Synlett 2010(10): 1493-1496  
DOI: 10.1055/s-0029-1219920
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Ethynyl-Substituted 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-one as a Versatile Precursor for Chiral Templates and Chiral Photocatalysts

Felix Voss, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49(89)28913315; e-Mail: thorsten.bach@ch.tum.de;
Further Information

Publication History

Received 7 March 2010
Publication Date:
06 May 2010 (online)

Abstract

The title compound was synthesized and separated into its enantiomers. The enantiomerically pure alkyne was ligated to several aryl azides and aryl halides. The resulting 7-substituted 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-ones were used either as chiral templates in the intramolecular [2+2] photocycloaddition of 4-allyloxyquinolone (up to 72% ee) or as a chiral photocatalyst for the intramolecular [2+2] photocycloaddition of 4-(3-butenyl­oxy)quinolone (up to 79% ee with 10 mol% catalyst).

    References and Notes

  • 1 Bach T. Bergmann H. Grosch B. Harms K. Herdtweck E. Synthesis  2001,  1395 
  • 2 Breitenlechner S. Selig P. Bach T. In Ernst Schering Foundation Symposium Proceedings ‘Organocatalysis’   Reetz MT. List B. Jaroch S. Weinmann H. Springer; Berlin: 2008.  p.255-280  
  • Examples:
  • 3a Bach T. Aechtner T. Neumüller B. Chem. Eur. J.  2002,  8:  2464 
  • 3b Bach T. Bergmann H. Grosch B. Harms K. J. Am. Chem. Soc.  2002,  124:  7982 
  • 3c Bach T. Grosch B. Strassner T. Herdtweck E. J. Org. Chem.  2003,  68:  1107 
  • 3d Grosch B. Orlebar CN. Herdtweck E. Kaneda M. Wada T. Inoue Y. Bach T. Chem. Eur. J.  2004,  10:  2179 
  • 3e Selig P. Herdtweck E. Bach T. Chem. Eur. J.  2009,  15:  3509 
  • Examples:
  • 4a Dressel M. Aechtner T. Bach T. Synthesis  2006,  2206 
  • 4b Dressel M. Bach T. Org. Lett.  2006,  8:  3145 
  • 4c Kapitán P. Bach T. Synthesis  2008,  1559 
  • 5 Bauer A. Westkämper F. Grimme S. Bach T. Nature (London)  2005,  436:  1139 
  • 6 Müller C. Bauer A. Bach T. Angew. Chem. Int. Ed.  2009,  48:  6640 
  • 7 Kemp DS. Petrakis KS. J. Org. Chem.  1981,  46:  5140 
  • 8 Faraoni R. Blanzat M. Kubicek S. Braun C. Schweizer WB. Gramlich V. Diederich F. Org. Biomol. Chem.  2004,  2:  1962 
  • 9 Bauer A. Bach T. Tetrahedron: Asymmetry  2004,  15:  3799 
  • Reviews:
  • 10a Sonogashira K. J. Organomet. Chem.  2002,  653:  46 
  • 10b Negishi E. Anastasia L. Chem. Rev.  2003,  103:  1979 
  • 10c Chinchilla R. Nájera C. Chem. Rev.  2007,  107:  874 
  • Reviews:
  • 11a Moses JE. Moorhouse AD. Chem. Soc. Rev.  2007,  36:  1249 
  • 11b Meldal M. Tornøe CW. Chem. Rev.  2008,  108:  2952 
  • 12 Maskill H. J. Chem. Soc., Perkin Trans. 1  1987,  1739 
  • 13 Barral K. Moorhouse AD. Moses JE. Org. Lett.  2007,  9:  1809 
  • 14 Szajnman SH. Yan W. Bailey BN. Docampo R. Elhalem E. Rodriguez JB. J. Med. Chem.  2000,  43:  1826 
  • 15 Han X. Stoltz BM. Corey EJ. J. Am. Chem. Soc.  1999,  121:  7600 
  • 17 Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  16:  4467 
  • 18a Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 
  • 18b Tornøe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 
  • 18c Giguère D. Patman R. Bellefleur MA.
    St-Pierre
    C. Sato S. Roy R. Chem. Commun.  2006,  2379 
  • 20a Kaneko C. Naito T. Somei M. J. Chem. Soc., Chem. Commun.  1979,  804 
  • 20b Kaneko C. Suzuki T. Sato M. Naito T. Chem. Pharm. Bull.  1987,  35:  112 
  • 21 Breitenlechner S. Bach T. Angew. Chem. Int. Ed.  2008,  47:  7957 
16

