A Tandem Amination/Lactamisation Route to 2-Azabicyclo[2.2.2]octanones

Abstract

An efficient one-pot amination/lactamisation sequence for the preparation of 2-azabicyclo[2.2.2]octanones from 6-carboalkoxycyclohex-2-enones and aqueous ammonia is described. Scope and limitation studies are reported for this tandem procedure and a range of bicyclic compounds have been prepared, two of which were characterised by X-ray crystallography.

amination - lactamisation - azabicyclo[2.2.2]octanones - bicyclic compounds - 6-carboalkoxycyclohex-2-enones

References and Notes

1 Perera P. Sandberg F. van Beek TA. Verpoorte R. Phytochemistry  1985,  24:  2097 

2 Bringmann G. Lang G. Steffens S. Schaumann K.
J. Nat. Prod.  2004,  67:  311 

3a Brooke GM. Matthews RS. Robson NS. J. Chem. Soc., Perkin Trans. 1  1980,  102 

3b McClure CK. Link JS. J. Org. Chem.  2003,  68:  8256 

4a Quirante J. Diaba F. Vila X. Bonjoch J. Magn. Reson. Chem.  2005,  43:  599 

4b Gong L. Hogg JH. Collier J. Wilhelm RS. Soderberg C. Bioorg. Med. Chem. Lett.  2003,  13:  3597 

5 Cuthbertson JD. Godfrey AA. Taylor RJK. Tetrahedron Lett.  2010, in press (http://dx.doi.org/10.1016/j.tetlet.2010.08.052)

6 Hamada Y. Hara O. Kawai A. Kohno Y. Shioiri T. Tetrahedron  1991,  47:  8635 

7

All novel compounds were fully characterised by ^¹H NMR, ^¹³C NMR, IR spectroscopies and by HRMS.

8 Pietrusiewicz KM. Monkiewicz J. J. Org. Chem.  1983,  48:  788 

9

Typical Procedure for the Synthesis of 8β-Methyl-2-azabicyclo[2.2.2]octane-3,5-dione (5a): A solution of β-keto ester 3a (46 mg, 0.25 mmol) in 35% aq NH₃ (1 mL) was stirred at r.t. until consumption of starting material was observed by TLC analysis (CH₂Cl₂-MeOH, 9:1), ca. 2 h. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO₂, CH₂Cl₂-MeOH, 98:2) to give the title compound 5a as a colourless crystalline sold (36 mg, 93%); mp 135-137 ˚C; R _f 0.40 (CH₂Cl₂-MeOH, 9:1). IR (thin film): 3244, 2961, 1730, 1681, 1335, 1105 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.92 (br s, 1 H, NH), 3.93-3.98 (m, 1 H), 3.03-3.11 (m, 1 H), 2.40-2.49 (m, 2 H), 2.28-2.37 (m, 1 H), 2.20 (dd, J = 18.5, 1.9 Hz, 1 H), 1.31 (ddd, J = 13.0, 4.6, 1.0 Hz, 1 H), 1.06 (d, J = 7.1 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 205.1 (CO), 171.8 (CO), 64.4 (CH), 47.0 (CH), 43.8 (CH₂), 35.4 (CH₂), 29.4 (CH), 20.8 (Me). MS: m/z (ESI) = 154 [MH]⁺. HRMS (ESI): m/z [M + H⁺] calcd for C₈H₁₂NO₂: 154.0863; found: 154.0864 (0.6 ppm error).