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

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.

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

References and Notes

<A NAME="RG21806ST-1A">1a</A> Webel M. Reissig H.-U. Synlett  1997,  1141 

<A NAME="RG21806ST-1B">1b</A> Lyapkalo IM. Webel M. Reissig H.-U. Eur. J. Org. Chem.  2001,  4189 

<A NAME="RG21806ST-1C">1c</A> Lyapkalo IM. Webel M. Reissig H.-U. Eur. J. Org. Chem.  2002,  1015 

<A NAME="RG21806ST-1D">1d</A> Lyapkalo IM. Webel M. Reissig H.-U. Eur. J. Org. Chem.  2002,  3646 

<A NAME="RG21806ST-1E">1e</A> Lyapkalo IM. Webel M. Reissig H.-U. Synlett  2001,  1293 

<A NAME="RG21806ST-2A">2a</A> For the synthesis of NfF and its first use in the synthesis of aryl nonaflates see: Beyl V. Niederprüm H. Voss P. Liebigs Ann. Chem.  1970,  731:  58 

<A NAME="RG21806ST-2B">2b</A> For a short review on the reagent, see: Zimmer R. Webel M. Reissig H.-U. J. Prakt. Chem.  1998,  340:  274 

<A NAME="RG21806ST-3">3</A> Review: Hoffmann HMR. Hartung IV. Angew. Chem. Int. Ed.  2004,  43:  1934 ; Angew. Chem. 2004, 116, 1968

<A NAME="RG21806ST-4">4</A> Lyapkalo IM. Högermeier J. Reissig H.-U. Tetrahedron  2004,  60:  7721 

<A NAME="RG21806ST-5">5</A> Högermeier J. Reissig H.-U. Brüdgam I. Hartl H. Adv. Synth. Catal.  2004,  346:  1868 

<A NAME="RG21806ST-6A">6a</A> Wada A. Ieki Y. Ito M. Synlett  2002,  1061 

<A NAME="RG21806ST-6B">6b</A> Wada A. Ieki Y. Nakamura S. Ito M. Synthesis  2005,  1581 

<A NAME="RG21806ST-6C">6c</A> Suffert J. Eggers A. Scheuplein SW. Brückner R. Tetrahedron Lett.  1993,  34:  4177 

<A NAME="RG21806ST-6D">6d</A> Okauchi T. Yano T. Fukamachi T. Ichikawa J. Minami T. Tetrahedron Lett.  1999,  40:  5337 

<A NAME="RG21806ST-6E">6e</A> Inoue S. Okauchi T. Minami T. Synthesis  2003,  1971 

<A NAME="RG21806ST-6F">6f</A> Okauchi T. Teshima T. Hayashi K. Suetsugu N. Minami T. J. Am. Chem. Soc.  2001,  123:  12177 

<A NAME="RG21806ST-6G">6g</A> Bellina F. Ciucci D. Rossi R. Vergatini P. Tetrahedron  1999,  55:  2103 

<A NAME="RG21806ST-6H">6h</A> Dieter RK. Oba G. Chandupatla KR. Topping CM. Lu K. Watson RT. J. Org. Chem.  2004,  69:  3076 

<A NAME="RG21806ST-6I">6i</A> Li S. Dieter RK. J. Org. Chem.  2003,  68:  969 

<A NAME="RG21806ST-6J">6j</A> Dunet G. Knochel P. Synlett  2006,  407 

For contributions of other groups to the Heck reaction of alkenyl nonaflates see:

<A NAME="RG21806ST-7A">7a</A> Voigt K. von Zezschwitz P. Rosauer K. Lansky A. Adams A. Reiser O. de Meijere A. Eur. J. Org. Chem.  1998,  1521 

<A NAME="RG21806ST-7B">7b</A> Bräse S. de Meijere A. Angew. Chem., Int. Ed. Engl.  1995,  34:  2545 ; Angew. Chem. 1995, 107, 2741

<A NAME="RG21806ST-7C">7c</A> Bräse S. Synlett  1999,  1654 

<A NAME="RG21806ST-8A">8a</A> Takagi J. Takahashi K. Ishiyama T. Miyaura N. J. Am. Chem. Soc.  2002,  124:  8001 

<A NAME="RG21806ST-8B">8b</A> Takagi J. Kamon A. Ishiyama T. Miyaura N. Synlett  2002,  1880 

<A NAME="RG21806ST-9">9</A>

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.

