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

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

N-Hydroxytetrachlorophthalimide

Advantages

  • Redox-active reagent, since it readily accepts electron during various oxidative transformations1,3
  • 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.
derived esters readily undergo cross-coupling with aryl zinc reagents

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

Suzuki coupling reactions
  1. 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
steroid- and triterpene-derived compounds
  1. 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
 tetrachlorophthalimido N-oxyl

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).

Allylic electrochemical oxidation

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.

Materials
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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. http://dx.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. http://dx.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. http://dx.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. http://dx.doi.org/10.1002/anie.201605463