Synthesis of Two New Azabicyclophosphinic Acids as Constrained Analogues of TPMPA

Abstract

Utilization of the Polniaszek reagent Cl₂PNi-Pr₂/AlCl₃ was used on amino dienes to generate new azabicyclophosphinic acid as constrained analogues of TPMPA.

phosphorus - bicyclic compounds - cyclizations - ­medicinal chemistry - receptors

References

Most recent reviews on GABA_C and references herein:

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Typical Procedure for Cyclization/Oxidation.
To a suspension of AlCl₃ (1.3 g, 10 mmol) in CH₂Cl₂ was added dropwise, at -20 °C and under N₂, Cl₂PNi-Pr₂ (2.0 g,10 mmol) in CH₂Cl₂. Then, the mixture was stirred at r.t. for 1 h. The mixture was cooled down to -20 °C and N-benzyl diallylamine (936 mg, 5 mmol) in CH₂Cl₂ was added dropwise. The mixture was allowed to warm up to r.t., stirred at r.t. for 16 h and refluxed for 1 h. The mixture was cooled down to 0 °C and 10 mL of a solution of 0.2 M EDTA-sat. NaHCO₃ (1:1) was added carefully. The mixture was then stirred at r.t. for 5 h. Then, 100 mL of H₂O were added and the aqueous phase was extracted several times with CHCl₃. The organic phases were combined, washed with brine, dried over Na₂SO₄ and concentrated in vacuo to afford a crude yellow oil (2 g). Purification was achieved by flash chromatography over silica gel using EtOAc-MeOH (100:0 to 80:20) as eluent. After concentration of the fractions, a yellow paste (1.05 g, 63%) was obtained.

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¹H NMR (400 MHz, D₂O): δ = 3.55 (m, 2 H), 3.03 (m, 2 H), 2.85 (m, 2 H), 1.82 (m, 2 H), 1.40 (m, 2 H).

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10 Protocol for purification over DOWEX resin see: Dumond YR. Montchamp J.-L. J. Organomet. Chem.  2002,  653:  252 

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¹H NMR (400 MHz, D₂O): δ = 5.87 (d, J = 31.7 Hz, 1 H), 3.79 (d, J = 14.0 Hz, 1 H), 3.56 (d, J = 15.9 Hz, 1 H), 3.42 (dd, J = 12.8 Hz, J = 2.4 Hz, 1 H), 3.01 (m, 1 H), 2.30 (m, 1 H), 2.15 (m, 2 H), 2.00 (m, 1 H), 1.63 (m, 1 H).