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Synlett 2011(8): 1097-1100  
DOI: 10.1055/s-0030-1260543
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Acetic Anhydride Generated Imidazolium Ylide in Ring Closures onto Carboxylic Acids; Part of the Synthesis of New Potential Bioreductive Antitumor Agents

Eamonn Joyce, Patrick McArdle, Fawaz Aldabbagh*
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
Fax: +353(91)525700; e-Mail: fawaz.aldabbagh@nuigalway.ie;
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Publication History

Received 10 January 2011
Publication Date:
20 April 2011 (online)

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Abstract

Acetic anhydride behaves as a traceless activating agent allowing thermal intramolecular condensation of 2-(benzimidazol-1-ylmethyl) benzoic and nicotinic acids. Autoxidation gives benzimidazo[1,2-b]isoquinoline-6,11-diones (intermediates characterized) and benzimidazo[2,1-g]-1,7-naphthyridine-5,12-diones in a facile, one-pot transformation. The 1,4-dimethoxy analogue of the former is converted into benzimidazo[1,2-b]isoquinoline-1,4,6,11-tetrone using cerium ammonium nitrate (CAN). The 1,7-naphthyridine-5,12-dione system readily ring-opens, and an X-ray crystal structure of the methanol adduct was obtained.

Key words

benzimidazoles - condensation - heterocycles - quin­ones - ylides

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General Procedure for Annulation: Carboxylic acid 1a-d (0.79 mmol) in Ac2O (50 mL) was heated under reflux for 15 min. The mixture was stirred at r.t. for 18 h, and evaporated to dryness for 3a, 3b and 3d. Ac2O was evaporated immediately after the reflux, and the dry residue (sample purified [¹²] ) heated in air at 50 ˚C for 18 h for 3c. Residues were purified by dry column vacuum chromatography¹0,¹6 using silica gel as absorbent with gradient elution of hexane, EtOAc and MeOH as eluent

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11-Hydroxy-1,4-dimethoxybenzimidazo[1,2- b ]-isoquinolin-6 (11 H )-one (8a): Yellow solid; R f  = 0.63 (EtOAc-MeOH, 9:1); mp 197-200 ˚C (dec.); IR (neat): 2927, 1676 (C=O), 1601, 1525, 1502, 1431, 1340, 1282, 1257, 1226, 1178, 1158, 1108, 1037 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 1 H), 7.82-7.75 (m, 2 H, 8,9-H), 7.63-7.60 (m, 1 H), 7.09 (s, 1 H, 11-H), 6.81 (d, J = 8.6 Hz, 1 H, 2,3-H), 6.62 (d, J = 8.6 Hz, 1 H, 2,3-H), 5.44 (br. s, 1 H, OH, disappears with D2O), 4.11 (s, 3 H, CH3), 3.98 (s, 3 H, CH3); ¹³C NMR (100 MHz, CDCl3): δ = 174.1 (C=O), 148.3, 141.8, 140.0, 138.0, 136.3 (all C), 134.4 (8,9-CH), 130.3 (C), 130.0 (CH), 128.7 (8,9-CH), 127.5 (CH), 125.1 (C), 106.6 (2,3-CH), 103.8 (2,3-CH), 76.8 (11-CH), 56.7 (CH3), 56.3 (CH3); HRMS (ESI): m/z calcd for C17H15N2O4: 311.1032; found: 311.1018 [M + H]+. 1,4-Dimethoxy-6-oxo-6,11-dihydrobenzimidazo[1,2- b ]isoquinolin-11-yl acetate (8b): Yellow solid; R f  = 0.56 (EtOAc); mp 171-174 ˚C (dec.); IR (neat): 2922, 2847, 1746 (C=O), 1679 (C=O), 1599, 1527, 1506, 1455, 1418, 1367, 1354, 1290, 1263, 1204, 1180, 1108, 1079, 1009 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 8.43 (s, 1 H, 11-H), 8.36 (dd, J = 7.8, 1.4 Hz, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.74-7.71 (m, 1 H, 8,9-H), 7.66-7.63 (m, 1 H, 8,9-H), 6.76 (d, J = 8.6 Hz, 1 H, 2,3-H), 6.65 (d, J = 8.6 Hz, 1 H, 2,3-H), 4.01 (s, 3 H, CH3), 3.91 (s, 3 H, CH3), 2.01 (s, 3 H, COOCH3); ¹³C NMR (100 MHz, CDCl3): δ = 174.1 (C=O), 169.9 (C=O), 147.8, 143.2, 141.6, 136.6, 136.1 (all C), 134.7 (8,9-CH), 130.8 (C), 130.6 (8,9-CH), 128.9 (CH), 127.8 (CH), 124.9 (C), 106.9 (2,3-CH), 104.4 (2,3-CH), 76.0 (11-CH), 56.4 (CH3), 55.9 (CH3), 21.2 (COOCH3); HRMS (ESI): m/z calcd for C19H17N2O5: 353.1137; found: 353.1124 [M + H]+ .

