An Expeditive Method for the Synthesis of Arginine-Based Chemical Libraries

Abstract

The synthesis of a stable guanidylated aldehyde and its use in an Ugi multicomponent reaction (U-4CR) was described and used for the synthesis of a library of arginine derivatives using both solution and solid phase synthesis.

Key words

arginine derivatives - solid phase synthesis - Ugi reaction

References

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16

Synthesis of Compound 1d:
A mixture of 4-aminobutanal diethylacetal (33 mmoles, 1 equiv) and 2,4-dimethoxybenzaldehyde (33 mmoles, 1 equiv) and benzene (90 mL) was heated at 105 °C for 3 h, using a Dean-Stark trap. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in anhyd MeOH (60 mL). NaBH₄ (43.8 mmoles, 1.3 equiv) was added in portion to the stirred solution at 10 °C. The reaction was warmed to r.t., stirred for a further 1 h, and quenched with sat. NH₄Cl solution. Then, the mixture was basified with sat. K₂CO₃ solution and evaporated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate and evaporated to give 10.9 g of an orange oil (compound 8). Yield: 100%.
¹H NMR (300 MHz, CDCl₃): δ = 1.17-1.21 (t, 6 H, J = 7.02 Hz), 1.54-1.65 (m, 4 H), 2.57-2.62 (t, 2 H, J = 6.85 Hz), 3.43-3.53 (m, 2 H), 3.58-3.68 (m, 2 H), 3.71 (s, 2 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 4.46-4.50 (t, 1 H, J = 5.29 Hz), 6.41-6.45 (m, 2 H), 7.11-7.13 (d, 1 H, J = 7.8 Hz).
A mixture of compound 8 (23.9 mmoles, 1 equiv) and pmc-1H-pyrazole-1-carboxamidine (26.3 mmoles, 1 equiv) in dry DMF (44 mL) was heated in a sealed tube for 48 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and a sat. NH₄Cl solution. The organic layer was washed with brine, dried with Na₂SO₄ and evaporated. The crude product was purified by chromatography on silica gel, eluting first with hexane/ethyl acetate (2/1) and then with hexane/ethyl acetate (1/1) to give 12.09 g of a colorless oil (compound 11). Yield: 82%.
¹H NMR (300 MHz, CDCl₃): δ = 1.13-1.18 (t, 6 H, J = 6.96 Hz), 1.30 (s, 6 H), 1.52-1.59 (m, 4 H), 1.77-1.82 (t, 2 H, J = 6.78 Hz), 2.09 (s, 3 H), 2.53-2.63 (m, 8 H), 3.32-3.44 (m, 4 H), 3.54-3.60 (m, 2 H), 3.77 (s, 6 H), 4.39-4.42 (m, 3 H), 6.34-6.44 (m, 4 H), 6.97-7.00 (d, 1 H, J = 8.67 Hz).
The compound 11 (19.5 mmoles, 1 equiv) was dissolved in HOAc/H₂O (2/1) (240 mL) and the mixture was stirred at r.t. overnight. The solution was cooled to 0 °C, alkalinised with sat. K₂CO₃ solution, and extracted with ethyl acetate. The organic layer was washed with sat. K₂CO₃ solution and then with brine, dried with Na₂SO₄ and evaporated under reduced pressure to give 10.6 g of a white foam (compound 1d).
¹H NMR (300 MHz, CDCl₃): δ = 1.31 (s, 6 H), 1.78-1.83 (m, 4 H), 2.10 (s, 3 H), 2.40-2.45 (t, 2 H, J = 6.54 Hz), 2.57-2.65 (m, 8 H), 3.30-3.36 (t, 2 H, J = 7.47 Hz), 3.80 (s, 6 H), 4.39 (s, 2 H), 6.36-6.57 (m, 4 H), 7.00-7.03 (d, 1 H, J = 8.4 Hz), 9.64 (s, 1 H).
¹³C NMR (200 MHz, CDCl₃): δ = 12.48, 17.86, 18.91, 20.19, 21.80, 27.14, 33.26, 41.01, 46.18, 46.98, 55.81, 73.93, 99.01, 104.87, 118.18, 124.17, 130.45, 134.48, 135.11, 135.78, 153.68, 156.02, 158.27, 161.19, 202.54.
R_f 0.62 (EtOAc)