Oxidation Strategy for the Synthesis of Regioisomeric Spiroisobenzofuranopyrroles: Facile Entries to Spiro[isobenzofuran-1,2′-pyrrole] and Spiro[isobenzofuran-1,3′-pyrrole] Derivatives

Abstract

Two practical and efficient approaches have been developed to synthesize two kinds of racemic spiroisobenzofuranopyrrole analogues as regioisomers. In the presence of sodium periodate, cis-indeno[1,2-b]pyrrol-4(1H)-ones were converted into spiro[isobenzofuran-1,2′-pyrrole] derivatives by a two-step process. In addition, oxidative reactions promoted by lead tetraacetate were demonstrated using cis-indeno[2,1-b]pyrrol-8(1H)-ones as substrates, affording spiro[isobenzofuran-1,3′-pyrrole] derivatives. The remarkable features of two approaches included mild and convenient reaction conditions, a broad substrate scope, and moderate to excellent yields. Possible mechanisms were proposed based on the comparison of the intermediates and products.

Key words

oxidation - regioisomer - cis-indeno[1,2-b]pyrrol-4(1H)-one - spiro[isobenzofuran-1,2′-pyrrole] - cis-indeno[2,1-b]pyrrol-8(1H)-one - spiro[isobenzofuran-1,3′-pyrrole]

