Synthesis of substituted pyridines from 1,2-nucleophilic addition products of functionalized N-acyl-2,3-dihydropyridones Mustafa Guzel a , Joshua Watts c,  , Matthew McGilvary d,à , Marcus Wright e,§ , Sezgin Kiren b,⇑ a Istanbul Medipol University International School of Medicine, REMER (Regenerative and Restorative Medicine Research Center), Kavacık Campus, Kavacık/Beykoz-ISTANBUL, Turkey b Winston Salem State University, 311 W.B. Atkinson Bldg., 601 MLK, Jr., Winston Salem, NC 27110, United States c 101 N Chestnut St. APT 3, Winston Salem, NC 27101, United States d 1524 Trinity Garden Circle, Clemmons, NC 27012, United States e Chemistry Department, Wake Forest University, Salem Hall, Box 7486, Winston-Salem, NC 27109, United States article info Article history: Received 25 June 2015 Revised 12 July 2015 Accepted 15 July 2015 Available online 28 July 2015 Keywords: Substituted pyridines N-Acyl-2,3-dihydropyridones Oxidative aromatization Chloranil 1,2-Nucleophilic addition abstract We describe herein a general and efficient synthetic approach toward substituted pyridines from functionalized N-acyl-2,3-dihydropyridones in two steps; 1,2-addition with organocerium reagents and subsequent oxidative aromatization with chloranil. This strategy allows the generation of pyridines with various substitution patterns and introduces a variety of substituents including aryl, alkyl, alkynyl, alkenyl, and heteroaryl groups at the desired positions. Published by Elsevier Ltd. Over the years, many synthetic tools have been developed to access substituted pyridines, which are among the most important and versatile organic substances. 1 Due to the significance as phar- maceuticals, agrochemicals, ligands, and in organocatalysis and materials, the development of new synthetic routes to build them has always been in the focus of organic chemists. 2 Even though current approaches offer many advantages, there is still need to improve efficiency, diversity, and flexibility of construction of pyr- idine derivatives from simple, inexpensive, and readily available starting materials under mild reaction conditions. A synthetic pro- tocol that introduces a variety of groups with various substitution patterns such as di, tri, tetra, etc. has been an important and attrac- tive research theme in the area of synthetic organic and medicinal chemistry. We report here an efficient and convenient methodol- ogy to reach pyridines having diverse substituents and controllable substitution patterns from readily available substituted N-acyl-2,3- dihydropyridones (1) in two steps (Scheme 1). 3 The key step in this strategy is the oxidative aromatization of a highly substituted adduct (2), which could be obtained via a 1,2 nucleophilic addition to 1. It was envisioned that pyridine ring formation from 2 could be realized via elimination of water, nitrogen deprotection, and sub- sequent oxidative aromatization in a single step. No detailed study has been reported in the literature for this type of transformation (e.g., 2 to 3), except for a limited study done by Munoz’s group. 4 They applied a similar strategy to N-resin-bound dihydropyridones and generated 2,4-disubstituted pyridines upon reaction of 1,2 adducts with TFA in CH 2 Cl 2 . However, this condition afforded pyridines in low yields (20–30%) and substrate scope was limited. A wide variety of reagents and conditions have been extensively studied to oxidatively aromatize such molecules as a,b- unsaturated cyclic compounds, 5 Hantzsch 1,4 dihydropyridines, 6 pyrazolines, 7 etc., some of which require heat and protic acids. In the case of 2, it seemed likely that some of these conditions will http://dx.doi.org/10.1016/j.tetlet.2015.07.045 0040-4039/Published by Elsevier Ltd. ⇑ Corresponding author. Tel.: +1 336 750 2057; fax: +1 336 750 2549. E-mail addresses: jlwatts112@gmail.com (J. Watts), mamcgilv@aggies.ncat.edu (M. McGilvary), wrightmw@wfu.edu (M. Wright), kirens@wssu.edu (S. Kiren).   Tel.: +1 (336)602 9599. à Tel.: +1 336 480 6881. § Tel.: +1 (336) 758 5981. N R 2 R 1 N O R 1 Cbz R 2 -MgX or N R 1 Cbz R 2 OH Conditions R R R R 2 -Li CeCl 3 1 2 3 Scheme 1. General approach toward substituted pyridines. Tetrahedron Letters 56 (2015) 5275–5277 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet