Tandem Oxidative Phenol Dearomatization/Formal [3+2] Annulation Protocol En Route to Highly Functionalized Benzothiophenes

Abstract

A new strategy for the synthesis of benzothiophenes through formal [3+2] annulation of sulfanylacetaldehyde and cyclohexa-2,4-dien-1-one monoketals has been developed. This approach relies on the ease of aromatization of tetrahydrobenzothiophenone derivatives prepared by the aforementioned protocol. Given the ready accessibility of various substituted cyclohexa-2,4-dien-1-one monoketals, a range of benzothiophene derivatives became available.

Key words

cyclohexadienones - benzothiophenes - cycloaddition - tandem reactions - dearomatization

• References and Notes

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Selected recent articles on the synthesis of benzothiophenes follow. For metal-catalyzed processes, see:
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For non-metal-mediated processes, see:
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• 16a See the Supporting Information for the synthetic procedures.
• 16b The relative stereochemistry of all the products was tentatively assigned on the basis of the 2D NOESY spectra of 4a and 4f. Literature precedents⁷ also indicate a similar stereochemical preference for the [3+2]-annulation product.
• 17 3-Hydroxy-5,5,6-trimethoxy-3,3a,5,7a-tetrahydro-1-benzothiophen-4(2H)-one (4a) and 5,6-dimethoxy-1-benzothiophene-4-ol (5a); Typical Procedure PhI(OAc)₂ (251 mg, 0.78 mmol, 1.2 equiv) was added to a solution of 2,3-dimethoxyphenol (2a; 100 mg, 0.65 mmol, 1.0 equiv) in MeOH (2 mL) at 0 °C, and the mixture was stirred for 15 min, after which NaHCO₃ (273 mg, 3.25 mmol, 5.0 equiv) and 2,5-dihydroxy-1,4-dithiane (1; 59 mg, 0.39 mmol, 0.6 equiv) were added sequentially and the mixture was stirred at r.t. for 4 h. The solvent was then evaporated and residue was diluted with H₂O, and the mixture was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated, and the crude residue was purified by column chromatography (silica gel, EtOAc–hexanes)/hexanes to give 4a as a yellow-to-orange gum; yield: 151 mg (90%). Alternatively, the crude product was diluted with 1,4-dioxane (0.5 mL), followed by addition of 4 N HCl in 1,4-dioxane (1 mL, 6.15 mmol, ~9.5 equiv). The resulting mixture was then heated at 50 °C for 2 h to give the benzothiophene derivative 5a; yield: 115 mg (84%). All the benzothiophene derivatives were obtained as dark-orange to brown solids. Note 1: In the case of quinone monoketals 3j (100 mg, 0.49 mmol, 1.0 equiv) and 3k (100 mg, 0.35 mmol, 1.0 equiv), 1.0 equivalent each of 2,5-dihydroxy-1,4-dithiane and triethylamine were used. Note 2: In the case of 4-chloro-2-methoxyphenol (2i; 100 mg, 0.63 mmol, 1.0 equiv), after the oxidation step, regular workup was performed, and the resulting crude dienone 3i was dissolved in 1,4-dioxane (2 mL), followed by addition of Et₃N (0.4 mL, 3.15 mmol, 5.0 equiv) and 2,5-dihydroxy-1,4-dithiane (1; 96 mg, 0.63 mmol, 1.0 equiv). After 2 h reaction time, 4 N HCl in 1,4-dioxane (1 mL, 6.3 mmol, 10 equiv) was added and the reaction mixture was heated at 50 °C for 16 h to give the benzothiophene derivatives 5i and 8i. 4a: ¹H NMR (400 MHz, CDCl₃): δ = 5.14 (d, J = 4.8 Hz, 1 H), 4.97–4.94 (m, 1 H), 4.56 (dd, J = 6.8, 4.8 Hz, 1 H), 3.64 (s, 3 H), 3.41 (dd, J = 6.8, 2.8 Hz, 1 H), 3.35 (dd, J = 11.6, 4.8 Hz, 1 H), 3.34 (s, 3 H), 3.29 (s, 3 H), 2.89 (dd, J = 11.6, 2.8 Hz, 1 H), 2.50 (d, J = 5.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.4 (C), 152.1 (C), 101.9 (CH), 96.8 (C), 74.6 (CH), 58.5 (CH), 55.4 (CH₃), 52.2 (CH₃), 51.5 (CH₃), 42.6 (CH), 39.9 (CH₂). ESI-MS: m/z = 229 [C₁₁H₁₆O₅S – CH₃OH + H]⁺. 5a: ¹H NMR (400 MHz, CDCl₃): δ = 7.39 (dd, J = 5.6, 0.8 Hz, 1 H), 7.19 (d, J = 5.6 Hz, 1 H), 6.94 (app s, 1 H), 6.21 (br s, 1 H), 3.925 (s, 3 H), 3.921 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 151.4 (C), 143.7 (C), 136.4 (C), 132.7 (C), 123.3 (C), 122.9 (CH), 120.1 (CH), 96.4 (CH), 61.3 (CH₃), 56.0 (CH₃). ESI-MS: m/z = 211 [C₁₀H₁₀O₃S + H]⁺. 