• References and Notes

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• 14 For the preparation of starting materials, see the Supporting Information. All chiral compounds in this manuscript were obtained as racemic mixtures.
• 15 Crystallographic data have been deposited with the accession number CCDC 1029163 in the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; e-mail: [e-mail]; website: www.ccdc.cam.ac.uk/conts/retrieving.html.
• 16 CCDC 1029164.
• 17 Typical Procedure for 2-{-[(6-Chloropyridin-3-yl)methyl]-5-hydroxy-7-nitro-6-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-5-yl}benzoic acid (3a) The suspension of 1-[(6-chloropyridin-3-yl)methyl]-4a,9a-dihydroxy-10-nitro-2,3,4a,9a-tetrahydroindeno[2′,1′:4,5]pyrrolo[1,2-a]imidazol-9(1H)-one (1a, 414 mg, 1 mmol) and NaIO₄ (214 mg, 1 mmol) in H₂O (10 mL) was stirred at r.t. for 4 h. The resulting solid 3a was isolated by filtration, washed with H₂O and dried; light yellow solid; yield 395 mg (92%); mp 151–152 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.11 (br s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 7.88 (dd, J ₁ = 8.4 Hz, J ₂ = 2.4 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.57–7.51 (m, 1 H), 7.49–7.41 (m, 2 H), 5.36 (d, J = 16.0 Hz, 1 H), 5.10 (d, J = 16.0 Hz, 1 H), 4.04 (td, J ₁ = 10.8 Hz, J ₂ = 3.6 Hz, 1 H), 3.90 (q, J = 10.8 Hz, 1 H), 3.54 (q, J = 10.8 Hz, 1 H), 3.27 (td, J ₁ = 9.6 Hz, J ₂ = 4.0 Hz, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ =185.7, 170.2, 164.4, 149.6, 148.9, 139.0, 133.4, 133.2, 131.4, 129.6, 128.8, 128.7, 127.3, 124.3, 110.9, 85.6, 52.9, 48.5, 39.4 ppm. ESI-HRMS: m/z calcd for C₁₉H₁₆N₄O₆ ³⁵Cl [M + H]⁺: 431.0758; found: 431.0755; m/z calcd for C₁₉H₁₆N₄O₆ ³⁷Cl [M + H]⁺: 433.0729; found: 433.0747
• 18 Typical Procedure for 1′-[(6-Chloropyridin-3-yl)methyl]-7′-nitro-2′,3′-dihydro-3H-spiro{isobenzofuran-1,5′-pyrrolo[1,2-a]imidazole}-3,6′(1′H)-dione (4a) The mixture of PTSA·H₂O (19.1 mg, 0.1 mmol) and 2-{1-[(6-chloropyridin-3-yl)methyl]-5-hydroxy-7-nitro-6-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-5-yl}benzoic acid (3a, 430 mg, 1 mmol) in MeOH (10 mL) was heated to 60 °C and stirred for 4 h. Product 4a precipitated and was separated from the mixture by filtration; light yellow solid; yield 358 mg (87%); mp 317–318 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.55 (d, J = 2.4 Hz, 1 H), 8.04 (d, J = 8.0 Hz), 8.01 (dd, J ₁ = 8.4 Hz, J ₂ = 2.4 Hz), 7.92 (t, J = 7.2 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.81 (t, J = 7.6 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 5.35 (d, J = 16.0 Hz, 1 H), 5.20 (d, J = 16.0 Hz, 1 H), 4.18–4.03 (m, 2 H), 3.67–3.57 (m, 1 H), 3.39–3.31 (m, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.1, 167.4, 164.6, 150.3, 149.9, 140.7, 139.9, 135.9, 132.5, 131.2, 127.3, 126.2, 124.8, 124.1, 111.4, 92.2, 54.4, 49.6, 40.6 ppm. ESI-HRMS: m/z calcd for C₁₉H₁₄N₄O₅ ³⁵Cl [M + H]⁺: 413.0653; found: 413.0641; m/z calcd for C₁₉H₁₄N₄O₅ ³⁷Cl [M + H]⁺: 415.0623; found: 415.0641
• 19 Typical Procedure for 3′,3′-Dimethyl-8′-nitro-1′,2′,3′,4′-tetrahydro-3H,7′H-spiro{isobenzofuran-1,6′-pyrrolo[1,2-a]pyri-midine}-3,7′-dione (4j) The suspension of 5a,10a-dihydroxy-3,3-dimethyl-11-nitro-1,2,3,4,5a,10a-hexahydro-10H-indeno[2′,1′:4,5]pyrrolo[1,2-a]-pyrimidin-10-one (1j, 331 mg, 1 mmol) and NaIO₄ (214 mg, 1 mmol) in H₂O (10 mL) was stirred at r.t. for 4 h. The mixture was filtered, and the precipitated product 4j was washed with H₂O and dried; white solid; yield 253 mg (77%); mp 165–166 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.94 (s, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.93–7.97 (m, 1 H), 7.86–7.77 (m, 2 H), 3.25 (q, J = 12.4 Hz, 2 H), 2.96 (d, J = 11.7 Hz, 1 H), 2.65 (d, J = 11.7 Hz, 1 H), 0.99 (s, 3 H), 0.98 (s, 3 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 175.4, 167.1, 157.9, 141.2, 135.6, 132.0, 126.9, 125.5, 123.5, 109.4, 93.5, 49.7, 47.6, 27.0, 23.4, 23.2 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₆N₃O₅ [M + H]⁺: 330.1090; found: 330.1093
• 20 Typical Procedure for 1′-[(6-Chloropyridin-3-yl)methyl]-7′-nitro-2′,3′-dihydro-1′,3H,5′-spiro{isobenzofuran-1,6′-pyrrolo[1,2-a]imidazole}-3,5′-dione (5a) The mixture of 1-[(6-chloropyridin-3-yl)methyl)-4a,9b-di­hydroxy-10-nitro-2,3,4a,9b-tetrahydroindeno[1′,2′:4,5]pyrrolo[1,2-a]imidazol-5(1H)-one (2a, 414 mg, 1 mmol) and Pb(OAc)₄ (488 mg, 1.1 mmol) in AcOH (5 mL) was stirred at r.t. for 3 h. The precipitate was separated from the mixture by filtration and washed with AcOH (2 mL) and EtOH (4 mL) to afford the pure product 5a; white solid; yield 387 mg (94%); mp 263–264 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.55 (s, 1 H), 7.97 (t, J = 7.2 Hz, 2 H), 7.87–7.83 (m, 2 H), 7.71–7.68 (m, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 5.48–5.37 (m, 2 H), 4.21 (t, J = 8.0 Hz, 2 H), 3.91 (t, J = 8.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.1, 164.3, 155.2, 150.4, 149.8, 145.5, 139.9, 135.4, 131.2, 131.0, 126.6, 125.5, 124.8, 122.8, 100.7, 89.5, 56.8, 49.2, 39.0 ppm. ESI-HRMS: m/z calcd for C₁₉H₁₃N₄O₅ ³⁵ClK [M + K]⁺: 451.0212; found: 451.0198; m/z calcd for C₁₉H₁₃N₄O₅ ³⁷ClK [M + K]⁺: 453.0182; found: 453.0174