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Synlett 2005(4): 637-639  
DOI: 10.1055/s-2005-862390
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Synthesis of Condensed Aza-d-homo-estrone Derivatives by 1,3-Dipolar Cycloaddition

Erzsébet Mernyák, Gabriella Benedek, Gyula Schneider, János Wölfling*
Department of Organic Chemistry, University of Szeged, Dóm tér 8., 6720 Szeged, Hungary
Fax: +36(62)544200; e-Mail: wolfling@chem.u-szeged.hu;
Further Information

Publication History

Received 14 December 2004
Publication Date:
22 February 2005 (online)

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Abstract

The halogen-induced intramolecular formation of 13α- and 13β-estrone nitrones, followed by 1,3-dipolar cycloaddition reactions with N-phenylmaleimide (NPM) stereoselectively furnished halogen-containing condensed heterocyclic d-homosteroids.

Key words

Estrone - d-homosteroids - 1,3-dipolar cycloadditions - stereoselective synthesis - halogenation

7

General Procedure for the Synthesis of 16-Bromomethyl Cycloadducts (7a, 8a).
Compound 3 or 4 (100 mg, ca. 0.33 mmol) was dissolved in CH2Cl2, and DDH (50 mg, ca. 0.17 mmol) or NBS (60 mg, 0.33 mmol) was added. The mixture was then stirred at r.t. for 0.5 h and the solvent was evaporated off. The crude product was dissolved in benzene (5 mL), NPM (58 mg, ca. 0.33 mmol) was added and the solution was stirred at 50 °C for 2 h. After evaporation of the solvent, purification by column chromatography with tert-butyl-methyl ether (30%)-hexane (70%) as eluent yielded 145 mg (81%) of 7a: mp 132-137 °C; R f = 0.33 (CH2Cl2). 1H NMR (CDCl3): δ = 1.38 (s, 3 H, 18-H3), 2.87 (m, 2 H, 6-H2), 3.42 (dd, 1 H, J = 9.9 Hz, J = 8.0 Hz, 16a-H), 3.80 (dd, 1 H, J = 9.9 Hz, J = 2.2 Hz, 16a-H), 3.44 (d, 1 H, J = 8.0 Hz, 17a-H), 3.78 (s, 3 H, 3-OMe), 4.33 (t, 1 H, J = 8.0 Hz, 4′-H), 5.09 (d, 1 H, J = 8.0 Hz, 3′-H), 6.64 (d, 1 H, J = 2.4 Hz, 4-H), 6.73 (dd, 1 H, J = 8.6 Hz, J = 2.4 Hz, 2-H), 7.23-7.26 and 7.46 (overlapping multiplets, 5 H, 1-, 2′′-, 3′′-, 5′′-, 6′′-H), 7.40 (t, 1 H, J = 7.3 Hz, 4′′-H) ppm. 13C NMR (CDCl3): δ = 26.4, 27.4, 27.7, 29.8, 34.3 (C-18), 34.9, 36.4, 36.6, 38.3, 42.0, 45.0, 50.3, 55.2, 55.6, 74.6 (C-17a), 77.3 (C-3′), 111.9 (C-2), 113.4 (C-4), 126.4 and 129.2 (2 × 2 C, C-2′′, -3′′, -5′′, -6′′), 126.7 (C-1), 129.0 (C-4′′), 131.1 and 132.3 (2 ¥ l C, C-1′′ and C-10), 137.6 (C-5), 157.8 (C-3), 170.8 and 173.6 (2 ¥ l C, C-2′ and C-5′) ppm. Compound 8a was purified by chromatography with CH2Cl2 as eluent, yielding 120 mg (67%) of the pure product: mp 155-158 °C; R f = 0.25 (CH2Cl2). 1H NMR (CDCl3): δ = 1.22 (s, 3 H, 18-H3), 2.78 (m, 1 H, 4′-H), 2.88 (m, 2 H, 6-H2), 3.52 (dd, 1 H, J = 10.1 Hz, J = 7.3 Hz, 16a-H), 3.74 (m, 1 H, 16a-H), 3.54 (d, 1 H, J = 9.2 Hz, 17a-H), 3.77 (s, 3 H, 3-OMe), 5.20 (d, 1 H, J = 8.0 Hz, 3′-H), 6.64 (d, 1 H, J = 2.2 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, J = 2.2 Hz, 2-H), 7.20 (d, 1 H, J = 8.6 Hz, 1-H), 7.29 (d, 2 H, J = 7.8 Hz, 2′′-, 6′′-H), 7.41 (t, 1 H, J = 7.8 Hz, 4′′-H), 7.48 (t, 2 H, J = 7.8 Hz, 3′′-, 5′′-H). 13C NMR (CDCl3): δ = 21.3 (C-18), 25.3, 26.5, 28.2, 29.8, 35.4, 37.2, 37.4, 38.4, 41.1, 43.2, 48.5 (C-4′), 55.2 (3-OCH3), 61.2 (C-16), 77.3 (C-17a), 77.9 (C-3′), 111.7 (C-2), 113.5 (C-4), 126.2 and 128.9 (2 × 1 C, C-1 and C-4′′), 126.3 and 129.2 (2 × 2 C, C-2′′, -3′′, -5′′, -6′′), 131.1 and 131.9 (2 ¥ l C, C-1′′ and C-10), 137.5 (C-5), 157.6 (C-3), 170.9 and 173.2
(2 ¥ l C, C-2′and -5′).