Modular Synthesis of Highly Substituted Pyridines via Enolate α-Alkenylation

Abstract

A novel methodology for the synthesis of highly substituted pyridines based on the palladium-catalyzed enolate α-alkenylation of ketones is presented; the formation of aromatic compounds is a new direction for this catalytic C-C bond forming reaction. In the key step, a protected β-haloalkenylaldehyde participates in α-alkenylation with a ketone to afford a 1,5-dicarbonyl surrogate, which then undergoes cyclization/double elimination to the corresponding pyridine product, all in one pot. The β-haloalkenylaldehyde starting materials can be obtained from the corresponding methylene ketone via Vilsmeier haloformylation. Using this concise route, a variety of highly substituted pyridines were synthesized in three steps from commercially available compounds.

Route to Highly Substituted Pyridines

“…With many options to choose from, the availability and cost of starting materials and reagents needed for a method are often taken into consideration. When faced with an apparent simple problem in pyridine ring construction from readily available starting materials, we were dismayed to find that neither the classic condensation routes, , a more modern hetero Diels–Alder approach, nor the recent organometallic methods were effective or applicable. − We developed an alternative route from several stalwart reactions that allowed us to construct the requisite pyridine target and report a brief exploration of the scope of the method herein.…”

“…Accessing pyridines without 6-substitution can be difficult using these methods. More recently, routes based on modern transition-metal catalysis have gained popularity, utilizing a variety of transition metals including Ti, Mn, Ni, Cu, Zr, Ru, Rh, and Pd . Although many of the recently published methods for synthesizing pyridines are high yielding, most require the use of expensive reagents and catalysts.…”

Catalytic α-Arylation of Imines Leading to N-Unprotected Indoles and Azaindoles

“…Discovered concomitantly by Hartwig, Buchwald, and Miura, 9 this process has rapidly evolved and can currently be performed on a wide range of coupling partners in a very efficient manner. 10 The well-known chemistry of carbonyl compounds makes these protocols particularly suitable for further functionalization toward complex molecules: 11 indeed, during the past decade, the application of the α-arylation (or vinylation) of carbonyl derivatives has provided a number of protocols achieving highly substituted heterocyclic moieties such as indole derivatives, 12 benzofurans, 13 isoquinolines, 14 and pyridines 15 (see Scheme 1 ).…”

Pyruvate Enolate Arylation and Alkylation: OBO Ester Protected Pyruvates as Useful Reagents in Organic Synthesis

“…Inspired by this problem, we designed an orthoester-masked pyruvate equivalent (oxabicyclo[2.2.2]­octyl orthoester, OBO) robust enough to tolerate basic conditions that could potentially allow an expansion of the scope of pyruvate chemistry via Pd-catalyzed α-arylation . Moreover, the α-arylated pyruvates that could be prepared via this transformation would have the potential to serve as important and versatile synthetic intermediates …”