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Benzimidazo[1,2- b ]isoquinoline-1,4,6,11-tetrone (9): CAN (0.296 g, 0.54 mmol) in H2O (5 mL) was added to 3c (83 mg, 0.27 mmol) in MeCN (20 mL) at -5 ˚C. After 5 min, H2O (20 mL) was added and the product was extracted with CH2Cl2 (30 mL). The organic extract was evaporated to dryness and the residue was recrystallized from CHCl3. Yield: 60 mg (79%); brown solid; mp 203-205 ˚C (dec.); IR (neat): 1752 (C=O), 1684 (C=O), 1671 (C=O), 1583, 1515, 1494, 1396, 1358, 1287, 1259, 1239, 1189, 1062 cm-¹; ¹H NMR (400 MHz, DMSO-d 6): δ = 8.32-8.30 (m, 1 H), 8.22-8.20 (m, 1 H), 8.01-7.99 (m, 2 H, 8,9-H), 6.98 [d (AB-q), J = 10.3 Hz, 1 H, 2,3-H], 6.93 [d (AB-q), J = 10.3 Hz, 1 H, 2,3-H]; ¹³C NMR (100 MHz, DMSO-d 6): δ = 181.3, 175.6, 173.7, 157.2 (all C=O), 146.6 (C), 143.4 (C), 139.1 (2,3-CH), 136.0 (8,9-CH), 135.9 (8,9-CH), 135.8 (2,3-CH), 132.8, 131.0, 130.3 (all C), 130.1 (CH), 127.4 (CH); HRMS (ESI): m/z calcd for C15H7N2O4: 279.0406; found: 279.0400 [M + H]+ .

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CCDC 805313 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data _request/cif, or by emailing data_request@ccdc.cam.ac.uk or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033

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Methyl 3-[(4,7-Dioxo-4,7-dihydro-1 H -benzimidazol-2-yl)carbonyl]pyridine-2-carboxylate (11): Synthesis as described previously¹³ with the residue recrystallized using EtOAc and hexane. Yield: 72 mg (86%); brown solid; mp 109-111 ˚C; IR (neat): 3408, 1671 (C=O), 1623 (C=O), 1436, 1290, 1062, 1037 cm-¹; ¹H NMR (400 MHz, CD3OD): δ = 8.83 (d, J = 3.6 Hz, 1 H, Pyr-6-H), 8.22 (d, J = 7.5 Hz, 1 H, Pyr-4-H), 7.86-7.83 (m, 1 H, Pyr-5-H), 6.78 (s, 2 H, BnIm-5,6-H), 3.75 (s, 3 H, CH3), NH not observed; ¹³C NMR (100 MHz, CD3OD): δ = 184.1, 179.5 (×2), 165.3 (all C=O), 150.6 (Pyr-6-CH), 148.2 (C), 146.4 (C), 138.3 (Pyr-4-CH), 137.3 (2 × C), 137.0 (BnIm-5,6-CH), 135.4 (C), 127.2 (Pyr-5-CH), 52.5 (CH3); HRMS (ESI): m/z calcd for C15H10N3O5: 312.0620; found: 312.0630 [M + H]+.