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Synlett 2004(3): 481-484  
DOI: 10.1055/s-2004-815440
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Synthetic Methods for Seven- and Eight-Membered Cyclic Ethers Based on the Ring-Expansion Reactions of Hydroxy or Lithioxy Methoxyallenylisochroman Derivatives

Yoshimitsu Nagao*a, Satoru Tanakaa, Kazuhiko Hayashia, Shigeki Sanoa, Motoo Shirob
a Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Fax: +81(88)6339503; e-Mail: ynagao@ph.tokushima-u.ac.jp;
b Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
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Publikationsverlauf

Received 24 December 2003
Publikationsdatum:
06. Februar 2004 (online)

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Abstract

The Pd(0)-catalyzed ring-expansion reactions of hydroxy methoxyallenyl-4,4-dialkylisochroman derivatives in the presence of P(o-tolyl)3 proceeded smoothly via hydropalladation to give 3-benzoxepan-1-one derivatives in high yields. Treatment of isochroman-1-one derivatives with lithio methoxyallene followed by quenching the reaction with water furnished 3-benzoxocan-6-one derivatives in good yields.

Key words

allenes - cyclic ether - palladium - hydropalladation - ring expansion

10

Typical Experimental Procedure for the Synthesis of Hydroxy Methoxyallenyl-4,4-dialkylisochromans 7a-c: A solution of methoxyallene (280.4 mg, 4.0 mmol) in dry THF (4.0 mL) was treated with 1.58 M n-BuLi in n-hexane (1.52 mL, 2.4 mmol) under an argon atmosphere at -30 °C. The solution was stirred for 30 min, and then the solution was added to a THF (2.0 mL) solution of 4,4-dimethyl-isochroman-1-one (6a; 352.4 mg, 2.0 mmol) at -30 °C. After being stirred at -30 °C for 1 h, the reaction mixture was quenched with H2O and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to afford a crude product, which was purified by column chromato-graphy on silica gel with n-hexane-EtOAc (3:1) to give 1-hydroxy-1-methoxyallenyl-4,4-dimethylisochroman (7a; 483.2 mg, 98%) as a pale yellow oil.
Compound 7a: pale yellow oil. IR (neat): 3428, 1956 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.33 (s, 3 H), 3.42 (s, 1 H), 3.47 (s, 3 H), 3.61 (d, J = 11.0 Hz, 1 H), 4.04 (d, J = 11.0 Hz, 1 H), 5.60 (d, J = 8.3 Hz, 1 H), 5.66 (d, J = 8.3 Hz, 1 H), 7.17-7.36 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 24.5, 28.2, 33.4, 56.8, 70.8, 94.3, 96.1, 124.4, 125.7, 127.4, 128.5, 133.7, 137.2, 144.1, 197.1. HRMS-EI calcd for C15H18O3: MW 246.1256. Found: m/z = 246.1254 (M+). Compound 7b: pale yellow oil. IR (neat): 3470, 1956 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.77 (t, J = 7.7 Hz, 3 H), 0.81 (t, J = 7.7 Hz, 3 H), 1.62-1.82 (m, 4 H), 3.48 (s, 3 H), 3.50 (s, 1 H), 3.76 (d, J = 11.2 Hz, 1 H), 4.11 (d, J = 11.2 Hz, 1 H), 5.52 (d, J = 8.3 Hz, 1 H), 5.55 (d, J = 8.3 Hz, 1 H), 7.16-7.31 (m, 3 H), 7.36-7.39 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 8.6, 8.7, 28.5, 31.3, 39.4, 56.9, 66.5, 94.0, 96.3, 125.5, 125.6, 127.6, 128.0, 135.2, 136.7, 141.2, 197.4. HRMS-EI calcd for C17H22O3: MW 274.1569. Found: m/z = 274.1569 (M+). Compound 7c: white powder. IR (KBr): 3420, 1957 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J = 7.3 Hz, 3 H), 0.86 (t, J = 7.3 Hz, 3 H), 1.06-1.29 (m, 4 H), 1.59-1.73 (m, 4 H), 3.48 (s, 3 H), 3.49 (s, 1 H), 3.76 (d, J = 11.5 Hz, 1 H), 4.10 (d, J = 11.5 Hz, 1 H), 5.52 (d, J = 8.3 Hz, 1 H), 5.55 (d, J = 8.3 Hz, 1 H), 7.15-7.30 (m, 3 H), 7.35-7.37 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 14.9, 15.0, 17.3, 17.4, 39.2, 39.4, 41.7, 57.0, 67.4, 94.1, 96.3, 125.4, 125.5, 127.6, 128.0, 134.7, 136.6, 141.9, 197.3. HRMS-EI calcd for C19H26O3: MW 302.1882. Found: m/z = 302.1888 (M+).

