Metal‐Free Synthesis of Highly Substituted Pyridines by Formal [2+2+2] Cycloaddition under Mild Conditions

Abstract

The synthesis of pyridines through direct intermolecular cycloaddition of alkynes and nitriles is acontemporary challenge in organic synthesis.ABrønsted acid mediated formal [2+ +2+ +2] cycloaddition of heteroalkynes and nitriles was developed that proceeds under mild conditions.T his constitutes am odular approach to highly substituted pyridine cores.

Regioselective difunctionalization of pyridines via 3,4-pyridynes

“…Pyridines are important heterocycles present in numerous biologically relevant molecules. 1 As a consequence, many synthetic methods have been developed for the functionalization of such N-heterocycles. 2 Especially, the regioselective metalation of pyridines has been broadly used.…”

NH4OAc-Promoted Domino Route to Hydroxyarylated Unsymmetrical Pyridines under Neat Conditions

“…In this context, massive efforts have been devoted by chemists since 19th century to establish many concise synthetic routes for the facile access to a diverse set of functionalized pyridine frameworks with unprecedentedly high molecular complexity. − Traditionally, several hallmark methods to prepare substituted pyridines via a condensation–cyclization reaction employing amines (or ammonia) and active carbonyl compounds/alkyl aldehydes were effectively established by Hantzsch, Chichibabin, and other groups independently. , Similarly, Bohlmann-Rahtz, Bagely, and Tsuda groups also synthesized functionalized pyridines from isolated or in situ produced enamines and enones/ynones in AcOH medium. During the past decades, many elegant and powerful approaches have been also discovered for the predominant synthesis of pyridine building blocks, which comprise [4 + 2]/[2 + 2 + 2] cycloaddition reactions of α,β-unsaturated oximes/enamides/nitriles with alkynes catalyzed by different kinds of transition-metal salts, 6π-electrocyclization, C–H functionalization on the pyridine rings, etc. Most importantly, the multicomponent reaction (MCR) has been greatly exercised as one of the most atom- and step-economical routes to functionalized pyridines. − For example, Kröhnke et al designed a three-component reaction of N -phenacylpyridinium salts and α,β-unsaturated ketones with NH 4 OAc in AcOH medium at 100–140 °C to produce 2,4,6-trisubstituted pyridines.…”

Regioselective access to di- and trisubstituted pyridines via a metal-oxidant-solvent-free domino reaction involving 3-chloropropiophenones

“…Moreover, various contemporary techniques have been extensively investigated aimed at different types of structurally complex pyridines. These methods cover several transition metal-salt-catalyzed [4 + 2] 17 /[2 + 2 + 2] 18,19 cycloaddition reactions between alkynes and nitriles/unsaturated oximes/enamides, 6π-electrocyclization, 20 C–H functionalization on the pyridine rings, 21 and multicomponent reactions. 22 Despite the magnificent advances, the above methods have a few practical snags: the use of non-commercial complex reactants, harsh reaction conditions, low tolerance of functionalities and unsatisfactory yields.…”