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Synlett 2019; 30(05): 600-604
DOI: 10.1055/s-0037-1611720
letter
© Georg Thieme Verlag Stuttgart · New York

Site-Selective Synthesis of 3,17-Diaryl-1,3,5,16-estratetraenes

Stefan Jopp
a   Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Ehlers
a   Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
,
Eva Frank
c   Department of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary
,
Erzsébet Mernyák
c   Department of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary
,
Gyula Schneider
c   Department of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary
,
János Wölfling
c   Department of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary
,
Alexander Villinger
a   Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Langer  *
a   Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
› Author AffiliationsFinancial support by the BMBF (Response – Zwanzig20) is gratefully acknowledged.
Further Information

Publication History

Received: 04 December 2018

Accepted: 09 January 2019

Publication Date:
07 February 2019 (online)

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Abstract

A straightforward, site-selective arylation of the bis(triflate) of estrone by Suzuki–Miyaura reactions has been developed. Monoarylation occurs selectively at the D-ring with good to excellent yield. Such products were exemplarily employed for the synthesis of estrones containing two different aryl substituents.

Key words

palladium - site selectivity - steroids - Suzuki–Miyaura reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611720.
  • Supporting Information
 

  • References and Notes

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  • 13 Onefold Suzuki–Miyaura Reaction of 1 – General Procedure Arylboronic acid (0.60 mmol), K3PO4 (0.60 mmol, 127 mg), Pd(OAc)2 (5 mol%, 2.2 mg), and cataCXium A® (10 mol%, 7.2 mg) were weighed into a pressure tube under argon. Compound 1 (0.20 mmol, 107 mg) was dissolved in toluene (4 mL) and added to the pressure tube. The reaction was stirred at 100 °C for 20 h. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate (3 × 10 mL). The crude products 3a–j were purified by column chromatography. 17-(4-Methylphenyl)-3-(trifluoromethylsulfonyloxy)-13β-estra-1,3,5(10),16-tetraene (3b) Compound 3b was synthesized according to the general procedure using 4-methylphenylboronic acid (0.60 mmol, 82 mg) and purified via column chromatography (heptane/dichloromethane, 10:1); yield 90 mg (95%); [α]D 28 –24.9 (CHCl3, β = 1.5 mg mL–1). 1H NMR (300 MHz, CDCl3): δ = 1.07 (s, 3 H, CH3), 1.48–1.59 (m, 1 H, CHAlkyl), 1.67–1.82 (m, 4 H, CHAlkyl), 1.99–2.26 (m, 3 H, CHAlkyl), 2.29–2.40 (m, 6 H, CH3 + CHAlkyl), 2.94–2.97 (m, 2 H, CHAlkyl), 5.92 (dd, 3 J = 3.19 Hz, 3 J = 1.74 Hz, 1 H, C=CH), 7.00–7.06 (m, 2 H, CHAr), 7.15 (d, 3 J = 7.91 Hz, 2 H, CHAr), 7.30–7.37 (m, 3 H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 16.6, 21.1 (CH3), 26.4, 27.3, 29.5, 31.2, 35.4 (CH2), 36.8, 44.2 (CH), 47.4 (C), 56.7 (CH), 118.1 (C=CH), 118.8 (q, 1 J = 320.8 Hz, CF3), 121.1, 126.2, 126.2, 126.9, 128.9 (CHAr), 134.2, 136.5, 139.5, 141.2, 147.5 (CAr), 154.7 (C=CH). 19F NMR (282 MHz, CDCl3): δ = –72.97. IR (ATR): ν = 2930 (w), 2850 (w), 1488 (w), 1416 (s), 1250 (m), 1201 (s), 1139 (s), 925 (s), 886 (m), 836 (m), 797 (s), 700 (w), 599 (s), 511 (w), 486 (m) cm–1. MS (EI, 70 eV): m/z (%) = 477 (16), 476 (83) [M+], 461 (58), 291 (24), 170 (34), 169 (75), 165 (23), 157 (40), 155 (33), 153 (29), 141 (39), 131 (20), 130 (28), 129 (51), 128 (44), 116 (25), 115 (89), 105 (44), 91 (47), 77 (15), 69 (100) [CF3 +]. HRMS (EI, 70 eV): m/z calcd for C26H27F3O3S [M+]: 476.16275; found: 476.16212.
  • 14 Twofold Suzuki–Miyaura Reaction – General Procedure 4-Methoxyphenylboronic acid (0.60 mmol, 91 mg), K3PO4 (0.60 mmol, 127 mg), Pd(OAc)2 (5 mol%, 2.2 mg), and SPhos (10 mol%, 8.2 mg) were weighed into a pressure tube under argon. Compound 3f (0.20 mmol, 96 mg) was dissolved in toluene (4 mL) and added to the pressure tube. The reaction was stirred at 100 °C for 20 h. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate (3 × 10 mL). The crude product 4a was purified via column chromatography (heptane/dichloromethane, 5:1); yield 64 mg (73%). [α]D 30= 28.5 (CHCl3, β = 1.1 mg mL–1); mp 181–183 °C. 1H NMR (300 MHz, CDCl3): δ = 1.08 (s, 3 H, CH3), 1.52–1.60 (m, 1 H, ­CHAlkyl), 1.70–1.90 (m, 4 H, CHAlkyl), 2.01–2.22 (m, 3 H, CHAlkyl), 2.32–2.39 (m, 3 H, CHAlkyl), 3.00–3.06 (m, 2 H, CHAlkyl), 3.87 (s, 3 H, OCH3), 5.92 (dd, 3 J = 3.15 Hz, 3 J = 1.73 Hz, 1 H, C=CH), 6.98–7.06 (m, 4 H, CHAr), 7.33–7.42 (m, 5 H, CHAr), 7.53–7.56 (m, 2 H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 16.6 (CH3), 26.6, 27.7, 29.6, 31.3, 35.5 (CH2), 37.2, 44.5 (CH), 47.6 (C), 55.3 (OCH3), 56.9 (CH), 114.1 (CHAr), 115.0 (d, 2 J = 21.1 Hz, CHAr), 124.0, 125.5 (CHAr), 127.0 (C=CH), 127.3, 128.0 (CHAr), 128.2 (d, 3 J = 7.72 Hz, CHAr), 133.3 (d, 4 J = 3.34 Hz, CAr), 133.7, 137.0, 138.2, 139.0 (CAr), 154.0 (C=CH), 158.9 (CAr), 161.9 (d, 1 J = 245.6 Hz, C–F). 19F NMR (282 MHz, CDCl3): δ = –115.92. IR (ATR): ν = 2924 (w), 2904 (w), 2850 (w), 1601 (w), 1508 (m), 1490 (m), 1279 (w), 1244 (m), 1222 (m), 1179 (m), 1038 (m), 843 (m), 807 (s), 647 (w), 556 (m), 521 (w), 504 (w) cm–1. MS (EI, 70 eV): m/z (%) = 439 (28), 438 (100) [M+], 250 (15), 249 (21), 247 (15), 173 (21), 165 (12), 133 (13), 109 (18). HRMS (EI, 70 eV): m/z calcd for C31H31FO [M+]: 438.23535; found: 438.23428.
  • 15 CCDCs 1882186 and 1882187 contain supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.