Application of Directed Metallation in Synthesis, Part 2 [1] : An Expedient Synthesis of Methoxybenzo[b]thiophenes

Abstract

A short, simple and expedient synthesis of substituted benzo[b]thiophenes involving directed ortho lithiation-side-chain deprotonation-cyclisation-reduction is described. This method is a valuable improvement over earlier syntheses of the same class of compounds, both with respect to the number of steps and overall yields.

Key words

benzo[b]thiophene - thioindoxyl - directed metallation

References

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9

Kamila, S.; Mondal, S. S.; De, A. unpublished work.

10

All the compounds reported in this paper showed correct elemental analysis and the structures were corroborated by characteristic spectroscopic data.

11

Representative Procedure for Synthesis of Compound 2: Compound 1 (R₁ = OMe, R₂ = H, R₃ = OMe, R₄ = H) was added to a stirred mixture of sec- BuLi (1.1 equiv) and TMEDA (1.1 equiv) in THF at -78 °C. After 40 minutes the ortho lithiated species was quenched with dimethyldisulfide (2 equiv) at -78 °C. The reaction mixture was allowed to attain room temperature and was kept at that temperature for 10 hours. Usual aqueous work up afforded compound 2d. Yield: 84%; mp 80 °C (Ether-Petroleum ether); IR (KBr) = 1637.5 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.4 (d, 1 H, J = 2 Hz), 6.27 (d, 1 H, J = 2 Hz), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.24 (q, 4 H), 2.42 (s, 3 H), 1.13 (t, 6 H); ¹³C NMR (300MHz, CDCl₃) δ_c: (167.15, 161.18, 157.13, 137.76, 119.75, 104.39, 96.09, 56.04, 55.83, 43.03, 39.14, 16.75, 14.22, 13.01.

12

Representative Procedure for Synthesis of Compound 3: Compound 2d was treated with LDA (2 equiv) in THF at -78 °C for 50 min and the reaction mixture was stirred for 12 h at room temperature. Usual work up of the reaction mixture afforded compound 3d. IR (KBr) = 1679.9 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.37 (d, 1 H, J = 1.8 Hz), 6.07 (d, 1 H, J = 1.8 Hz), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.68 (s, 2 H); ¹³C NMR (300 MHz, CDCl₃) δ_c: 196.47, 167.47, 161.85, 160.05, 113.91, 100.2, 96.05, 56.27, 40.12.

13

Representative Procedure for the Synthesis of Compound 4: To a solution of compound 3d in methanol and 10% NaOH (6:1), NaBH₄ (2 equiv) in methanol and 10% NaOH solution (10:3) were added. This mixture was refluxed for 1 h on steam bath and then allowed to stand just under boiling condition for 12 h. Methanol was removed and the reaction mixture was acidified with 10% H₂SO₄ and extracted with ether. Usual aqueous work up and removal of solvent afforded compound 4d. ¹H NMR (300 MHz, CDCl₃) δ_H: 7.28 (d, 1 H, J = 5.49 Hz), 7.05 (d, 5.49), 6.82 (d, 1 H, J = 1.8 Hz), 6.31 (d, 1 H, J = 1.8), 3.81 (s, 3 H), 3.75 (s, 3 H); ¹³C NMR (300 MHz, CDCl₃) δ_c: 159.23, 155.78, 142.5, 125.41, 122.25, 120.61, 96.62, 96.21, 56.06, 55.83.