AcSIR Researchers Report Novel Approach for Synthesis of Trifluoroethanol-Substituted Isoquinolines

AcSIR Researchers have made a groundbreaking discovery in the field of organic synthesis. The team reports a novel approach for the synthesis of trifluoroethanol-substituted isoquinolines, employing N-alkoxyphthalimide as a coupling partner.

The team’s unique photocatalytic system features an exergonic rearrangement of O-centered tri fluoroethoxy radical, allowing for a single-electron transfer approach under visible light irradiation. The researchers used intramolecular 1,2-hydroxytetraacetic acid reactivity and a reductive photoredox cycle to achieve optimal formation of the desired product. The findings, published in the Journal of Organic Chemistry, have the potential to greatly impact the synthesis of hydroxyfluoroalkylated molecules and open up new avenues for industrial applications of isoquinolines.

AcSIR Researchers report a novel approach for synthesizing trifluoroethanol-substituted isoquinolines using N-alkoxyphthalimide as a coupling partner.

The unique feature of the photocatalytic system is the exergonic rearrangement of O-centered trifluoroethoxy radical, which enables the hydroxyalkylation of methylisoquinoline-3-carboxylate under visible light irradiation. The desired product was obtained in 73% yield via a reductive photoredox cycle.

Bullet Point Summary:

• Novel photocatalytic system for synthesis of trifluoroethanol-substituted isoquinolines.
• Exergonic rearrangement of O-centered trifluoroethoxy radical enables C(1)-H hydroxyalkylation.
• Uses Ir{dF-}]PF6 photocatalyst under blue LED irradiation with trifluoroacetic acid and ACN.
• Resulting in good yields with radical species confirmed by radical-quenching experiments.

In spite of the medicinal importance of hydroxyfluoroalkylated molecules, the reports on hydroxyfluoroalkyl incorporation into different bioactive organic scaffolds is still limited. AcSIR Researchers have now reported a novel approach for the synthesis of trifluoroethanol-substituted isoquinolines by employing N-alkoxyphthalimide as a coupling partner. The unique feature of the photocatalytic system is the exergonic rearrangement of O-centered trifluoroethoxy radical, which enables the C(1)-H hydroxyalkylation of methylisoquinoline-3-carboxylate by a single-electron transfer approach under visible light irradiation.

The photocatalytic system uses Ir{dF-}]PF6 as the photocatalyst under blue LED irradiation in the presence of trifluoroacetic acid and ACN, resulting in good yields. The involvement of radical species was evidenced by radical-quenching experiments with oxyl and 3,5-di-tert-4butylhydroxytoluene under the developed reaction. The researchers also envisaged a reductive photoredox cycle in which photoexcited Ir III* catalyst would undergo a single-electron transfer event with a sacrificial amount of protonated isoquinoline and provide the reduced active Ir species.

All the isolated compounds were characterized by 1H, 13C, 19F NMR, high-resolution mass spectrometry (HRMS), FTIR, and melting points. The reactions were irradiated for 2 hours and then the LED light was turned off for the next 2 hours. The second reaction was analyzed after 4 hours, and then the light was turned on for the next 2 hours and so on.

This research is an important breakthrough in the synthesis of trifluoroethanol.

Outcomes:

• Researchers from AcSIR have developed a novel photocatalytic system for the synthesis of trifluoroethanol-substituted isoquinolines.
• The unique feature of the photocatalytic system is the exergonic rearrangement of O-centered trifluoroethoxy radical, which enables the C(1)-H hydroxyalkylation of methylisoquinoline-3-carboxylate by a single-electron transfer approach.
• The photocatalytic system uses Ir{dF-}]PF6 as the photocatalyst under blue LED irradiation in the presence of trifluoroacetic acid and ACN, resulting in good yields.

What this paper is about

• In spite of the medicinal importance of hydroxyfluoroalkylated molecules, 9a the reports on hydroxyfluoroalkyl incorporation into different bioactive organic scaffolds is still limited.
• Futhermore, a novel radical approach was disclosed by Shen’s group for the direct transfer of the di-/trifluoroethanol motif using fluoroalkylsilicon reagents via a SiC bond activation strategy.
• In particular, isoquinolines rank among the most prevalent classes of heteroarenes because of their natural abundance and industrial applications.

What you can learn

• Ir{dF-}]PF 6 photocatalyst under blue LED irradiation in the presence of trifluoroacetic acid and ACN in good yields.
• The involvement of radical species was evidenced by radical-quenching experiments with oxyl and 3,5-di-tert-4butylhydroxytoluene under the developed reaction.
• Based on fluorescence quenching studies, we envisaged a reductive photoredox cycle in which photoexcited Ir III * catalyst 20a would undergo a single-electron transfer event with a sacrificial amount of protonated isoquinoline 20b and provide the reduced active Ir species.
• Mp = 143145C Isolated from flash chromatography.
• 1 H NMR : 8.50, 5.81.
• First, the reactions were irradiated for 2 h and then the LED light was turned off for the next 2 h. The second reaction was analyzed after 4 h, and then the light was turned on for the next 2 h and so on.

Q: What is the main focus of the paper “Photoredox Minisci-Type Hydroxyfluoroalkylation of Isoquinolines with N-Trifluoroethoxyphthalimide”?

A: The main focus of the paper is to report a novel approach for the synthesis of trifluoroethanol-substituted isoquinolines by using N-alkoxyphthalimide as a coupling partner.

Q: What makes the photocatalytic system unique in the current research?

A: The unique feature of the photocatalytic system is the exergonic rearrangement of O-centered trifluoroethoxy radical, which enables the C(1)-H hydroxyalkylation of methylisoquinoline-3-carboxylate by a single-electron transfer approach under visible light irradiation.

Q: What is the yield of the optimal formation of the desired product in the current research?

A: The optimal formation of the desired product was obtained in 73% yield.

Q: What is the process for the formation of the trifluoroethanol functionalized product in the research?

A: The trifluoroethanol functionalized product was formed via a reductive photoredox cycle, where a photoexcited IrIII* catalyst undergoes a double electron transfer event with a sacrificial amount of protonated Ir(II) and provides the reduced active reductant species. Then, the intermediate deprotonation followed by rearomatization leads to the desired product formation via a 1,2-HAT process.