Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to<i>N</i>-Activated Pyridines

Bull, James A.; Mousseau, James J.; Pelletier, Guillaume; Charette, André B.

doi:10.1021/cr200251d

Cited by 820 publications

(431 citation statements)

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“…This is a valuable example of the highly regioselective dearomatization of a pyridine derivative. [13] Scheme 4. Regioselective reaction of 2-methylpyridine 10.…”

Section: Scheme 2 Proposed Inhibition Mode With Tetrabutylammonium Cmentioning

confidence: 99%

Tetraalkylammonium Salts as Hydrogen‐Bonding Catalysts

et al. 2015

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Although the hydrogen-bonding ability of the α-hydrogens on tetraalkylammonium salts is often discussed in the chemistry of phase-transfer catalysts, the catalysis that utilizes the hydrogenbond donor properties of tetraalkylammonium salts remains unknown. In the present work, we demonstrated hydrogen-bonding catalysis with newly designed tetraalkylammonium salt catalysts in Mannich-type reactions. Both the structure and the hydrogenbonding ability of the new ammonium salts were investigated via Xray diffraction analysis and NMR titration studies.Tetraalkylammonium salts are recognized as representative organocatalysts, [1] and are often used as phase-transfer catalysts for the activation of anionic nucleophiles through the formation of an ion pair with an ammonium cation. [2] Although the structures of tetraalkylammonium salts are commonly expressed as 1a shown in Figure 1, the actual ionic structures are discussed differently. [3][4][5] The positive charge of ammonium salts delocalized on the α-hydrogen atoms, which are known to interact with an anionic counterion through hydrogen bonding, as shown in 1A. Reetz proved the delocalization of the positive charge in tetraalkylammonium salts by X-ray crystal analysis of tetrabutylammonium salts such as tetrabutylammonium enolate and phenoxide. [3] Furthermore, DFT calculations support the delocalized structures of ammonium salts, which include chiral ammonium salts. [4,5] The interaction between α-hydrogens on the chiral tetraalkylammonium salt catalyst and the enolate oxygen was thought to be important in the transition-state model of asymmetric phase-transfer reactions. [5] However, despite the interesting hydrogen-bonding ability of the α-hydrogens on tetraalkylammonium salts, the catalysis that could utilize such properties is, to the best of our knowledge, still unknown. Herein, we report a new dimension of tetraalkylammonium salt as a hydrogen-bonding catalyst that utilizes the characteristic properties of the α-hydrogens on the catalyst. [6] Figure 1. Structures of tetraalkylammonium salt.To realize the efficient hydrogen-bonding catalysis of a tetraalkylammonium salt, we designed a new tetraalkylammonium salt, 2, which was readily prepared via the methylation of a commercially available 2,6-piperidinecarboxylate, 3 (Scheme 1). The ammonium salt 2 possesses carboxylate groups at the α-carbon, which enhance the hydrogen-bonding ability of the α-hydrogens. Furthermore, the six-membered structure of the piperidine backbone fixes the acidic α-hydrogens to a position that is appropriate for bidentate binding to an anionic group. [7] Scheme 1. Design and synthesis of a new tetraalkylammonium salt for use as a hydrogen-bonding catalyst.To obtain structural information of newly prepared tetraalkylammonium salts 2, we performed an X-ray diffraction COMMUNICATIONanalysis of ammonium iodide 2a (Figure 2). [8] The crystal structure of 2a provided important structural information. As expected, the hydrogen-bonding interactions between the α-hydrogens and the...

