Issue Date: January 8, 2018 | Web Date: January 3, 2018
Sulfones expand the reach of radical cross-couplings
Cross-coupling reactions, wherein a catalyst brings together molecular partners to forge a new bond, are powerful transformations that are among the most used tools in synthesis. For decades, researchers have mined this area of chemistry, developing methods for a litany of coupling partners. Now chemists have found a novel, and valuable, pairing.
A team of researchers led by Phil Baran at Scripps Research Institute, California, has introduced alkylsulfones as coupling partners for radical cross-coupling reactions, providing access to valuable fluorinated structures that would be cumbersome to make with typical alkyl coupling partners (ChemRxiv 2017, DOI: 10.26434/chemrxiv.5715106.v1). Whereas classic cross-couplings conjoin two aryl partners, this type of cross-coupling is particularly well-suited for threading together aryl and alkyl partners.
With the help of a nickel catalyst and pyridine ligand, the reaction couples arylzinc compounds with alkylsulfone reagents—in which the oxidized sulfur atom is connected to a five-membered ring loaded with nitrogens. The researchers demonstrated the scope of the reaction by reacting compounds containing a variety of substitution patterns and by synthesizing known biologically relevant molecules to highlight the shortened synthetic routes enabled by the technique.
Notably, the sulfone reagents let researchers directly install fluorine atoms at the alkyl coupling site, whereas previously chemists would have had to run difficult deoxyfluorination reactions to make the requisite fluorinated coupling partner, says Scott Denmark of the University of Illinois, Urbana-Champaign. “The unique reactivity of the N-phenyltetrazole sulfones is surpassed only by their practicality as bench stable and odorless, crystalline compounds,” he says.
The team produced a handful of the fluorinated sulfone reagents on a large scale. In a tweet, the Baran lab offered up free samples of the compounds, giving interested chemists the opportunity to try out the method before the work is published in a peer-reviewed journal.
Dear Medicinal Chemists - We are giving away all of our sulfone reagents (“freagents”?). Email email@example.com to request free samples (https://t.co/aC1sqpbD8S) before it even finds a final home in a journal after scholarly peer-review. Happy Holidays from the Baran lab! pic.twitter.com/urwRQdF6Wy— Baran Lab (@BaranLabReads) December 19, 2017
Cathleen Crudden of Queen’s University in Ontario and Masakazu Nambo of the Institute of Transformative Bio-Molecules at Nagoya University, who collaborated with each other on a different cross-coupling reaction using phenyl sulfones, also highlight the value of the new sulfone reagents’ ability to incorporate fluorine, especially in medicinal chemistry applications. “There is no doubt that this work is going to be game-changing and illustrates that there is still much to do in the field of cross coupling,” they told C&EN.
The authors declined to speak with C&EN except to confirm the scientific accuracy of our reporting as per the embargo policies of the journal where they have submitted their manuscript.
CORRECTION: This article was updated on Jan. 18, 2018, to correctly name the N-phenyltetrazole sulfone reagents mentioned by commenter Scott Denmark.
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