Synthesis of Highly Substituted Pyridines via [4 + 2] Cycloadditions of Vinylallenes and Sulfonyl Cyanides

Abstract

A convergent strategy for the synthesis of multisubstituted pyridines is described. Vinylallenes combine with commercially available arylsulfonyl cyanides in Diels–Alder cycloadditions to generate isopyridine cycloadducts that are converted to pyridines upon further heating or addition of a base. The 2-sulfonylpyridine products undergo nucleophilic aromatic substitution reactions with oxygen and carbon nucleophiles to provide access to a variety of highly substituted pyridines.

Rhodium(I)‐Catalyzed Three‐Component [4+2+1] Cycloaddition of Two Vinylallenes and CO

“…Many important skeletons or potentially useful compounds in drug discovery have been synthesized by these methods [5] . Especially, intermolecular or intramolecular cycloaddition reactions using vinylallenes, such as [4+1], [1a–f] [4+2], [1g–m] [4+4], [1n] [4+4+1], [1o] and [3+2]/[2+3] [1p] cycloadditions, developed, respectively by Siegel et al., Murakami et al., and Lee and co‐workers, have become powerful methods to synthesize various ring compounds (Scheme 1 a). It is interesting to note that all these ring formation reactions (except one in Scheme 1 b, see below) using vinylallenes cannot be used to synthesize seven‐membered rings.…”

5-Bromo-2-chloro-4-fluoro-3-iodopyridine as a Halogen-rich Intermediate for the Synthesis of Pentasubstituted Pyridines

“…In order to direct the lithiation of 9 to the C3 position, we reasoned that if the C2 methyl was replaced with a chlorine, as in 2,4dichloropyridine, the lithiation would occur predominantly at C3 due to the enhanced kinetic acidity at this site. However, we planned to carry out an S N Ar reaction at C4 with an amine, so the readily available 2-chloro-4-fluoropyridine (12) was selected as a more suitable substrate. Indeed, treatment of 12 with 1.1 equiv of LDA at −78 °C for 30 min followed by quenching with CBrCl 2 CBrCl 2 provided 11 in 58% yield on a 13 g scale along with 18 as a minor product (9% yield).…”

“…In addition to its presence in drug molecules, the pyridine heterocycle is also prevalent in natural products as exemplified by streptonigrin ( 3 , Figure ), a broad-spectrum anticancer agent that reached phase II clinical trials in the late 1970s. , Despite the termination of clinical trials due to toxicity, there is still significant interest in analogues of streptonigrin as potential drug candidates. , A recent total synthesis of 3 by Donohoe et al involved a nine-step de novo formation of pentasubstituted pyridine 4 using ring-closing metathesis. , However, there have been very few reports on the synthesis of pentasubstituted pyridines such as 4 with diversified functionalities suitable for further chemical manipulation even though a number of novel de novo syntheses have been developed in the past two decades. − Therefore, there is still a great need to develop new methods to prepare highly functionalized pyridines. The unique series of the 60 possible pyridines containing one each of bromine, chlorine, fluorine, iodine, and hydrogen atoms represents a potential novel class of intermediates for regio- and halo-selective transformations to a multitude of possible pentasubstituted pyridines.…”

Intermolecular Dearomative [4+2] Cycloaddition of Naphthalenes via Visible-Light Energy-Transfer-Catalysis

“…9, 10 In fact, this thermally allowed process has been a fundamental reaction type demonstrating its molecular complexity generating power for many years. [11][12][13] In this context, polycyclic aromatic hydrocarbon such as naphthalene also contains alternating double bonds. Besides, they are abundant and inexpensive feed-stock chemicals (present at about 10% in typical coal tar).…”