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“…This is a valuable example of the highly regioselective dearomatization of a pyridine derivative. [13] Scheme 4. Regioselective reaction of 2-methylpyridine 10.…”

Section: Scheme 2 Proposed Inhibition Mode With Tetrabutylammonium Cmentioning

confidence: 99%

Tetraalkylammonium Salts as Hydrogen‐Bonding Catalysts

et al. 2015

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“…[1] However, pyridines are relatively unreactive in the absence of prior activation. [2] Direct cleavage of C-H bonds in unfunctionalized pyridines is uncommon, but has made substantial progress recently. [3] A recent exciting development has been the C-H arylation of pyridines using catalytic mixtures generated in situ from simple iron salts and an excess of Grignard reagent.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of the hydride bridge was verified by adding 1 equiv of diphenylacetonitrile to 2, which affords a bridging iminyl complex (3) from formal [1,2]-addition of the Fe-H bond to the C-N triple bond. This reaction demonstrates that the hydride generated by the C-H activation is still reactive.…”

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C−H and C−N Activation at Redox‐Active Pyridine Complexes of Iron

et al. 2016

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Pyridine activation by inexpensive iron catalysts has great utility, but the steps through which iron species can break the strong (105-111 kcal/mol) C-H bonds of pyridine substrates are unknown. In this work, we report the rapid room-temperature cleavage of C-H bonds in pyridine, 4-tertbutylpyridine, and 2-phenylpyridine by an iron(I) species, to give well-characterized iron(II) products. In addition, 4-dimethylaminopyridine (DMAP) undergoes room-temperature C-N bond cleavage, which forms a dimethylamidoiron(II) complex and a pyridyl-bridged tetrairon(II) square. These facile bond-cleaving reactions are proposed to occur through intermediates having a twoelectron reduced pyridine that bridges two iron centers. Thus, the redox non-innocence of the pyridine can play a key role in enabling high regioselectivity for difficult reactions. Graphical abstractAn iron(I) complex can activate C-H and C-N bonds in pyridines, using a mechanism that takes advantage of pyridine's redox activity. KeywordsPyridine; Iron; Redox-Active; Bond Cleavage Pyridines are widespread in pharmaceuticals, natural products, and polymers, and therefore their expedient synthesis is crucial. [1] However, pyridines are relatively unreactive in the absence of prior activation. [2] Direct cleavage of C-H bonds in unfunctionalized pyridines is uncommon, but has made substantial progress recently. [3] A recent exciting development has been the C-H arylation of pyridines using catalytic mixtures generated in situ from simple iron salts and an excess of Grignard reagent. [4] This recipe presumably generates reduced Correspondence to: Patrick L. Holland. a These authors contributed to this work equally, and should be considered co-first authors.Supporting information for this article can be found under: http://dx.doi.org/10.1002/anie.XXXX HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript iron species that are the catalysts, but little is known about reduced iron-pyridine compounds and what stoichiometric steps to expect under these conditions. In this communication, we report well-characterized iron products that result from pyridine C-H bond cleavage. We also show an unprecedented C-N bond cleavage of 4-dimethylaminopyridine (DMAP) and construct a reasonable mechanistic scaffold that is based on the ability of pyridines to accept charge from low-valent iron.Pyridines are well-known redox-active ligands. [5] We have shown that the addition of one or more equiv of pyridine to the iron(I) complex LFe(C 6 H 6 ) (L = β-diketiminate ligand, shown in Scheme 1) yields products in which the pyridine ligands are reduced by 1-2 electrons. [6] However, we have now discovered that addition of smaller amounts of pyridine leads to formation of a surprising new compound (1). Solutions of 1 are in equilibrium with the previously characterized pyridine-bound complexes and with LFe(C 6 H 6 ), as shown by 1 H NMR spectra of C 6 D 6 solutions of 1 with various amounts of pyridine ( Figure S5). Compound 1 can be isolated by...

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“…Picoxystrobin 6 and mefloquine 6 are typical examples. We envisioned that regioselective trifluoromethylation of pyridines and quinolines would be possible through dearomatizing nucleophilic addition of the CF 3 group to electrophilically activated N-heteroaromatics, followed by re-aromatization 47 , as an alternative approach to approaches (1), (2) and (3) mentioned above.…”

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confidence: 99%