Synthesis of Perfluoroalkylated Pyrazoles from α-Perfluoroalkenylated Aldehydes

Abstract

Within this study, we report a simple two-step process for the synthesis of perfluoroalkylated pyrazoles from aliphatic aldehydes. In the photocatalytic first step, the aldehydes are transformed into the corresponding perfluoroalkylated enals, which then undergo nucleophilic attack by hydrazine and subsequent ring closure, providing the fluorinated 3,4-substituted pyrazole products in a 64-84% yield. Using triphenylphosphine and imidazolidinone as organocatalysts, the method is operationally simple and omits heavy metal-containing waste.

Keywords: aldehydes; heterocycles; perfluoroalkylations; photocatalysis; pyrazoles.

Scheme 1

Methods for the synthesis of perfluoroalkylated pyrazoles [23,24,25].

Scheme 2

Photocatalytic synthesis of perfluoroalkylenals.

Scheme 3

Synthesis of 3-(perfluoroalkylated)-1H-pyrazoles; [a] reaction conditions: 3 (0.5 mmol), hydrazine monohydrate (1.85 mmol), in 2 mL ethanol at 100 °C under nitrogen. Isolated yields only. [b] Reduced yield due to high volatility of the product at reduced pressure.

Scheme 4

One-pot transformation of n-octanal (2a) to pyrazole 4a. Reaction conditions: 2a (0.53 mmol), 1 (0.1 equiv), PPh₃ (0.1 equiv), 2,6-lutidine (1.5 equiv), nonafluoro-1-iodobutane (1.9 equiv), in 0.33 mL DMF at r.t., 20 h under irradiation of blue light (461 nm). Then, addition of hydrazine hydrate (3.5 equiv) in 1.5 mL ethanol and heating to 100 °C for 21 h.

Scheme 5

Proposed mechanism for the cyclization of the enal to the pyrazole.