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Hindered Dialkyl Ether Synthesis via Electrogenerated Carbocations

preprint
submitted on 17.05.2019 and posted on 20.05.2019 by Jinbao Xiang, Ming Shang, Yu Kawamata, Helena Lundberg, Solomon Reisberg, Miao Chen, Pavel Mykhailiuk, Gregory Beutner, Michael Collins, Alyn Davies, Matthew Del Bel, Gary Gallego, Jillian Spangler, Jeremy T. Starr, Shouliang Yang, Donna Blackmond, Phil Baran

Hindered ethers represent an underexplored area of chemical space due to the difficulty and inoperability associated with conventional reactions, despite the high-value of such structural motifs in a variety of societal applications. Demonstrated herein is an exceptionally simple solution to this problem that leverages the power of electrochemical oxidation to liberate high-energy carbocations from simple carboxylic acids. The controlled formation of these reactive intermediates takes place with low electrochemical potentials under non-acidic conditions to capture an alcohol donor thereby producing a range (>80) of ethers that would be extremely difficult to otherwise access. Simple nucleophiles can also intercept such cations, leading to hindered alcohols and even alkyl fluorides. This method has been field tested to solve the synthetic bottlenecks encountered on twelve real-world chemical scaffolds with documented societal impact, resulting in a dramatic reduction in step-count and labor required, accompanied with a higher yield (average step-count, time, and yield = 6.3, ca. 100 h, 19% vs. 1.5, 9.8 h, 43%). Finally, the use of molecular probes coupled to kinetic studies support the proposed mechanism and role of additives in the conditions employed.

Funding

NIH (GM-118176)

NSF (CCI Phase 1 grant 1740656)

Pfizer

History

Email Address of Submitting Author

pbaran@scripps.edu

Institution

Scripps Research

Country

United States

ORCID For Submitting Author

0000-0001-9193-9053

Declaration of Conflict of Interest

No conflict of interest

Version Notes

Version Notes 1

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