# Dearomative Functionalization with Arenophiles

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $333,312

## Abstract

PROJECT SUMMARY
 Small, heteroatom-containing complex molecules are common motifs of biological relevance and are
highly desired in medicinal chemistry, but they are also often difficult to access. Selective transformations of
aromatic compounds could provide a more direct route to such desirable targets; however, the many challenges
associated with dearomative functionalization have left these types of reactions widely underdeveloped. The
proposed research strives to address this need by bridging the gap between dearomatization and alkene-type
chemistry. Fundamentally, the goal of this proposal is to access desirable structural motifs from simple aromatic
compounds by developing dearomative functionalizations using small molecules – arenophiles – that formally
enable olefin-like reactions on arene substrates. Specifically, in this proposal, we describe several dearomative
approaches on non-activated arenes based on catalytic 1,2- and 1,4-difunctionalizations as well as annulations.
These transformations will provide unique disconnections and open new horizons for the preparation of complex
small molecules. For example, we have made good progress in bottom-up chemical synthesis of 2-DOS
aminoglycoside antibiotics using enantioselective 1,2-hydroamination of simple benzene. This strategy will serve
the preparation and study of a library of aminoglycosides that are modified at the aminocyclitol core, and grant
access to other less-explored derivatives, such as 2-DOF-based antibiotics. Moreover, we propose an extension
of arenophile-based dearomatizations to heteroaromatic substrates. Compelling preliminary data demonstrate
that several well-established olefin reactions, such as dihydroxylation, reduction, and epoxidation, can now be
translated into dearomative functionalization of pyridines. Additionally, transition-metal-catalyzed processes
involving pyridine-arenophile adducts will enable a rapid synthesis of a diverse range of functionalized
heterocyclic compounds. While traditional approaches to directly functionalize (hetero)aromatic compounds
provide limited functionalization options and are hampered by overreaction or decomposition, the arenophile-
based strategy permits the selective and controlled introduction of a variety of functional complexity. Finally, this
approach provides products that are both challenging to synthesize via existing methods and are complementary
to those acquired through chemical or biological dearomative processes.
 Overall, the development of a general dearomative functionalization platform with arenophiles has the
potential to make a profound impact on the pharmaceutical, agricultural, and materials sciences by providing
expedient access to complex small molecules with tailored properties from simple and readily available arenes.

## Key facts

- **NIH application ID:** 10444505
- **Project number:** 2R01GM122891-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** David Sarlah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,312
- **Award type:** 2
- **Project period:** 2017-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444505

## Citation

> US National Institutes of Health, RePORTER application 10444505, Dearomative Functionalization with Arenophiles (2R01GM122891-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10444505. Licensed CC0.

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