6-Chloro-5-methoxy-1-benzothiophene-4-ol (5f) brown solid: yield: 78 mg (58%). ¹H NMR (400 MHz, CDCl₃): δ = 7.43 (td, J = 5.6, 0.8 Hz, 2 H), 7.35 (d, J = 5.6 Hz, 1 H), 6.13 (s, 1 H), 3.95 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.3 (C), 138.7 (C), 136.9 (C), 128.4 (C), 126.1 (CH), 124.6 (C), 120.2 (CH), 114.5 (CH), 61.5 (CH₃); ESI-MS: m/z = 215 [C₉H₇ClO₂S + H]⁺. 5-Methoxy-7-methyl-1-benzothiophene-4-ol (5m) brown solid: yield: 103 mg (73%). ¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J = 5.6 Hz, 1 H), 7.36 (d, J = 5.6 Hz, 1 H), 6.86 (s, 1 H), 5.87 (s, 1 H), 3.93 (s, 3 H), 2.50 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.4 (C), 138.5 (C), 134.0 (C), 128.4 (C), 125.6 (CH), 122.7 (C), 120.6 (CH), 111.1 (CH), 57.3 (CH₃), 19.9 (CH₃). ESI-MS: m/z = 195 [C₁₀H₁₀O₂S + H]⁺. 4,5-Dihydroxy-1-benzothiophene-6-carbaldehyde (8c) dark orange solid: yield: 53 mg (65%). ¹H NMR (400 MHz, CDCl₃): δ = 10.7 (s, 1 H), 9.95 (s, 1 H), 7.66 (d, J = 0.8 Hz, 1 H), 7.64 (d, J = 5.6 Hz, 1 H), 7.50 (dd, J = 5.6, 0.8 Hz, 1 H), 6.01 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.2 (C), 142.1 (C), 138.9 (C), 134.3 (C), 132.2 (CH + C), 120.4 (CH), 119.7 (CH), 119.5 (C). ESI-MS: m/z = 193 [C₉H₆O₃S – H]^–. 6,7-Dichloro-3-hydroxy-5-methoxy-3,3a,7,7a-tetrahydro-1-benzothiophen-4(2H)-one (10) orange gum: yield: 23 mg (14%). ¹H NMR (400 MHz, CDCl₃): δ = 5.10 (t, J = 2.8 Hz, 1 H), 4.27–4.25 (m, 1 H), 3.85 (s, 3 H), 3.84–3.83 (m, 1 H), 3.13–3.09 (m, 1 H), 2.92 (br s, 1 H), 2.86 (dd, J = 15.2, 1.6 Hz, 1 H), 2.59 (dd, J = 15.2, 3.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 188.8 (C), 149.8 (C), 133.5 (C), 68.2 (CH), 60.8 (CH₃), 57.7 (CH), 56.5 (CH), 48.7 (CH), 28.6 (CH₂). ESI-MS: m/z = 269 [C₉H₁₀Cl₂O₃S + H]⁺. 5,6-dimethoxy-3-methyl-1-benzothiophene-4-ol (14a); Typical Procedure 2,5-Dimethyl-2,5-dihydroxy-1,4-dithiane (13; 97 mg, 0.54 mmol, 1.0 equiv) and Et₃N (0.075 mL, 0.54 mmol, 1.0 equiv) were added sequentially to a solution of the cyclohexa-2,4-dien-1-one 3a (100 mg, 0.54 mmol, 1.0 equiv) in CH₂Cl₂ (2 mL) at r.t. After 30 min, the mixture was diluted with H₂O, and extracted with EtOAc. The organic extracts were then dried (Na₂SO₄), filtered, and concentrated. The crude product was treated with 4 N aq HCl (1 mL, 7.4 mmol, ~14 equiv) and the mixture was stirred at r.t. for 10 min, then heated to 50 °C for 16 h. The solvents were evaporated and the residue was diluted with H₂O then extracted with EtOAc. The organic extracts were dried (Na₂SO₄), filtered, and concentrated, and the residue was purified by column chromatography (silica gel, EtOAc–hexanes) to give a brown solid: yield: 80 mg (55%). All benzothiophene derivatives 14 were obtained as brown solids.

When in situ-generated cyclohexa-2,4-dien-1-ones were used in the subsequent reactions, NaHCO₃ was added to the mixture to neutralize AcOH released from PhI(OAc)₂; see:
• 18a Liu W.-C, Liao C.-C. Chem. Commun. 1999; 117-117
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• 19 Nevertheless, small amounts of unexpected products were isolated from these reactions. See the Supporting Information.
• 20a Although products 4k and 4k′ were eventually separated, to our disappointment, only 4j′ could be cleanly separated from 4j/4j′.
• 20b The diastereoisomers were tentatively assigned on the basis of ¹H and ¹³C NMR δ values. See the Supporting Information.
• 21 Compound 9, on heating to 50 °C for 3 h in the presence of 4 N HCl in 1,4-dioxane, gave a 4:1 ratio of 5e and 9, as indicated by diagnostic peak integration of the ¹H NMR spectra of the crude reaction mixture.
• 22a Chittimalla SK, Bandi C. RSC Adv. 2013; 3: 13663-13663
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• 24 To our surprise, upon column chromatography of one of the reactions at the [3+2]-annulation stage, dienone 3a was recovered in 50% yield. This result indicated that either the Michael adduct or the Michael–aldol product is unstable to isolation.