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

Yoshimitsu Nagao; Satoru Tanaka; Kazuhiko Hayashi; Shigeki Sano; Motoo Shiro

doi:10.1055/s-2004-815440

LETTER

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 Tanaka^a, Kazuhiko Hayashi^a, Shigeki Sano^a, Motoo Shiro^b
^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

Abstract

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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

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References

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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.

12

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.

13a Bhide BH. Shah KK. Indian J. Chem., Sect. B 1980, 19: 9

13b Lamaty G. Moreau C. Mouloungui Z. Can. J. Chem. 1983, 61: 2643

13c Isobe K. Takeda N. Mohri K. Tsuda Y. Chem. Pharm. Bull. 1989, 37: 3390

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.

15

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.