Publication Date:
2012-12-04
Description:
Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 degrees C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518649/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518649/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujiwara, Yuta -- Dixon, Janice A -- O'Hara, Fionn -- Funder, Erik Daa -- Dixon, Darryl D -- Rodriguez, Rodrigo A -- Baxter, Ryan D -- Herle, Bart -- Sach, Neal -- Collins, Michael R -- Ishihara, Yoshihiro -- Baran, Phil S -- GM-073949/GM/NIGMS NIH HHS/ -- R01 GM073949/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Dec 6;492(7427):95-9. doi: 10.1038/nature11680. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201691" target="_blank"〉PubMed〈/a〉
Keywords:
Air
;
Alkylation
;
Biological Products/chemistry
;
Carbon/*chemistry
;
Drug Design
;
Hydrogen/*chemistry
;
Hydrogen Bonding
;
Indicators and Reagents/chemistry
;
Methylation
;
Nitrogen/chemistry
;
Pharmaceutical Preparations/chemistry
;
Sulfinic Acids/chemistry
;
Water
;
Zinc/chemistry
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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