Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan 24;23(1):100755.
doi: 10.1016/j.isci.2019.100755. Epub 2019 Dec 4.

Visible-Light-Induced Alkoxyl Radicals Enable α-C(sp3)-H Bond Allylation

Jing Zhang  1 , Dan Liu  1 , Song Liu  2 , Yuanyuan Ge  1 , Yu Lan  3 , Yiyun Chen  4
Affiliations

Visible-Light-Induced Alkoxyl Radicals Enable α-C(sp3)-H Bond Allylation

Jing Zhang et al. iScience. .

Abstract

The alkoxyl radical is an essential reactive intermediate in mechanistic studies and organic synthesis with hydrogen atom transfer (HAT) reactivity. However, compared with intramolecular 1,5-HAT or intermolecular HAT of alkoxyl radicals, the intramolecular 1,2-HAT reactivity has been limited to theoretical studies and rarely synthetically utilized. Here we report the first selective 1,2-HAT of alkoxyl radicals for α-C(sp3)-H bond allylation of α-carbonyl, α-cyano, α-trifluoromethyl, and benzylic N-alkoxylphthalimides. The mechanistic probing experiments, electron paramagnetic resonance (EPR) studies, and density functional theory (DFT) calculations confirmed the 1,2-HAT reactivity of alkoxyl radicals, and the use of protic solvents lowered the activation energy by up to 10.4 kcal/mol to facilitate the α-C(sp3)-H allylation reaction.

Keywords: Organic Chemistry; Organic Reaction; Physical Organic Chemistry.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

None
Graphical abstract
Scheme 1
Scheme 1
Selective C(sp3)-H Functionalization via Hydrogen Atom Transfer of Alkoxyl Radicals phth, Phthalimide. (A) Alkoxyl radicals enable C(sp3)-H functionalization with intermolecular HAT, intramolecular 1,5-HAT or 1,2-HAT. (B) α-C(sp3)-H allylation via 1,2-HAT of alkoxyl radical by photoredox catalysis with Hantzsch ester.
Scheme 2
Scheme 2
1,2-HAT Reaction of N-alkoxylphthalimide 1
Scheme 3
Scheme 3
Substrate Scope of the 1,2-HAT Reactions Reaction condition is in entry 8 in Table 1, and isolated yields are reported.
Scheme 4
Scheme 4
1,2-HAT Reaction of N-alkoxylphthalimide 34
Scheme 5
Scheme 5
1,2-HAT Reaction of N-alkoxylphthalimide 38
Scheme 6
Scheme 6
1,2-HAT Reaction of N-alkoxylphthalimide 40
Scheme 7
Scheme 7
Mechanistic Investigations of the 1,2-HAT of Alkoxyl Radicals (A) The crossover experiment with N-alkoxylphthalimide 16 and alcohol 42. (B) The investigation of potential reaction pathways of alkoxyl radicals.
Scheme 8
Scheme 8
EPR Studies of the 1,2-HAT of Alkoxyl Radicals
Scheme 9
Scheme 9
DFT Calculation of the 1,2-HAT of Alkoxyl Radicals (A) The free energy profile of two reaction pathways of N-alkoxylphthalimides. (B) The free energy profile of methanol-assisted 1,2-HAT of alkoxyl radicals.
Scheme 10
Scheme 10
Mechanistic Proposals
See this image and copyright information in PMC

References

    1. Azizi S., Ulrich G., Guglielmino M., le Calve S., Hagon J.P., Harriman A., Ziessel R. Photoinduced proton transfer promoted by peripheral subunits for some Hantzsch esters. J. Phys. Chem. A. 2015;119:39–49. - PubMed
    1. Bietti M., Salamone M. Reaction pathways of alkoxyl radicals. The role of solvent effects on C–C bond fragmentation and hydrogen atom transfer reactions. Synlett. 2014;25:1803–1816.
    1. Burke S.D., Silks L.A., Strickland S.M.S. Remote functionalization and molecular modeling: observations relevant to the barton and hypoiodite reactions. Tetrahedron Lett. 1988;29:2761–2764.
    1. Buszek R.J., Sinha A., Francisco J.S. The isomerization of methoxy radical: intramolecular hydrogen atom transfer mediated through acid catalysis. J. Am. Chem. Soc. 2011;133:2013–2015. - PubMed
    1. Čeković Ž. Reactions of δ-carbon radicals generated by 1,5-hydrogen transfer to alkoxyl radicals. Tetrahedron. 2003;59:8073–8090.

LinkOut - more resources