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

Stefan Jopp; Peter Ehlers; Eva Frank; Erzsébet Mernyák; Gyula  Schneider; János Wölfling; Alexander Villinger; Peter Langer

doi:10.1055/s-0037-1611720

Synlett, Table of Contents

Synlett 2019; 30(05): 600-604
DOI: 10.1055/s-0037-1611720

letter

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

Stefan Jopp

^aUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany Email: peter.langer@uni-rostock.de

,

Peter Ehlers

^aUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany Email: peter.langer@uni-rostock.de

^bLeibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany

,

Eva Frank

^cDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary

,

Erzsébet Mernyák

^cDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary

,

Gyula Schneider

^cDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary

,

János Wölfling

^cDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary

,

Alexander Villinger

^aUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany Email: peter.langer@uni-rostock.de

,

Peter Langer *

^aUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany Email: peter.langer@uni-rostock.de

^bLeibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany

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Abstract

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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

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References

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, CH_Alkyl), 1.67–1.82 (m, 4 H, CH_Alkyl), 1.99–2.26 (m, 3 H, CH_Alkyl), 2.29–2.40 (m, 6 H, CH₃ + CH_Alkyl), 2.94–2.97 (m, 2 H, CH_Alkyl), 5.92 (dd, ³ J = 3.19 Hz, ³ J = 1.74 Hz, 1 H, C=CH), 7.00–7.06 (m, 2 H, CH_Ar), 7.15 (d, ³ J = 7.91 Hz, 2 H, CH_Ar), 7.30–7.37 (m, 3 H, CH_Ar). 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 (CH_Ar), 134.2, 136.5, 139.5, 141.2, 147.5 (C_Ar), 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, CH_Alkyl), 1.70–1.90 (m, 4 H, CH_Alkyl), 2.01–2.22 (m, 3 H, CH_Alkyl), 2.32–2.39 (m, 3 H, CH_Alkyl), 3.00–3.06 (m, 2 H, CH_Alkyl), 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, CH_Ar), 7.33–7.42 (m, 5 H, CH_Ar), 7.53–7.56 (m, 2 H, CH_Ar). 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 (CH_Ar), 115.0 (d, ² J = 21.1 Hz, CH_Ar), 124.0, 125.5 (CH_Ar), 127.0 (C=CH), 127.3, 128.0 (CH_Ar), 128.2 (d, ³ J = 7.72 Hz, CH_Ar), 133.3 (d, ⁴ J = 3.34 Hz, C_Ar), 133.7, 137.0, 138.2, 139.0 (C_Ar), 154.0 (C=CH), 158.9 (C_Ar), 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.

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