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DOI: 10.1055/s-0030-1258135
Selective Metalation of 4,6-Dibromoresorcinol Dimethyl Ether with LiTMP
Publication History
Publication Date:
09 July 2010 (online)
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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
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- Supporting Information
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References and Notes
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.