Scalable and sustainable electrochemical allylic C–H oxidation

Abstract

New methods and strategies for the direct functionalization of C–H bonds are beginning to reshape the fabric of retrosynthetic analysis, impacting the synthesis of natural products, medicines, and even materials1. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C–H functionalization due to the utility of enones and allylic alcohols as versatile intermediates, along with their prevalence in natural and unnatural materials2. Allylic oxidations have been featured in hundreds of syntheses, including some natural product syntheses regarded as “classics”3. Despite many attempts to improve the efficiency and practicality of this powerful transformation, the vast majority of conditions still employ highly toxic reagents (based around toxic elements such as chromium, selenium, etc.) or expensive catalysts (palladium, rhodium, etc.)2. These requirements are highly problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. As such, this oxidation strategy is rarely embraced for large-scale synthetic applications, limiting the adoption of this important retrosynthetic strategy by industrial scientists. In this manuscript, we describe an electrochemical solution to this problem that exhibits broad substrate scope, operational simplicity, and high chemoselectivity. This method employs inexpensive and readily available materials, representing the first example of a scalable allylic C–H oxidation (demonstrated on 100 grams), finally opening the door for the adoption of this C–H oxidation strategy in large-scale industrial settings without significant environmental impact.

Electrifying Organic Synthesis

“…This process proceeds through oxidation in the α‐position of the double bond, using Cl 4 NHPI ( N ‐hydroxytetrachlorophthalimide) as the mediator, and subsequent peroxide formation/elimination to afford the final α,β‐unsaturated ketone 169. This work is a perfect example of the further development of a known method 170.…”

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

“…For example, Baran and co-workers reported a scalable means for allylic oxidation using tetrachloro- N -hydroxyphthalimide (TCNHPI) as the mediator (Figure 35B). 538 Under basic conditions, it was believed that the anion of the mediator molecule can be oxidized anodically, giving rise to a reactive N -oxyl radical which can homolyze allylic C–H bonds. The electron-withdrawing chloride groups confers the nitroxyl species additional reactivity—the use of nonchlorinated NHPI led to inferior results.…”

Organic Electrosynthesis: Applications in Complex Molecule Synthesis

“…The method was applied to a variety of natural product scaffolds, such as sesquiterpenes and steroids. Finally, the feasibility of the reaction was exemplified by carrying out the electrochemical oxidation on 100 g scale for both steroid‐ and terpene‐derived substrates . Compared to traditional reagent‐based oxidation protocols, electrochemical oxidation has numerous advantages which include operational simplicity, reduced toxicity, simple workup and ease of product isolation.…”