Single point activation of pyridines enables reductive hydroxymethylation

The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.

[1]  T. Donohoe,et al.  Rhodium catalysed C-3/5 methylation of pyridines using temporary dearomatisation† , 2020, Chemical science.

[2]  Christopher J Huck,et al.  Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization. , 2020, Chem.

[3]  T. Donohoe,et al.  Reductive Hydroxymethylation of 4‐Heteroarylpyridines , 2020, Chemistry.

[4]  Zhanwei Bu,et al.  Chalcone-Based Pyridinium Salts and Their Diastereoselective Dearomatization To Access Bibridged Benzoazepines. , 2020, Organic letters.

[5]  F. Duarte,et al.  Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes. , 2019, Angewandte Chemie.

[6]  Zhanwei Bu,et al.  Regio- and diastereoselective dearomatizations of N-alkyl activated azaarenes: the maximization of the reactive sites† , 2019, Chemical science.

[7]  T. Donohoe,et al.  Transition‐Metal‐Free Reductive Hydroxymethylation of Isoquinolines , 2019, Angewandte Chemie.

[8]  Zhentao Wang,et al.  Strategic C-C Bond-Forming Dearomatization of Pyridines and Quinolines. , 2019, Organic letters.

[9]  F. Glorius,et al.  Selective Arene Hydrogenation for Direct Access to Saturated Carbo‐ and Heterocycles , 2019, Angewandte Chemie.

[10]  T. Donohoe,et al.  The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation , 2019, Nature Chemistry.

[11]  Anthony Wood,et al.  Organic synthesis provides opportunities to transform drug discovery , 2018, Nature Chemistry.

[12]  Yuta Watanabe,et al.  Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines. , 2016, Journal of the American Chemical Society.

[13]  Dong Wang,et al.  The golden age of transfer hydrogenation. , 2015, Chemical reviews.

[14]  S. You,et al.  Hydrogenative dearomatization of pyridine and an asymmetric aza-Friedel-Crafts alkylation sequence. , 2014, Angewandte Chemie.

[15]  Jianliang Xiao,et al.  Efficient and Chemoselective Reduction of Pyridines to Tetrahydropyridines and Piperidines via Rhodium-Catalyzed Transfer Hydrogenation , 2013 .

[16]  Jianliang Xiao,et al.  The remarkable effect of a simple ion: iodide-promoted transfer hydrogenation of heteroaromatics. , 2012, Chemistry.

[17]  Yong‐Gui Zhou,et al.  Asymmetric hydrogenation of heteroarenes and arenes. , 2012, Chemical reviews.

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

[19]  A. Katritzky,et al.  Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications , 2011 .

[20]  K. Goa,et al.  Paroxetine: an update of its use in psychiatric disorders in adults. , 2002, Drugs.

[21]  A. Katritzky,et al.  Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry and Biochemistry and the Role of Heterocycles in Science, Technology, Medicine and Agriculture , 1997 .