Visible-Light-Promoted Continuous-Flow Iodination of Primary C(sp³)-H Bonds: An Undirected and Regioselective...

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Catalysis

Background:

• Selective functionalization of primary C(sp3)-H bonds is challenging due to high bond energies and unstable radical intermediates.
• Existing methods often require directing groups or lack regioselectivity, especially in the presence of more reactive sites.

Purpose of the Study:

• To develop a practical and regioselective method for functionalizing primary C(sp3)-H bonds in alkanes without directing assistance.
• To achieve selective iodination of primary C(sp3)-H bonds over secondary, tertiary, and benzylic positions.

Main Methods:

• A continuous-flow protocol utilizing iodine, sodium nitrite (NaNO2), and aqueous hydrochloric acid (HCl) under visible-light irradiation in carbon tetrachloride.
• Employing inexpensive and readily available reagents for a scalable and practical approach.

Main Results:

• Successful regioselective iodination of primary C(sp3)-H bonds in a wide array of alkanes, including linear, branched, and complex molecules like drugs and natural products.
• Demonstrated selectivity for primary C-H bonds over more reactive sites, yielding primary alkyl iodides with excellent functional-group compatibility.
• Mechanistic studies revealed a reversible C-H activation followed by kinetically controlled iodination that favors primary radical trapping.

Conclusions:

• The developed continuous-flow method provides an efficient and practical route for the selective functionalization of primary C(sp3)-H bonds.
• The resulting primary alkyl iodides are versatile intermediates for late-stage functionalization, enabling access to complex molecules.
• This work overcomes significant hurdles in C-H activation chemistry, offering a valuable tool for synthetic chemists.