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Typical Procedure for the Ring-Expansion Reaction of Hydroxy Methoxyallenyl-4,4-dialkylisochromans 7a-c: A mixture of 1-hydroxy-1-methoxyallenyl-4,4-dimethyl-isochroman (7a; 173.1 mg, 0.703 mmol), Pd(PPh3)4 (40.6 mg, 5.0 mol%), P(o-tolyl)3 (21.4 mg, 10.0 mol%) in THF (7.0 mL) was refluxed under an argon atmosphere for 3 h. The reaction mixture was evaporated in vacuo to afford a solid residue, which was purified by column chromato-graphy on silica gel with n-hexane-EtOAc (3:1) to give 5,5-dimethyl-2-methoxy-2-vinyl-3-benzoxepan-1-one (8a; 137.4 mg, 79%) as colorless prisms.
Compound 8a: colorless prisms; mp 78.5-79.5 °C (n-hexane-EtOAc). IR (KBr): 1711 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.14 (s, 3 H), 1.60 (s, 3 H), 3.36 (s, 3 H), 3.69 (d, J = 13.2 Hz, 1 H), 4.03 (d, J = 13.2 Hz, 1 H), 5.37 (dd, J = 1.6, 10.3 Hz, 1 H), 5.53 (dd, J = 1.6, 17.3 Hz, 1 H), 5.65 (dd, J = 10.3, 17.3 Hz, 1 H), 7.21-7.25 (m, 1 H), 7.41-7.50 (m, 3 H). HRMS-EI calcd for C15H18O3: MW 246.1256. Found: m/z = 246.1258 (M+). Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.03; H, 7.38. Compound 8b: colorless oil. IR (neat): 1700 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.46 (t, J = 7.5 Hz, 3 H), 1.07 (t, J = 7.5 Hz, 3 H) 1.44-1.58 (m, 2 H), 1.76-1.89 (m, 1 H), 2.13-2.23 (m, 1 H), 3.35 (s, 3 H), 3.86 (d, J = 13.7 Hz, 1 H), 4.10 (d, J = 13.7 Hz, 1 H), 5.35 (dd, J = 1.5, 10.5 Hz, 1 H), 5.48 (dd, J = 1.5, 17.3 Hz, 1 H), 5.62 (dd, J = 10.5, 17.3 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.24 (d, J = 7.8 Hz, 1 H), 7.42 (dd, J = 1.5, 7.7 Hz, 1 H), 7.46-7.50 (m, 1 H). HRMS-EI calcd for C17H22O3: MW 274.1569. Found: m/z = 274.1558 (M+). Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.17; H, 8.08. Compound 8c: colorless oil. IR (neat): 1701 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.54-0.73 (m, 4 H), 0.92-1.04 (m, 4 H), 1.33-1.50 (m, 3 H), 1.63-1.78 (m, 3 H), 3.34 (s, 3 H), 3.87 (d, J = 13.7 Hz, 1 H), 4.11 (d, J = 13.7 Hz, 1 H), 5.35 (dd, J = 1.5, 10.5 Hz, 1 H), 5.48 (dd, J = 1.5, 17.3 Hz, 1 H), 5.61 (dd, J = 10.5, 17.3 Hz, 1 H), 7.21-7.24 (m, 1 H), 7.36 (d, J = 7.8 Hz, 1 H), 7.40 (dd, J = 1.5, 7.8 Hz, 1 H), 7.46-7.50 (m, 1 H). HRMS-EI calcd for C19H26O3: MW 302.1882. Found: m/z = 302.1888 (M+). Anal. Calcd for C19H26O3: C, 75.46; H, 8.67. Found: C, 75.21; H, 8.71.