Representative Procedure for the Synthesis of 10c
An oven-dried Schlenk tube was charged with alkyne 5 (20.0 mg, 97.4 µmol), triflate 8c (34.0 mg, 106 µmol) Pd(PPh3)4 (11.0 mg, 9.74 µmol), CuI (1.9 mg, 9.74 µmol), and LiCl (24.7 mg, 584 µmol) and was 5 times evacuated and purged with argon. A mixture of DMF (2.3 mL) and Et3N (770 µL, 1.95 mmol) was degassed by 3 freeze-pump-thaw cycles, added to the Schlenk tube, and the resulting suspension was heated to 60 ˚C for 71 h. The reaction mixture was cooled to r.t. and diluted with EtOAc (20 mL) and H2O (15 mL). After separation of the layers the aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, pentane-EtOAc = 5:1 to 1:1) yielded compound 10c (33.7 mg, 89.7 µmol, 92%) as a colorless grease.
¹H NMR (360 MHz, CDCl3): δ = 1.02 (s, 3 H), 1.15 (d, ² J = 13.4 Hz, 1 H), 1.19 (s, 3 H), 1.22-1.27 (m, 2 H), 1.29-1.34 (m, 5 H), 1.71-1.96 (m, 8 H), 2.20 (dt, ² J = 13.4 Hz, 4 J = 2.1 Hz, 1 H), 2.52 (tt, ³ J = 10.3 Hz, ³ J = 5.5 Hz, 1 H), 2.71-2.77 (m, 4 H), 3.12 (d, ² J = 11.6 Hz, 1 H), 3.43 (ddd, ² J = 11.6 Hz, 4 J = 3.2 Hz, 4 J = 1.5 Hz, 1 H), 5.42 (s, 1 H), 6.96 (s, 2 H) ppm. ¹³C NMR (90.6 MHz, CDCl3): δ = 22.6, 25.6, 29.2, 29.9, 30.4, 30.6, 30.8, 33.8, 36.3, 38.4, 44.3, 48.5, 51.7, 52.4, 79.9, 94.1, 120.6, 128.8, 136.6, 137.7, 176.4 ppm. HRMS: m/z calcd for C26H33NO: 375.2562; found: 375.2564.

19

Representative Procedure for the Synthesis of 11c
A round-bottom flask was charged with alkyne 5 (19.6 mg, 95.5 µmol), azide 9c (45.0 mg, 188 µmol), and CuI (1.8 mg, 9.56 µmol) in THF (2.0 mL). Et3N (192 µL, 191 µmol) was added, and the flask was closed with a rubber septum and heated to 50 ˚C for 3 h. The reaction mixture was cooled to r.t. and diluted with EtOAc (15 mL) and H2O (10 mL). After separation of the layers the aqueous phase was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, EtOAc) yielded compound 11c (42.0 mg, 94.9 µmol, 99%) as a yellow solid.
¹H NMR: (360 MHz, CDCl3): δ = 1.12 (s, 3 H), 1.29 (s, 3 H), 1.33 (s, 3 H), 1.38-1.44 (m, 2 H), 1.52 (d, ² J = 14.2 Hz, 1 H), 1.80 (d, ² J = 13.5 Hz, 1 H), 2.71 (d, ² J = 14.2 Hz, 1 H), 3.02 (d, ² J = 12.2 Hz, 1 H), 3.17-3.28 (m, 2 H), 5.81 (s, 1 H), 7.10 (d, ³ J = 9.1 Hz, 1 H), 7.45 (ddd, ³ J = 8.0 Hz, ³ J = 7.1 Hz, 4 J = 1.0 Hz, 1 H), 7.55 (ddd, ³ J = 8.5 Hz, 4 J = 1.0 Hz, 4 J = 0.5 Hz, 1 H), 7.76-7.81 (m, 1 H), 8.04 (dd, ³ J = 9.1 Hz, 4 J = 2.7 Hz, 1 H), 8.30 (dd, ³ J = 8.0 Hz, 4 J = 1.3 Hz, 1 H), 8.47 (s, 1 H), 8.63 (d, 4 J = 2.7 Hz, 1 H) ppm. ¹³C NMR (90.6 MHz, CDCl3): δ = 25.7, 29.8, 30.5, 34.6, 37.1, 38.3, 45.2, 47.6, 47.8, 51.9, 116.5, 117.8, 118.5, 118.9, 121.3, 121.6, 124.4, 126.4, 126.9, 133.7, 135.3, 154.6, 154.6, 155.8, 176.2, 176.3 ppm. HRMS: m/z calcd for C26H26N4O3: 442.2005; found: 442.2002.

22

Representative Irradiation Procedure (Table 1, Entry 3)
An oven-dried Duran tube was charged with 4-allyloxy-quinolone (12, 7.6 mg, 37.9 µmol) and template 10c (35.6 mg, 94.8 µmol) in dry toluene (7.6 mL), and the solution was degassed by three freeze-pump-thaw cycles. The reaction mixture was irradiated under argon at -70 ˚C (λ = 300 nm, light source: Rayonet RPR-3000 Å) for 3 h, and the solvent was removed in vacuo. Purification of the crude product by flash chromatography (silica gel, pentane-EtOAc = 1:1 to EtOAc) yielded the recovered template 10c (25.6 mg, 68.3 µmol, 72%) and product 13 (6.9 mg, 34.3 µmol, 91%, 72% ee) as colorless solids. The analytical data of product 13 were in agreement with the values previously reported.³b,²0,²¹