Synthesis of New Bridgehead Substituted Azabicyclo-[2.2.1]heptane and -[3.3.1]nonane Derivatives as Potent and Selective α7 Nicotinic Ligands

Slowinski, Franck; Ayad, Omar Ben; Vache, Julien; Saady, Mourad; Leclerc, Odile; Lochead, Alistair W.

doi:10.1021/ol102170q

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…Controlling selectivity in these reactions has synthetic value in terms of additional transformations of the olefin-substituted heterocycles . In addition, the azabicyclo[2.2.1]heptane product contains motifs found in natural products and biologically active substances, and the exo and endo selectivity is also important for their applications. − …”

Section: Introductionmentioning

confidence: 99%

β-SiH-Containing Tris(silazido) Rare-Earth Complexes as Homogeneous and Grafted Single-Site Catalyst Precursors for Hydroamination

et al. 2017

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A series of homoleptic rare-earth silazido compounds and their silica-grafted derivatives were prepared to compare spectroscopic and catalytic features under homogeneous and interfacial conditions. Trivalent tris-(silazido) compounds Ln{N(SiHMe 2 )tBu} 3 (Ln = Sc (1), Y (2), Lu (3)) are prepared in high yield by salt metathesis reactions. Solution-phase and solid-state characterization of 1− 3 by NMR and IR spectroscopy and X-ray diffraction reveals Ln↼H−Si interactions. These features are retained in solventcoordinated 2·Et 2 O, 2·THF, and 3·THF. The change in spectroscopic features characterizing the secondary interactions (ν SiH , 1 J SiH ) from the unactivated SiH in the silazane HN(SiHMe 2 )tBu follows the trend 3 > 2 > 1 ≈ 2·Et 2 O > 2·THF ≈ 3· THF. Ligand lability follows the same pattern, with Et 2 O readily dissociating from 2·Et 2 O while THF is displaced only during surface grafting reactions. 1 and 2·THF graft onto mesoporous silica nanoparticles (MSN) to give Ln{N(SiHMe 2 )tBu} n @MSN (Ln = Sc (1@MSN), Y (2@MSN)) along with THF and protonated silazido as HN(SiHMe 2 )tBu and H 2 NtBu. The surface species are characterized by multinuclear and multidimensional solid-state (SS) NMR spectroscopic techniques, as well as diffuse reflectance FTIR, elemental analysis, and reaction stoichiometry. A key 1 J SiH SSNMR measurement reveals that the grafted sites most closely resemble Ln·THF adducts, suggesting that siloxane coordination occurs in grafted compounds. These species catalyze the hydroamination/bicyclization of aminodialkenes, and both solution-phase and interfacial conditions provide the bicyclized product with equivalent cis:trans ratios. Similar diastereoselectivities mediated by catalytic sites under the two conditions suggest similar effective environments.

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Section: Introductionmentioning

confidence: 99%

β-SiH-Containing Tris(silazido) Rare-Earth Complexes as Homogeneous and Grafted Single-Site Catalyst Precursors for Hydroamination

et al. 2017

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“…Transformation of 2-methoxypyridines into Nsubstituted 3 or N-unsubstituted 4 2-pyridones or replacement of the 2-methoxy substituent by chlorine by using phosphoryl chloride 5 followed by cross-coupling reactions 6 permits the preparation of hundreds of derivatives containing a pyridine ring, including alkaloids 7 and pharmacophores. 8 Moreover, the 2-methoxy group of 2methoxypyridine can be directly replaced by an aryl moiety in a cross-coupling reaction. 9 Halogen-metal exchange in a bromo-or iodo-substituted pyridine, followed by reaction with an electrophile, is a useful method for the functionalization of the pyridine ring.…”

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confidence: 99%

Noncryogenic Synthesis of Functionalized 2-Methoxypyridines by Halogen-Magnesium Exchange Using Lithium Dibutyl(isopropyl)magnesate(1-) and Lithium Chloride

