Synthesis of Benzimidazolequinone Analogue of Cyclopropamitosene Antitumor Agents

John O’Shaughnessy; Desmond Cunningham; Paul Kavanagh; Dónal Leech; Patrick McArdle; Fawaz Aldabbagh

doi:10.1055/s-2004-831341

LETTER

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;

Abstract

All articles of this category

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

Full Text

References

1 Wolkenberg SE. Boger DL. Chem. Rev. 2002, 102: 2477

2a Jones GB. Moody CJ. J. Chem. Soc., Perkin Trans. 1 1989, 2449

2b Jones GB. Moody CJ. J. Chem. Soc., Perkin Trans. 1 1989, 2455

2c Jones GB. Moody CJ. Padwa A. Kassir JM. J. Chem. Soc., Perkin Trans. 1 1991, 1721

2d Cotterill AS. Hartopp P. Jones GB. Moody CJ. Norton CL. O’Sullivan N. Swann E. Tetrahedron 1994, 50: 7657

3a Cotterill AS. Moody CJ. Mortimer RJ. Norton CL. O’Sullivan N. Stephens MA. Stradiotto NR. Swann E. Stratford IJ. J. Med. Chem. 1994, 37: 3834

3b Moody CJ. O’Sullivan N. Stratford IJ. Stephens MA. Workman P. Bailey SM. Lewis A. Anti-Cancer Drugs 1994, 5: 367

3c Moody CJ. Norton CL. Slawin AMZ. Taylor S. Anti-Cancer Drug Design 1998, 13: 611

4 Antonini I. Claudi F. Cristalli G. Franchetti P. Grifantini M. Martelli S. J. Med. Chem. 1988, 31: 260

Representative papers:

5a Schulz WG. Islam I. Skibo EB. J. Med. Chem. 1995, 38: 109

5b Skibo EB. Islam I. Schulz WG. Zhou R. Bess L. Boruah R. Synlett 1996, 297

5c Skibo EB. Gordon S. Bess L. Boruah R. Heileman MJ. J. Med. Chem. 1997, 40: 1327

5d Craigo WA. LeSueur BW. Skibo EB. J. Med. Chem. 1999, 42: 3324

6 Felix D. Muller RK. Horn U. Joos R. Schreiber J. Eschenmoser A. Helv. Chim. Acta 1972, 55: 1276

7

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.

8

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.

9a Weinberger L. Day AR. J. Org. Chem. 1959, 24: 1451

9b Shaikh IA. Johnson F. Grollman AP. J. Med. Chem. 1986, 29: 1329

9c Nose M. Suzuki H. Synthesis 2000, 1539

10 Gawinecki R. Omialowski B. Kolehmainen E. Janota H. Heterocycl. Commun. 2003, 9: 275

11

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.