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Synlett 2006(17): 2759-2762  
DOI: 10.1055/s-2006-950257
LETTER
© Georg Thieme Verlag Stuttgart · New York

Suzuki Couplings of New Bicyclic Boronic Esters Derived from 8-Heterobicyclo[3.2.1]octenyl Nonaflates and Application to the Synthesis of an Epibatidine-Atropine Hybrid

Jens Högermeier, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, 14165 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
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Publication History

Received 1 August 2006
Publication Date:
09 October 2006 (online)

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Abstract

Palladium-catalyzed reactions of alkenyl nonaflates 1, 2, and 3 derived from 8-oxabicyclo[3.2.1]octan-3-ones with bis(pinacolato)diboron as coupling partner led to bicyclic boronic esters 4, 5, and 6, respectively. They were further transformed in a subsequent coupling step either using iodobenzene or a second equivalent of the corresponding bicyclic alkenyl nonaflate. Products 7 and 10 were obtained in reasonable to fair yields. Applying this method to N-carbethoxytropinone derived nonaflate 11 provided an epibatidine-atropine hybrid 13 in only three steps with 65% overall yield.

Key words

alkenyl nonaflates - boronic esters - heterocycles - palladium catalysis - alkaloids

9

Preparation of Boronic Ester 4; Typical Procedure: In a heat-gun-dried and argon-flushed two-neck flask, nonaflate 1 (400 mg, 0.862 mmol), bis(pinacolato)diboron (241 mg, 0.948 mmol), KOPh (171 mg, 1.29 mmol), PPh3 (12 mg, 0.05 mmol) and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in anhyd toluene (4 mL) were stirred at 60 °C for 1 h. After cooling to r.t., the reaction mixture was dissolved in EtOAc, washed with H2O and brine, dried with MgSO4 and the solvent was removed in vacuo. The crude mixture was purified by column chromatography on silica gel with hexane-EtOAc (90:10). For complete removal of phenol the product was further purified by HPLC [Nucleosil 50-5, hexane-EtOAc (88:12), 2 mL/min] to afford 4 (179 mg, 68%) as a colorless solid (mp 48-51 °C). Analytical data for 4-methoxy-1,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-diene (4): 1H NMR (500 MHz, CDCl3): δ = 1.24, 1.25 [2 × s, 12 H, 2 × C(CH3)2], 1.36 (s, 3 H, 5-CH3), 1.58 (s, 3 H, 1-CH3), 3.55 (s, 3 H, OCH3), 3.78 (d, J = 1.5 Hz, 1 H, 4-H), 5.78, 6.35 (2 × d, J = 5.8 Hz, 2 H, 6-H, 7-H), 6.88 (d, J = 1.5 Hz, 1 H, 2-H). ¹³ C NMR (126 MHz, CDCl3): δ = 21.1 (q, 5-CH3), 23.0 (q, 1-CH3), 24.5, 24.9 [2 × q, C(CH3)2], 60.4 (q, OCH3), 78.8 (d, C-4), 83.2, 86.9 (2 × s, C-1, C-5), 83.3 [s, C(CH3)2], 133.6 (d, C-6), 142.4 (d, C-7), 151.1 (d, C-2). The signal for C-3 could not be detected due to C-B coupling. IR (KBr): 3070-3050 (=CH), 2980-2820 (CH), 1620 (C=C), 1450, 1410, 1380-1370, 1340-1310, 1240, 1190 1150, 1100 cm-1. MS (EI, 80 eV, 50 °C): m/z (%) = 292 (12) [M+], 249 (19) [M+ - CH3CO], 203 (23), 177 (15), 161 (14), 149 (22), 133 (74), 119 (56), 118 (29), 117 (29), 109 (15), 105 (21), 101 (12), 91 (34), 83 (56), 77 (11), 69 (23), 59 (22), 43 (100) [CH3CO+]. HRMS: m/z calcd for C16H25BO4: 292.18460; found: 292.18533. Anal Calcd for C16H25BO4 (292.2): C, 65.77; H, 8.62. Found: C, 65.18; H, 8.53.

11

Typical One-Pot Procedure for Synthesis of 7: In a heat-gun-dried and argon-flushed two-neck flask equipped with a reflux condenser and a septum, nonaflate 1 5 (300 mg, 0.646 mmol), bis(pinacolato)diboron (164 mg, 0.646 mmol), KOPh (117 mg, 0.881 mmol), PPh3 (9 mg, 0.04 mmol) and PdCl2(PPh3)2 (13 mg, 0.02 mmol) in anhyd toluene (4 mL) were stirred at 60 °C for 1 h. After cooling to r.t., iodobenzene (120 mg, 0.587 mmol), K3PO4 (374 mg, 1.76 mmol), dppf (10 mg, 0.02 mmol) and anhyd DMF (4 mL) were added. The mixture was heated for 18 h at 80 °C. After cooling to r.t., the reaction mixture was dissolved in EtOAc, washed with H2O and brine, dried with MgSO4 and the solvent was removed in vacuo. The crude mixture was purified by column chromatography on silica gel with hexane-EtOAc (95:5) to afford 7 (45 mg, 32%) as a colorless solid (mp 86-88 °C). Analytical data for 4-methoxy-3-phenyl-1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-diene (7): 1H NMR (500 MHz, CDCl3): δ = 1.44, 1.67 (2 × s, 6 H, 1-CH3, 5-CH3), 3.23 (s, 3 H, OCH3), 4.25 (d, J = 1.2 Hz, 1 H, 4-H), 5.85, 6.43 (2 × d, J = 5.7 Hz, 2 H, 6-H, 7-H), 6.30 (d, J = 1.2 Hz, 1 H, 2-H), 7.23-7.26 (m, 1 H, Ph), 7.28-7.35 (m, 4 H, Ph). ¹³ C NMR (126 MHz, CDCl3): δ = 21.8, 23.4 (2 × q, 1-CH3, 5-CH3), 59.8 (q, OCH3), 79.7 (d, C-4), 83.0, 86.7 (2 × s, C-1, C-5), 126.9, 127.4, 128.3 (3 × d, Ph), 132.4, 142.5 (2 × d, C-6, C-7), 135.6 (d, C-2), 138.2, 139.5 (2 × s, Ph, C-3). IR (KBr): 3080-3030 (=CH), 2930-2830 (CH), 1600 (C=C), 1500, 1450, 1370, 1340, 1190, 1100
cm-1. Anal. Calcd for C16H18O2 (242.3): C, 79.31; H, 7.49. Found: C, 79.15; H, 7.59.