Visible-Light Photoredox Catalyst to Synthesize 2-Subsituted Piperazines

Photoredox catalysts can form an excited triplet state under visible light irradiation. The lifetime of the excited state is relatively long since the transition of the spin state is forbidden. This quenching process contributes to photoinduced one-electron oxidation or reduction. The piperazine moiety is one scaffold used in medicinal chemistry and some efficient synthetic pathways are well studied.¹⁾ Bousquet and Bigot et al. reported a photocatalytic approach to the construction of 2-substituted piperazines from glycine derivatives using Ir[(ppy)₂(dtbbpy)]PF₆ (1).²⁾ This process is called the CarboxyLic Amine Protocol (CLAP) and an imine intermediate is formed with N-(2-aminoethyl)-N-benzylglycine bis(trifluoroacetate) (2) and aldehydes under basic conditions. The photoinitiated decarboxylative annulation then proceeds to give 2-substituted piperazines under blue LED irradiation in the presence of 1. One of the features of this approach is that it can be applied not only to a batch process but also to a continuous flow process.

Practical Example: Synthesis of 3-arylpiperazine using visible light with 1²⁾
An oven-dried Schlenck tube was charged with 2 (88 mg, 0.20 mmol), and the system was degassed through N₂ purging (3 x 5 min). 1 mol/L KOH solution in methanol (0.82 mL, 0.82 mmol) and 4-fluorobenzaldehyde (35 mg, 0.28 mmol) were subsequently added. The reaction mixture was stirred at room temperature for 0.5 h. A solution of 1 (1.8 mg, 2.0 x 10^-3 mmol) in dry acetonitrile (3.2 mL) was added. The reaction was degassed with N2 bubbling before starting the irradiation and was stirred at room temperature under the exposure of blue LEDs for 3 h. The solution was filtered to remove the trifluoroacetate salt formed. The resulting mixture was concentrated under vacuum and purified with column chromatography (1 : 99 methanol / ethyl acetate on SiO₂) to give 1-benzyl-3-(4-fluorophenyl)piperazine as a yellow oil (43 mg, 80%).

References

• 1) Synthetic applications of photoredox catalysis with visible light
  • Y. Xi, H. Yi, A. Lei, Org. Biomol. Chem. 2013, 11, 2387.
• 2) Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the Synthesis of 2‑Substituted Piperazines under Batch and Flow Conditions
  • R. Gueret, L. Pelinski, T. Bousquet, M. Sauthier, V. Ferey, A. Bigot, Org. Lett. 2020, 22, 5157.

Related Compounds

D5817

[Ir[dF(CF₃)ppy]₂(dtbbpy)]PF₆

T1655

Ru(bpy)₃Cl₂ Hexahydrate

F0191

4-Fluorobenzaldehyde

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