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Synlett 2004(13): 2382-2384  
DOI: 10.1055/s-2004-831341
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Benzimidazolequinone Analogue of Cyclopropamitosene Antitumor Agents

John O’Shaughnessy, Desmond Cunningham, Paul Kavanagh, Dónal Leech, Patrick McArdle, Fawaz Aldabbagh*
Department of Chemistry, National University of Ireland, Galway, Ireland
Fax: +353(91)525700; e-Mail: Fawaz.Aldabbagh@nuigalway.ie;
Further Information

Publication History

Received 16 July 2004
Publication Date:
08 September 2004 (online)

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Abstract

The preparation of a pyrrolo[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole and pyrrolo[1,2-a]benzimidazolequinone containing a fused cyclopropane ring is reported. Their synthesis involved the thermolysis of the respective benzimidazole-2-Eschenmoser hydrazones (aziridinyl imines), which facilitated an intramolecular 1,3-dipolar cycloaddition. X-ray crystal structure of one [3+2] pyrazoline-cycloadduct is presented. The redox potential of -1.052 V (vs. ferrocene) for the cyclopropapyrrolo[1,2-a]benzimidazolequinone was determined by cyclic voltammetry indicating single-electron reduction occurs more easily than mitomycin C or the cyclopropamitosenes.

Key words

benzimidazoles - bioreductive - diazo-compounds - hete­rocycles - hydrazones

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1-[(3-Butenyl)-benzimidazol-2-yl-methylidene]-2,3-diphenyl-1-aziridinamine (9b): yellow oil. IR (neat): 1603, 1449, 1458, 1334, 1008 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.06-2.15 (2 H, m, 2′-CH2), 3.76 (2 H, s, aziridine-H), 4.14-4.18 (t, 2 H, J = 7.3 Hz, N-CH2), 4.77-4.85 (m, 2 H, 4′-CH2), 5.38-5.49 (m, 1 H, 3′-CH), 7.00-7.33 (m, 13 H, ArH), 7.64-7.66 (d, 1 H, J = 7.8 Hz, ArH), 8.43 (s, 1 H, CH=N). 13C NMR (100 MHz, CDCl3): δ = 33.8 (2′-CH2), 44.4 (N-CH2 and aziridine-CH), 110.0 (ArCH), 117.1 (4′-CH2), 120.5 (ArCH), 122.6 (ArCH), 124.1 (ArCH), 128.0 (ArCH), 128.5 (ArCH), 134.2 (3′-CH), 136.2 (C), 142.9 (CH=N), 146.2 (C), 151.4 (Im-2-C). Aziridinamine 9b (0.36 g, 0.92 mmol) was refluxed in xylene (20 mL) for 2 h. The solution was evaporated to dryness, and purified by column chromatography using neutral alumina as absorbent with CH2Cl2 and EtOAc as eluent to yield 1a,2,3,9b-tetrahydrocyclopropa[3,4]pyrido[1,2-a]benzimidazole (10b) as a white solid (90 mg, 53%); mp 123-124 °C. IR (neat): 1614, 1532, 1455, 1416, 1316, 1232, 1165, 1036, 1003 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.01-1.05 (m, 1 H, 1-H), 1.15-1.21 (m, 1 H, 1-H), 1.80-1.81 (m, 1 H, 1a-H or 9b-H), 2.07-2.15 (m, 1 H, 2-H), 2.29-2.32 (m, 1 H, 2-H), 2.39-2.44 (m, 1 H, 1a-H or 9b-H), 3.50-3.58 (m, 1 H, 3-H), 4.13-4.17 (m, 1 H, 3-H), 7.16-7.22 (m, 3 H, Ar-H), 7.65-7.67 (m, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 9.6 (1-CH2), 11.4 (1a-CH or 9b-CH), 13.6 (1a-CH or 9b-CH), 20.5 (2-CH2), 37.5 (3-CH2), 108.3 (ArCH), 118.7 (ArCH), 121.6 (ArCH), 121.7 (ArCH), 134.6 (C), 143.0 (C), 153.5 (Im-9a-C). HRMS: m/z calcd for C12H12N2: 184.1001; found: 184.0998.

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The X-ray data of 3,3a,4,10b-tetrahydropyrazo-lo[3′,4′:3,4]pyrrolo[1,2-a]benzimidazole (8) has been deposited in the Cambridge Crystallographic Centre.

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1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benz-imidazole-3,6-dione (3): red-orange solid, mp 119-120 °C. IR (neat): 1653 (C=O), 1507, 1292, 1072, 1053 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.77-0.80 (m, 1 H, 1-H), 1.43-1.49 (m, 1 H, 1-H), 2.52-2.56 (m, 2 H, 1a-H and 8a-H), 4.28-4.30 (m, 2 H, 8-CH2), 6.54-6.65 (AB-q, J = 10.3 Hz, 2 H, 4-H and 5-H). 13C NMR (100 MHz, CDCl3): δ = 14.2
(1a-CH or 8a-CH), 15.8 (1-CH2), 21.1 (1a-CH or 8a-CH), 48.0 (8-CH2), 129.5 (C), 134.8 (4-CH or 5-CH), 136.9 (4-CH or 5-CH), 145.2 (C), 161.7 (Im-1b-C), 177.6 (C=O), 181.0 (C=O). HRMS: m/z calcd for C11H7N2O2: 199.0502 [M - H]+; found: 199.0503.