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Synlett 2006(10): 1497-1502  
DOI: 10.1055/s-2006-944194
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Controlled Synthesis of Nature-Mimicking Benzofurans and their Corresponding Dimers [1]

Manish Dixita, Ashoke Sharonb, Prakas R. Maulikb, Atul Goel*a
a Medicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Fax: +91(522)2623405; e-Mail: agoel13@yahoo.com;
b Molecular & Structural Biology, Central Drug Research Institute, Lucknow 226001, India
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Publication History

Received 22 March 2006
Publication Date:
12 June 2006 (online)

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Abstract

Benzofurans functionalized with hydroxy and acetyl functionalities are not only the core structures found in a large number of biologically important natural products, but also the vital precursors for several naturally occurring furanoflavonoids. Numerous synthetic methodologies are available in the literature for the ­synthesis of functionalized benzofurans but access to benzofurans with adjacent hydroxy and acetyl functionalities shows paucity of references. In this paper we report highly convenient synthesis of nature-mimicking benzofurans and their dimers from easily accessible precursors.

Key words

benzofuran - dihydrobenzofuran - benzofuran dimer - Amberlyst 15 - bibenzofuran

1

C.D.R.I. Communication No. 6734.

1

C.D.R.I. Communication No. 6734.

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Crystal data of 6: C20H16O6, M = 352.33, triclinic, space group P-1, a = 8.186 (1), b = 9.265 (2), c = 12.134 (3) Å, α = 95.27 (1)°, β = 100.54 (1)°, γ = 112.47 (2)°, V = 822.7 (3) Å3, T = 293 K, Z = 2, µ (MoKα) = 0.11 mm-1, R1 = 0.1302 for 993 I > 4σ(I) and 0.2971 for all 2838 data. CCDC (No. 604409) contains the supplementary crystallographic data. These data can be obtained free of charge from www.ccdc.cam.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44(1223)336033; email: deposit@ccdc.cam.ac.uk]. Programs: XSCANS [Siemens Analytical X-ray Instrument Inc.: Madison, Wisconsin, USA 1996], SHELXTL-NT [Bruker AXS Inc.: Madison, Wisconsin, USA 1997].

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Synthesis of ortho -Hydroxybenzofuran Methyl Ketones (3,4,9,12,13) - General Procedure. The phenoxyacetal (2, 8, 11; 20 g, 0.075 mol) was refluxed in dry toluene (30 mL) with Amberlyst 15 (2.5 g) at 120 °C for 6-8 h with concomitant removal of the azeotrope using a Dean-Stark apparatus. The resulting reaction mixture was filtered and the resin was washed with an excess of toluene. The filtrate thus obtained was concentrated to dryness and two pure compounds were isolated by silica gel column chromatography using EtOAc-hexane (1:10) as eluent.
Compound 3: white solid; mp 92-93 °C (Lit. [4h] 92-93 °C). MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1640 (CO), 3421 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.66 (s, 3 H, CH3), 7.00 (d, J = 2.2 Hz, 1 H, H-3), 7.04 (d, 1 H, J = 8.8 Hz, H-7), 7.57 (d, 1 H, J = 2.2 Hz, H-2), 7.66 (d, 1 H, J = 8.8 Hz, H-6), 13.28 (s, 1 H, OH).
Compound 4: white solid; mp 101-102 °C (Lit. [9a] 96 °C). MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1638 (CO), 3426 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.70 (s, 3 H, CH3), 6.72 (d, 1 H, J = 2.2 Hz, H-3), 7.04 (s, 1 H, H-7), 7.56 (d, 1 H, J = 2.2 Hz, H-2), 8.00 (s, 1 H, H-4), 12.40 (s, 1 H, OH).
Compound 9: white solid; mp 111-112 °C (Lit. [9c] 110 °C). MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1638 (CO), 3432 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.90 (s, 3 H, CH3), 6.76 (d, J = 2.2 Hz, 1 H, H-3), 6.90 (d, 1 H, J = 8.6 Hz, H-5), 7.62 (d, 1 H, J = 2.2 Hz, H-2), 7.66 (d, 1 H, J = 8.6 Hz, H-4), 12.85 (s, 1 H, OH).
Compound 12: white solid; mp 120-121 °C. MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1629 (CO), 3447 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 6.86 (s, 1 H, ArH), 6.91 (d, J = 2.2 Hz, 1 H, H-3), 7.02 (s, 1 H, ArH), 7.19 (d, 1 H, J = 2.2 Hz, H-2), 11.81 (s, 1 H, OH).
Compound 13: white solid; mp 98-99 °C (Lit. [9a] 103-104 °C). MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1628 (CO), 3443 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.80 (s, 3 H, CH3), 6.94 (d, 1 H, J = 9.0 Hz, CH), 6.98 (d, 1 H, J = 2.2 Hz, H-3), 7.64 (d, 1 H, J = 9.0 Hz, ArH), 7.76 (d, 1 H, J = 2.2 Hz, H-2), 13.02 (s, 1 H, OH).
Compound 14: white solid; mp 104-105 °C (Lit. [4h] 105 °C). MS (FAB): m/z = 193 [M+ + 1]. IR (KBr): 1678 (CO), 3502 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.97 (s, 3 H, OCH3), 6.98 (d, J = 2.2 Hz, 1 H, H-3), 7.03 (d, 1 H, J = 8.8 Hz, H-7), 7.57 (d, 1 H, J = 2.2 Hz, H-2), 7.78 (d, 1 H, J = 8.8 Hz, H-6), 13.18 (s, 1 H, OH).

