gel (EtOAc-hexane, 1:99) gave the title compound 3 in 98% yield, which crystallized from hexane as white plates; mp 67-68 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 6.45 (s, 1 H), 5.96-5.86 (m, 1 H), 5.12-5.07 (m, 2 H), 3.92 (s, 6 H), 3.87 (d, J = 8.00 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 140.2, 133.1, 116.5, 105.8, 95.3, 56.5, 40.9. HRMS (EI): m/z calcd for C₁₁H₁₂Br₂O₂: 335.9184; found: 335.9189. (2,6-Dibromo-3,5-dimethoxyphenyl)(phenyl)methanol (4): Purification by column chromatography on silica gel (EtOAc-hexane, 1:9) gave the title compound 4 in 72% yield, which crystallized from benzene-hexane (1:3) as white prisms; mp 147-148 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.25 (m, 5 H), 6.80 (d, J = 11.2 Hz, 1 H), 6.55 (s, 1 H), 3.94 (s, 6 H), 3.87 (d, J = 11.2 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.2, 141.5, 141.4, 128.1, 126.9, 125.4, 96.3, 96.3, 76.5, 56.6. HRMS (EI): m/z calcd C₁₅H₁₄Br₂O₃: 401.9289; found: 401.9294. (2-Bromophenyl)(2,6-dibromo-3,5-dimethoxy-phenyl)methanol (5): Purification by column chromatography on silica gel (EtOAc-hexane, 1:9) gave the title compound 5 in 55% yield, which crystallized from benzene-hexanes (3:1) as a white powder; mp 190-191 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.22 (t, J = 8.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.54 (s, 1 H), 3.93 (s, 6 H), 3.50 (d, J = 8.0 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.2, 139.8, 139.2, 133.4, 129.8, 129.3, 126.8, 123.7, 105.8, 96.5, 77.2, 56.7. HRMS (EI): m/z calcd for C₁₅H₁₃Br₃O₃: 367.9446; found: 367.9450. 1-(2,6-Dibromo-3,5-dimethoxyphenyl)butan-1-ol (6): Purification by column chromatography on silica gel (EtOAc-hexane, 1:9) gave the title compound 6 in 53% yield as a pale-yellow viscous liquid which solidified upon drying in vacuo; mp 73-74 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 6.44 (s, 1 H), 5.54-5.48 (m, 1 H), 3.89 (s, 6 H), 3.27 (d, J = 8.0 Hz, 1 H), 2.12-2.03 (m, 1 H), 1.87-1.78 (m, 1 H), 1.65-1.53 (m, 1 H), 1.41-1.28 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 141.9, 95.7, 75.9, 56.6, 37.2, 19.2, 13.9. HRMS (EI): m/z calcd for C₁₂H₁₆Br₂O₃: 367.9446; found: 367.9450. 2,6-Dibromo-1-iodo-3,5-dimethoxybenzene (7): Purification by column chromatography on silica gel (EtOAc-hexane, 1:9) gave the title compound 7 in 75% yield, which crystallized from hexanes as white needles; mp 181-182 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 6.57 (s, 1 H), 3.91 (s, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.3, 112.2, 111.5, 96.9, 56.9. HRMS (EI): m/z calcd for C₈H₇Br₂IO₂: 421.7837; found: 421.7845.