Reaction of 2-Alkylidenetetrahydrofurans with Boron Tribromide: Chemo- and Regioselective Synthesis of 6-Bromo-3-oxoalkanoates by ­Application of a ‘Cyclization-Ring-Opening’ Strategy

Abstract

6-Bromo-3-oxoalkanoates, benzofurans and 1,7-dibromoheptan-4-ones were chemo- and regioselectively prepared by ­reaction of 2-alkylidenetetrahydrofurans with boron tribromide.

Key words

boron tribromide - domino reactions - nucleophilic substitution - halogenation - tetrahydrofurans

References

• Review:
• 1a Bhatt MV. Kulkarni SU. Synthesis  1983,  249 
• 1b See also: McOmie JFW. Watts ML. West DE. Tetrahedron  1968,  24:  2289 
• 2 Cleavage of cyclic ethers: Kulkarni SU. Patil VD. Heterocycles  1982,  18:  163 
• 3 Cleavage of lactones: Olah GA. Karpeles R. Narang SC. Synthesis  1982,  963 
• 4 7-Bromoheptane-2,4-dione has been prepared by reaction of 5-bromopent-1-yne with acetic anhydride: Tanabe Y. Mukaiyama T. Chem. Lett.  1985,  673 
• 5 Lambert PH. Vaultier M. Carrié R. J. Org. Chem.  1985,  50:  5352 
• 6a Langer P. Holtz E. Karimé I. Saleh NNR. J. Org. Chem.  2001,  66:  6057 
• 6b Langer P. Bellur E. J. Org. Chem.  2003,  68:  9742 
• 6c For Suzuki reactions of 2-alkylidenetetrahydrofurans, see: Bellur E. Langer P. Synlett, preceeding paper
• 7 Hampton KG. Light RJ. Hauser CR. J. Org. Chem.  1965,  30:  1413 
• 9 Langer P. Armbrust H. Eckardt T. Magull J. Chem.-Eur. J.  2002,  8:  1443 ; and references cited therein
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• The reaction of 2-acetyl-γ-butyrolactone with HBr has been reported to give 1-bromopentan-4-one by ring-opening and subsequent decarboxylation. See:
• 13a Cornish CA. Warren S. J. Chem. Soc., Perkin Trans. 1  1985,  2585 
• 13b Baldwin JE. Li C.-S. J. Chem. Soc., Chem. Commun.  1988,  261 
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8

Typical Experimental Procedure for 2h: To a CH₂Cl₂ solution (5 mL) of 3h (0.130 g, 0.5 mmol) was added BBr₃ (0.525 g, 2.1 mmol) at 0 °C. The reaction mixture was allowed to warm to 20 °C during 12 h. Water (2 mL) was added and the solution was stirred for 3 h at 20 °C. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, n-hexane-EtOAc, 30:1 to 1:1) to give 2h as a brownish solid (0.118 g, 72%). The product mainly resides in the keto tautomeric form (keto-enol = 10:1). ¹H NMR (300 MHz, CDCl₃): δ = 2.09 (quint, J = 6.6 Hz, 2 H, CH₂), 2.68 (t, J = 6.9 Hz, 2 H, CH₂), 3.35 (t, J = 6.9 Hz, 2 H, CH₂-Br), 3.76 (s, 3 H, OCH₃), 4.70 (s, 1 H, CH), 5.65 (br, 1 H, OH), 6.83 (d, J = 8.7 Hz, 2 H, Ar), 7.20 (d, J = 8.7 Hz, 2 H, Ar), 13.03 (br, 1 H, enol from, OH). ¹³C NMR (75 MHz, CDCl₃): δ = 26.33, 32.69 (CH₂), 39.44 (CH₂-Br), 52.76 (OCH₃), 63.92 (CH), 103.92 (C=C-O, enol), 115.96 (CH), 123.71 (C), 130.55 (CH), 156.08 (C), 169.64 (O=C-O), 175.04 (O-C=C, enol), 203.55 (C=O). IR (KBr): 3396 (m, OH), 3184 (w), 2957 (w, C-H), 1735 (s, O=C-O), 1703 (s, C=O), 1614 (w), 1594 (w), 1516 (s), 1439 (m), 1359 (m), 1335 (w), 1302 (w), 1274 (m), 1249 (m), 1213 (s), 1161 (m), 1095 (w), 991 (w), 832 (w), 557 (w), 528 (w) cm^-1. MS (EI, 70 eV): m/z (%) = 315 (1) [M⁺], 284 (14), 234 (5), 203 (1), 175 (5), 165 (85), 150 (29), 118 (3), 109 (100), 106 (55). Anal. Calcd for C₁₃H₁₅O₄Br (315.163): C, 49.54; H, 4.80. Found: C, 49.63; H, 5.03. All products gave satisfactory spectroscopic and analytical and/or high-resolution mass data.

11

Typical Experimental Procedure for 5: To a CH₂Cl₂ solution (10 mL) of 4 (0.150 g, 0.6 mmol) was added BBr₃ (0.605 g, 2.4 mmol) at 0 °C. The reaction mixture was allowed to warm to 20 °C and was stirred for 24 h. Water (15 mL) was slowly added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with EtOAc (4 × 30 mL). The combined organic extracts were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, n-hexane-EtOAc, 100:1 to 1:1) to give 5 (0.163 g, 92%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.34 (quint, J = 7.2 Hz, 2 H, CH₂), 3.35 (t, J = 7.5 Hz, 2 H, CH₂), 3.47 (t, J = 6.9 Hz, 2 H, CH₂-Br), 3.95 (s, 3 H, OCH₃), 7.28-7.33 (m, 2 H, 2 × CH), 7.42-7.45 (m, 1 H, CH), 7.95-7.98 (m, 1 H, CH). ¹³C NMR (75 MHz, CDCl₃): δ = 26.83, 30.80 (CH₂), 32.41 (CH₂-Br), 51.44 (OCH₃), 109.17 (C=C-O), 110.88, 121.87, 123.86, 124.58 (CH), 125.82, 153.62 (C), 164.52 (O=C-O), 165.17 (O-C=C). IR (neat): 2952 (m, C-H), 1714 (s, O=C-O), 1593 (s), 1478 (m), 1451 (s), 1437 (s), 1386 (m), 1342 (w), 1284 (m), 1235 (s), 1174 (s), 1127 (w), 1106 (m), 1073 (s), 1010 (w), 959 (w), 935 (w), 861 (w), 790 (m), 752 (s) cm^-1. MS (EI, 70 eV): m/z (%) = 297 (38) [M⁺], 266 (7), 217 (16), 203 (10), 188 (100), 174 (5), 170 (29), 158 (47), 144 (4). Anal. Calcd for C₁₃H₁₃O₃Br (297.148): C, 52.55; H, 4.41. Found: C, 52.84; H, 4.74.