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Synthesis of 2′,3′-Dihydro[2,3′]bibenzofurans (5, 6 and 15-18) - General Procedure.
The ortho-hydroxybenzofuran methyl ketone (10 mmol) was refluxed in toluene (35 mL) with Amberlyst 15 (0.22 g) at 120 °C for 6-10 h. The resulting reaction mixture was filtered and the resin was washed with an excess of toluene. The filtrate thus obtained was concentrated to dryness and a pure compound was isolated by silica gel column chromatography using 7% EtOAc in hexane (1:10) as eluent.
Compound 5: yellow solid; mp 149-150 °C. MS (FAB): m/z = 353 [M+ + 1]. IR (KBr): 1638 (CO), 3433 (OH) cm-1. 1H NMR (200 MHz CDCl3): δ = 2.57 (s, 3 H, CH3), 2.64 (s, 3 H, CH3), 4.81-4.88 (m, 1 H, CH), 4.89-4.94 (m, 2 H, CH2), 6.48 (d, 1 H, J = 8.6 Hz, ArH), 6.68 (s, 1 H, CH), 6.96 (d, 1 H, J = 8.8 Hz, ArH), 7.60 (d, 1 H, J = 8.8 Hz, ArH), 7.70 (d, 1 H, J = 8.6 Hz, ArH), 12.83 (s, 1 H, OH), 13.15 (s, 1 H, OH).
Compound 6: yellow solid; mp 189-190 °C. MS (FAB): m/z = 353 [M+ + 1]. IR (KBr): 1641 (CO), 3427 (OH) cm-1. 1H NMR (200 MHz CDCl3): δ = 2.53 (s, 3 H, CH3), 2.68 (s, 3 H, CH3), 4.75-4.80 (m, 2 H, CH2), 4.92-4.96 (m, 1 H, CH), 6.43 (s, 1 H, ArH), 6.46 (s, 1 H, CH), 6.99 (s, 1 H, ArH), 7.58 (s, 1 H, ArH), 7.91 (s, 1 H, ArH), 12.46 (s, 1 H, OH), 13.02 (s, 1 H, OH).
Compound 15: yellow solid; mp 110-111 °C. MS (FAB): m/z = 353 [M+ + 1]. IR (KBr): 1637 (CO), 3449 (OH) cm-1. 1H NMR (200 MHz CDCl3): δ = 2.69 (s, 3 H, CH3), 2.82 (s, 3 H, CH3), 4.80-4.88 (m, 2 H, CH2), 4.97-5.02 (m, 1 H, CH), 6.44 (s, 1 H, CH), 6.52 (d, 1 H, J = 8.4 Hz, ArH), 6.88 (d, 1 H, J = 8.6 Hz, ArH), 7.30 (d, 1 H, J = 8.4 Hz, ArH), 7.56 (d, 1 H, J = 8.6 Hz, ArH), 12.74 (s, 1 H, OH), 12.81 (s, 1 H, OH). 13C NMR (200 MHz CDCl3): δ = 31.6 (CH3), 32.0 (CH3), 41.1 (CH), 77.2 (CH2), 103.5 (=CH), 107.3, 107.5, 110.3, 114.5, 117.2, 120.5, 128.5, 131.9, 154.2, 156.5, 161.8, 161.9, 164.0, 202.3, 203.5.
Compound 16: yellow solid; mp 192-193 °C. MS (FAB): m/z = 353 [M+ + 1]. IR (KBr): 1648 (CO), 3422 (OH) cm-1. 1H NMR (200 MHz CDCl3): δ = 2.53 (s, 3 H, CH3), 2.68 (s, 3 H, CH3), 4.75-4.80 (m, 2 H, CH2), 4.82-4.99 (m, 1 H, CH), 6.43 (s, 1 H, ArH), 6.46 (s, 1 H, CH), 6.99 (s, 1 H, ArH), 7.58 (s, 1 H, ArH), 7.91 (s, 1 H, ArH), 12.47 (s, 1 H, OH), 13.03 (s, 1 H, OH).
Compound 17: yellow semi-solid. MS (FAB): m/z = 353 [M+ + 1]. IR (KBr): 1645 (CO), 3437 (OH) cm-1. 1H NMR (200 MHz CDCl3): δ = 2.50 (s, 3 H, CH3), 2.57 (s, 3 H, CH3), 4.73-4.88 (m, 3 H, CH and CH2), 6.41 (d, 1 H, J = 8.6 Hz, ArH), 6.61 (s, 1 H, CH), 6.95 (d, 1 H, J = 8.6 Hz, ArH), 7.50-7.66 (m, 2 H, ArH), 12.76 (s, 1 H, OH), 13.08 (s, 1 H, OH).
Compound 18: yellow solid; mp 184-185 °C. MS (FAB): m/z = 385 [M+ + 1]. IR (KBr): 1678 (CO), 3426 (OH) cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.91 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 4.78-4.95 (m, 3 H, CH and CH2), 6.65 (s, 1 H, CH), 6.47 (d, 1 H, J = 8.6 Hz, ArH), 6.96 (d, 1 H, J = 8.8 Hz, ArH), 7.72 (d, 1 H, J = 8.8 Hz, ArH), 7.81 (d, 1 H, J = 8.6 Hz, ArH), 12.42 (s, 1 H, OH), 13.01 (s, 1 H, OH).