<A NAME="RG21806ST-10">10</A> Potassium phenolate was synthesized using the described method: Kornblum N. Lurie AP. J. Am. Chem. Soc.  1959,  81:  2705 

<A NAME="RG21806ST-11">11</A>

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.

<A NAME="RG21806ST-12">12</A> The two diastereomers were clearly separated by GC with a chiral column since the meso-compound gave only one peak, whereas the racemate clearly showed two peaks. Conditions: Chiraldex Gamma Cyclodextrin phase: G-TA (trifluoro-acetylcyclodextrine) 30 m × 0.32 mm, flow: 1.2 mL/min; program: start 40 °C in 50 ° steps to 180 °C, 10 min hold, to 200 °C in 50 ° steps, 2 min hold. Retention times 11.35 min (meso- 9), 13.35 min and 13.47 min (rac-9)

<A NAME="RG21806ST-13A">13a</A> Högermeier J. Dissertation   Freie Universität Berlin: Germany: 2006. 

<A NAME="RG21806ST-13B">13b</A> Reviews: Cox PJ. Simpkins NS. Tetrahedron: Asymmetry  1991,  2:  1 

<A NAME="RG21806ST-13C">13c</A> Koga K. J. Synth. Org. Chem. Jpn.  1990,  48:  463 

<A NAME="RG21806ST-13D">13d</A> O’Brien P. J. Chem. Soc., Perkin Trans. 1  1998,  1439 

<A NAME="RG21806ST-13E">13e</A>

For desymmetrization of a meso-ketone via nonaflate see also ref. 1e.

<A NAME="RG21806ST-14A">14a</A> Chen Z. Trudell ML. Chem. Rev.  1996,  96:  1179 

<A NAME="RG21806ST-14B">14b</A> Bäckvall J.-E. Pure Appl. Chem.  1999,  71:  1065 

<A NAME="RG21806ST-15A">15a</A> Daly JW. Garroffo HM. Spande TF. Decker MW. Sullivan JP. Williams M. Nat. Prod. Rep.  2000,  17:  131 

<A NAME="RG21806ST-15B">15b</A> Cox CD. Malpass JR. Gordon J. Rosen A. J. Chem. Soc., Perkin Trans. 1  2001,  2372 

<A NAME="RG21806ST-15C">15c</A> Hodgson DM. Maxwell CR. Wisedale R. Matthews IR. Carpenter KJ. Dickenson AH. Wonnacott S. J. Chem. Soc., Perkin Trans. 1  2001,  3150 

<A NAME="RG21806ST-16A">16a</A> Rádl S. Hezký P. Hafner W. Budesínský M. Hejnová L. Bioorg. Med. Chem. Lett.  2000,  10:  55 

<A NAME="RG21806ST-16B">16b</A> Rádl S. Hafner W. Budesínský M. Hejnová L. Krejcí I. Arch. Pharm. Pharm. Med. Chem.  2000,  333:  167 

<A NAME="RG21806ST-17">17</A> Olivio HF. Colby DA. Hemenway MS. J. Org. Chem.  1999,  64:  4966 

<A NAME="RG21806ST-18A">18a</A> The required boronic acid was synthesized according to: Bouillon A. Lancelot J.-C. Collot V. Bovy PR. Rault S. Tetrahedron  2002,  58:  2885 

<A NAME="RG21806ST-18B">18b</A> For a review on heteroaryl boronic acid synthesis, see: Tyrrell E. Brookes P. Synthesis  2004,  469