Electrochemical Allylic C–H Oxidation with N-Hydroxytetrachlorophthalimide (TCNHPI)

Introduction

Professor Phil Baran and coworkers have developed a new reagent, N-Hydroxytetrachlorophthalimide (ALD00564), which provides a cheap, scalable, and safe synthetic alternative to highly used transformations like allylic oxidations, as well as Negishi and Suzuki–Miyaura type cross-coupling reactions. In these cases, this reagent obviates the requirement for toxic reagents or precious metals, thereby lending itself to application on scale and in industrial applications.²

Advantages

• Redox-active reagent, since it readily accepts electron during various oxidative transformations^1,3
• Due to the presence of electron-withdrawing groups (-Cl), it is superior to N-hydroxyphthalimide for use as a mediator in the synthesis of natural products²
• Replaces toxic reagents or expensive catalysts in several highly-used synthetic reactions, allowing its adoption on industrial scale

Representative Applications

1. TCNHPI (ALD00564) has been used in the synthesis of various redox-active esters via reaction with an alkyl acid.^1,4  Listed below are some of the TCNHPI-derived, redox-active esters synthesized using TCNHPI in dichloromethane at room temperature.

TCNHPI-derived esters readily undergo cross-coupling with aryl zinc reagents¹ and are ideal coupling partners for Suzuki coupling reactions.⁴

2. TCNHPI can also be employed as a mediator in allylic C–H oxidation reactions useful for natural product synthesis, for which Baran and coworkers provide 40 examples, including steroid- and triterpene-derived compounds.²

3. TCNHPI plays the role of a catalyst in various electrochemical allylic oxidation reactions. Due to its high oxidation potential (0.87 V versus Ag/AgCl), it effectively generates a higher-energy and more reactive tetrachlorophthalimido N-oxyl radical species during the oxidation reaction.²

The proposed step-wise mechanism of the electrochemical allylic oxidation of an olefin by TCNHPI is described below:²
a)  TCNHPI undergoes deprotonation with pyridine to afford tetrachlorophthalimido N-oxyl anion.
b)  Anion undergoes anodic oxidation to afford tetrachlorophthalimido N-oxyl radical species.
c)  Olefin compound (I) undergoes hydrogen abstraction, thus regenerating TCNHPI back and a stable allylic radical (II).
d)  Allylic radical (II) reacts with electrochemically generated t-BuOO (from t-BuOOH) to afford allylic peroxide (III).
e)  Removal of t-BuOH from (III) affords enone (IV).

Conclusions

In sum, ALD00564 is a cheap, scalable stoichiometric reagent that enables important transformations such as allylic oxidation as well as the Ni-catalyzed cross-coupling of carboxylic acids to boronic acids. These last are so well represented commercially that this technology (and reagent) will force a rethink in how molecules of all sizes and complexity are designed and synthesized.

References

1. Cornella J, Edwards JT, Qin T, Kawamura S, Wang J, Pan C, Gianatassio R, Schmidt M, Eastgate MD, Baran PS. 2016. Practical Ni-Catalyzed Aryl?Alkyl Cross-Coupling of Secondary Redox-Active Esters. J. Am. Chem. Soc.. 138(7):2174-2177. https://doi.org/10.1021/jacs.6b00250

2. Horn EJ, Rosen BR, Chen Y, Tang J, Chen K, Eastgate MD, Baran PS. 2016. Scalable and sustainable electrochemical allylic C?H oxidation. Nature. 533(7601):77-81. https://doi.org/10.1038/nature17431

3. Qin T, Cornella J, Li C, Malins LR, Edwards JT, Kawamura S, Maxwell BD, Eastgate MD, Baran PS. 2016. A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science. 352(6287):801-805. https://doi.org/10.1126/science.aaf6123

4. Wang J, Qin T, Chen T, Wimmer L, Edwards JT, Cornella J, Vokits B, Shaw SA, Baran PS. 2016. Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids. Angew. Chem. Int. Ed.. 55(33):9676-9679. https://doi.org/10.1002/anie.201605463