Uncovering Synthetic Potential of Distonic Radical Cations

NIH RePORTER · NIH · R15 · $427,507 · view on reporter.nih.gov ↗

Abstract

Distonic radical cations, which possess a spatially separated radical moiety and a cation moiety, have great synthetic potential because they can enable difunctionalization at the two distinct sites by orthogonally adding a nucleophile to the cation moiety and intercepting the radical moiety with a radical acceptor. However, capturing the bimodal reactivity of distonic radical cations remains elusive because of the limitations in access to precursors, suitable producing conditions, and understanding of their reactivities to gain orthogonal control of the two reactive moieties. We develop the ring opening of cyclopropyl- and cyclobutyl-amines as a general reaction platform to produce distonic radical cations but encounter many challenges to utilize their bimodal reactivity. Our central hypothesis of the difficulty is that because the ring opening is reversible, how to perturb the reversibility effectively will be critical to harness the bimodal reactivity. We identify two strategies to affect the reversibility: the use of a nucleophile and resonance stabilization of the cation moiety in distonic radical cations. Two specific aims are developed based on these two strategies: 1) difunctionalization of distonic radical cations of cyclopropylanilines and cyclobutylanilines; 2) functionalization of distonic radical cations of spirocyclic N,N aminals or N, O acetals. If this bimodal reactivity can be successfully harnessed to enable the difunctionalization of distonic radical cations, such reactions could represent a new way for synthetic chemists to utilize cycloalkylamines as synthetic building blocks and could provide a guiding principle to discover more useful ways to employ these distonic radical cations accessed beyond the ring opening processes. These transformations fit into an emerging theme in organic synthesis: diversify carbon backbones via deconstructive functionalization of carbo- or hetero-cycles. Cleavage of a strong bond such as carbon-carbon bonds is often employed in this process to enable the functionalization of a remote and unactivated carbon.

Key facts

NIH application ID
10360129
Project number
1R15GM144874-01
Recipient
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
Principal Investigator
NAN ZHENG
Activity code
R15
Funding institute
NIH
Fiscal year
2021
Award amount
$427,507
Award type
1
Project period
2021-09-15 → 2025-08-31