Parallel Synthesis of Pyrazolines on Soluble Polymer Support

Abstract

An efficient and rapid parallel liquid-phase synthesis of pyrazolines has been developed. The one-pot three-components reaction of polyethylene glycol (PEG)-supported acrylate 1, aldehyde 2 and aryl hydrazine 3 in the presence of chloramine-T in methanol gave the corresponding PEG-supported pyrazolines 5. Cleavage from the support under mild conditions afforded pyrazolines 6 in good yields (69-91%) and high purities (91-100%).

Key words

pyrazolines - 1,3-dipolar cycloaddition - soluble polymer - liquid-phase synthesis - polyethylene glycol (PEG)

References

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8

Typical Procedure for Pyrazoline Synthesis: After combining aldehyde (1.0 mmol), hydrazine hydrochloride (1.0 mmol) and trioctylamine (TOA, 1.0 mmol) in MeOH (8 mL) at r.t. for 10 min, PEG-supported acryloyl ester (0.25 mmol) and chloramine-T (1.0 mmol) were added and the mixture was stirred for 24 h under N₂. Upon completion of the reaction, cold Et₂O (30 mL) was added to the reaction mixture to precipitate the PEG-bound pyrazoline. The precipitate was then collected on a sintered glass funnel and thoroughly washed with Et₂O (10 mL × 3). PEG-bound pyrazoline was then dried under vacuum. Finally, the resulting PEG-bound pyrazoline was cleaved by 0.1 N MeONa in MeOH (5 mL) at r.t. for 6 h. Cold Et₂O (30 mL) was added to precipitate the detached PEG-OH. The polymer was filtered and the combined filtrate was flash passed through a short column to remove trace amount of PEG and MeONa. The solvent was removed to give the corresponding crude product. All compounds listed in Table [1] give satisfactory ¹H NMR, ¹³C NMR, GC-MS and HRMS data. For compound 6p is as follows: ¹H NMR (500 MHz, CDCl₃): δ = 1.64 (s, 3 H), 3.24 (d, J = 16.7 Hz, 1 H), 3.65 (d, J = 16.7 Hz, 1 H), 3.76 (s, 3 H), 6.49 (s, 1 H), 6.60 (d, J = 3.4 Hz, 1 H), 6.90 (t, 1 H), 7.08 (d, J = 8.0 Hz, 2 H), 7.24 (m, 2 H), 7.5 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 174.3, 148.0, 143.7, 143.3, 137.9, 129.3, 120.6, 115.0, 111.9, 109.6, 68.9, 53.3, 48.1, 21.3. MS (EI): m/z = 284. HRMS calcd for C₁₆H₁₆N₂O₃ ([M + H]⁺): 285.1161. Found: 285.1170.