C−H Cyanation of 6‐Ring N‐Containing Heteroaromatics

Abstract Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.

[1]  Joshua B. McManus,et al.  Predictive Model for Site-Selective Aryl and Heteroaryl C-H Functionalization via Organic Photoredox Catalysis. , 2017, Journal of the American Chemical Society.

[2]  P. Fier.  A Bifunctional Reagent Designed for the Mild, Nucleophilic Functionalization of Pyridines. , 2017, Journal of the American Chemical Society.

[3]  D. Dixon,et al.  Iridium-Catalyzed Reductive Strecker Reaction for Late-Stage Amide and Lactam Cyanation. , 2017, Angewandte Chemie.

[4]  Joshua B. McManus,et al.  Direct C-H Cyanation of Arenes via Organic Photoredox Catalysis. , 2017, Journal of the American Chemical Society.

[5]  A. McNally,et al.  Selective Functionalization of Pyridines via Heterocyclic Phosphonium Salts. , 2016, Journal of the American Chemical Society.

[6]  Yu Ping,et al.  Advances in C–CN Bond Formation via C–H Bond Activation , 2016 .

[7]  Yusheng Wu,et al.  Efficient synthesis of 5-substituted-3-pyridazine carbonitrile via regioselective Reissert-type reaction , 2016 .

[8]  Wei Zhang,et al.  A Robust Kilo-Scale Synthesis of Doravirine , 2016 .

[9]  Q. Peng,et al.  Unraveling innate substrate control in site-selective palladium-catalyzed C–H heterocycle functionalization , 2016, Chemical science.

[10]  Tim Cernak,et al.  The medicinal chemist's toolbox for late stage functionalization of drug-like molecules. , 2016, Chemical Society reviews.

[11]  L. Ackermann,et al.  Cobalt-catalyzed C-H cyanation of arenes and heteroarenes. , 2015, Angewandte Chemie.

[12]  Matthew D. Wodrich,et al.  General and practical formation of thiocyanates from thiols. , 2015, Chemistry.

[13]  S. Buchwald,et al.  Copper-Catalyzed RegioselectiveorthoCH Cyanation of Vinylarenes , 2014 .

[14]  J. Hartwig,et al.  Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution , 2014, Journal of the American Chemical Society.

[15]  S. Buchwald,et al.  Copper-catalyzed regioselective ortho C-H cyanation of vinylarenes. , 2014, Angewandte Chemie.

[16]  Richard D. Taylor,et al.  Rings in drugs. , 2014, Journal of medicinal chemistry.

[17]  J. Wang,et al.  Iron(II)-catalyzed direct cyanation of arenes with aryl(cyano)iodonium triflates. , 2014, Angewandte Chemie.

[18]  P. Lu,et al.  Copper-mediated cyanation reactions , 2014 .

[19]  Lei Liu,et al.  Rhodium-catalyzed directed C-H cyanation of arenes with N-cyano-N-phenyl-p-toluenesulfonamide. , 2013, Journal of the American Chemical Society.

[20]  J. Mousseau,et al.  Synthesis of pyridine and dihydropyridine derivatives by regio- and stereoselective addition to N-activated pyridines. , 2012, Chemical reviews.

[21]  M. Beller,et al.  Recent developments and perspectives in palladium-catalyzed cyanation of aryl halides: synthesis of benzonitriles. , 2011, Chemical Society reviews.

[22]  H. Neumann,et al.  A novel and convenient synthesis of benzonitriles: electrophilic cyanation of aryl and heteroaryl bromides. , 2011, Chemistry.

[23]  F. Fleming,et al.  Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore. , 2010, Journal of medicinal chemistry.

[24]  A. Fatiadi.  Preparation and synthetic applications of cyano compounds , 2010 .

[25]  D. Sen,et al.  Triselenium Dicyanide (TSD) as a New Cyanation Reagent: Synthesis of Cyano Pterins and Quinoxalines Along with Library of Cyano N-Heterocyclic Compounds , 2009 .

[26]  jin-quan yu,et al.  Cu(II)-catalyzed functionalizations of aryl C-H bonds using O2 as an oxidant. , 2006, Journal of the American Chemical Society.

[27]  E. Corey,et al.  Selective 4-arylation of pyridines by a nonmetalloorganic process. , 2005, Organic letters.

[28]  A. Katritzky,et al.  Preparation of cyanopyridines by direct cyanation , 2005 .

[29]  M. Beller,et al.  Palladium‐Catalyzed Cyanation of Aryl Halides: Recent Developments and Perspectives , 2003 .

[30]  M. Beller,et al.  Ein praktikables Verfahren zur Palladium‐katalysierten Cyanierung von Arylhalogeniden , 2003 .

[31]  M. Beller,et al.  A convenient procedure for the palladium-catalyzed cyanation of aryl halides. , 2003, Angewandte Chemie.

[32]  C. Galli.  Radical reactions of arenediazonium ions: An easy entry into the chemistry of the aryl radical , 1988 .

[33]  A. Miyashita,et al.  Studies on Pyrazolo [3, 4-d] pyrimidine Derivatives. XVI. Preparation of Reissert Compounds from Condensed Pyrimidine Systems Catalyzed by Lewis Acids , 1987 .

[34]  G. P. Ellis,et al.  Cyanation of aromatic halides , 1987 .

[35]  G. Heinisch,et al.  Pyridazines. XXXI: A facile synthesis of 3-pyridazinecarbonitriles via 2-(4-toluenesulfonyl)-2,3-dihydro-3-pyridazinecarbonitriles , 1986 .

[36]  D. Boger,et al.  Direct introduction of nitriles via use of unstable Reissert intermediates: convenient procedures for the preparation of 2-cyanoquinolines and 1-cyanoisoquinolines , 1984 .

[37]  J. Lindley.  Tetrahedron report number 163 , 1984 .

[38]  W. E. Mcewen,et al.  The Chemistry of N-Acyldihydroquinaldonitriles and N-Acyldihydroisoquinaldonitriles (Reissert Compounds) , 1955 .

[39]  H. Fischer,et al.  Preparation of 1-Acyl-1,2-dihydroquinaldonitriles and their Hydrolysis to Aldehydes* , 1941 .

[40]  Arnold Reissert.  Ueber die Einführung der Benzoyl‐gruppe in tertiäre cyclische Basen , 1905 .