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X-ray data for 8a: C15H18O3, MW = 246.31, colorless block, orthorhombic, space group Aba2 (#41), a = 22.4114 Å, b = 7.929(2) Å, c = 14.737 (4) Å, V = 2618 (1) Å3, Z = 8, R = 0.181, Rw = 0.181. The structure factors are available from the author upon request.

14

Typical Experimental Procedure for the Ring-Expansion Reaction of Isochroman-1-ones 9a-e: A solution of methoxyallene (140.2 mg, 2.0 mmol) in dry THF (2.0 mL) was treated with 1.58 M n-BuLi in n-hexane (0.76 mL, 1.2 mmol) under an argon atmosphere at -30 °C with stirring for 30 min. Then the solution was added to a THF (1.0 mL) solution of 7-methoxy-isochroman-1-one (9d; 178.2 mg, 1.0 mmol) at -30 °C. After being stirred at -30 °C for 1 h, the reaction mixture was quenched with H2O and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to afford a crude product, which was purified by column chromatography on silica gel with n-hexane-EtOAc (3:1) to give 5,8-dimethoxy-4-methyl-1,2-dihydro-3-benzoxocin-6-one (10d; 166.6 mg, 69%) as colorless plates.
Compound 10a: colorless oil. IR (neat): 1619, 1596 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.12 (s, 3 H), 2.98 (t, J = 5.7 Hz, 2 H), 3.73 (s, 3 H), 4.02 (t, J = 5.7 Hz, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H). HRMS-EI calcd for C13H14O3: MW 218.0943. Found: m/z = 218.0957 (M+). Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.32; H, 6.43. Compound 10b: colorless needles; mp 72.5-73.5 °C (CHCl3-n-hexane-Et2O). IR (KBr): 1620, 1601
cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.36 (s, 3 H), 2.94 (t, J = 5.9 Hz, 2 H), 3.72 (s, 3 H), 4.00 (t, J = 5.9 Hz, 2 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.23-7.26 (m, 1 H), 7.56 (d, J = 0.7 Hz, 1 H). HRMS-EI calcd for C14H16O3: MW 232.1100. Found: m/z = 232.1104 (M+). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.13; H, 6.96. Compound 10c: colorless prisms; mp 56.0-56.5 °C (n-hexane-Et2O). IR (KBr): 1617, 1608 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.37 (s, 3 H), 2.95 (t, J = 5.7 Hz, 2 H), 3.72 (s, 3 H), 4.01 (t, J = 5.7 Hz, 2 H), 6.97 (s, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 1 H); HRMS-EI calcd for C14H16O3: MW 232.1100. Found: m/z = 232.1092 (M+). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.17; H, 6.98. Compound 10d: colorless plates; mp 81.0 °C (n-hexane-EtOAc). IR (KBr): 1613, 1600 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.12 (s, 3 H), 2.92 (t, J = 5.6 Hz, 2 H), 3.72 (s, 3 H), 3.83 (s, 3 H), 3.99 (t, J = 5.6 Hz, 2 H), 7.00 (dd, J = 2.0, 8.3 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H). HRMS-EI calcd for C14H16O4: MW 248.1049. Found: m/z = 248.1049 (M+). Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.76; H, 6.52. Compound 10e: colorless needless; mp 147.0-147.5 °C (n-hexane-EtOAc); IR (KBr) 1617, 1596 cm-1; 1H NMR (400 MHz, CDCl3) d = 2.11 (s, 3 H), 2.97 (t, J = 5.7 Hz, 2 H), 3.72 (s, 3 H), 3.92 (s, 3 H), 3.94 (s, 3 H), 4.03 (t, J = 5.7 Hz, 2 H), 6.62 (s, 1 H), 7.44 (s, 1 H). HRMS-EI calcd for C15H18O5 MW 278.1154, found m/z 278.1172 (M+). Anal. Calcd for C15H18O5: C, 64.47; H, 6.52. Found: C, 64.74; H, 6.58.

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X-ray data for 10b: C14H16O3, MW = 232.28, colorless needle, monoclinic, space group P21/c (#14), a = 10.223(3) Å, b = 8.743(2) Å, c = 14.193(3) Å, V = 1237.9(5) Å3, β = 102.64(1)o, Z = 4, R = 0.087, Rw = 0.131. The structure factors are available from the author upon request.