Struk¹,

Sośnicki²

2012

Synthesis

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2-Methoxypyridines functionalized in the 3-, 5-, or 6-position and 2,6-dimethoxypyridines functionalized in the 3-position were prepared from the corresponding bromo or iodo analogues by using lithium dibutyl(isopropyl)magnesate(1-) and lithium chloride under noncryogenic conditions. The procedure was optimized in terms of the choice between two magnesates and the presence or absence of lithium chloride in the reaction medium.The functionalized 2-alkoxypyridine ring is a common structural motif that is present in many organic compounds that exhibit a broad spectrum of biological activities. 1 Functionalized 2-methoxypyridines are particularly valuable examples of such derivatives because, apart from their biological activities, 2 they are also useful in synthesis. Transformation of 2-methoxypyridines into Nsubstituted 3 or N-unsubstituted 4 2-pyridones or replacement of the 2-methoxy substituent by chlorine by using phosphoryl chloride 5 followed by cross-coupling reactions 6 permits the preparation of hundreds of derivatives containing a pyridine ring, including alkaloids 7 and pharmacophores. 8 Moreover, the 2-methoxy group of 2-methoxypyridine can be directly replaced by an aryl moiety in a cross-coupling reaction. 9Halogen-metal exchange in a bromo-or iodo-substituted pyridine, followed by reaction with an electrophile, is a useful method for the functionalization of the pyridine ring. The most common synthetic approach of this type involves the use of organolithium compounds as exchange reagents; however, these reactions must be performed at low temperatures, typically between -78 and -65°C. 10 In the case of organomagnesium compounds, Grignard derivatives, particularly isopropylmagnesium chloride, 11 or its complex with lithium chloride 12 can be used. In the past decade, increasing attention has been paid to the use of magnesate complexes of the type [R 3 Mg]Li as halogenmagnesium exchange reagents; these complexes are relatively stable at temperatures between -10°C and 0°C. 13 Magnesate reagents have been used in the functionalization of substituted pyridines, 13c-k,t,x,aa among other reactions. Other promising candidates for use as stable halogen-exchange reagents include zincate 'ate' complexes. Recently, dilithium tetrabutylzincate and its complex with N,N,N¢,N¢-tetramethylethylenediamine have been used in the chemoselective zincation of bromopyridines at room temperature. 14 In our recent study on the application of magnesates in synthesis, we introduced the use of lithium allyl(dibutyl)magnesate(1-) as a powerful allylating agent, useful in nucleophilic addition reactions of 2-(thio)pyridones. 15 Recently, we also presented some preliminary results on the use of lithium tributylmagnesate(-1) as an exchange reagent for the noncryogenic 5-functionalization of 2-methoxypyridine, starting from the 5-bromo-substituted analogue. 16 Here, we report further studies on the functionalization of 5-bromo-2-methoxypyridine by halogenmagnesium exchange and the extension of this reaction to 6-bromo-and 3-iodo-su...

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“…NMR ( 1 H and 13 C) and melting point data are identical with those obtained in our previous work. 17 Using this strategy, we save three steps in the global synthesis of both scaffolds starting with the same gram-scale affordable commercial reagent, pyridin-3-ylacetonitrile (17), while we had to synthesize 3 in the first synthesis. As for compounds 22 and 27, no acidic proton was available at the bridgehead position.…”

Section: ' Results and Discussionmentioning

confidence: 57%

“…The desired key chlorinated scaffolds 1 and 2 were thus obtained in 49 and 62% yields, respectively (Scheme ). NMR ( 1 H and 13 C) and melting point data are identical with those obtained in our previous work . Using this strategy, we save three steps in the global synthesis of both scaffolds starting with the same gram-scale affordable commercial reagent, pyridin-3-ylacetonitrile ( 17 ), while we had to synthesize 3 in the first synthesis.…”

Section: Resultsmentioning

confidence: 75%

“…In a previous publication, 17 scaffolds 1 and 2 were prepared via a nine-step chemical synthetic pathway, starting from the commercially available 6-methoxynicotinic acid methyl ester 3 (Figure 4). The chlorine atom on the 6-position of the pyridinyl moiety was then used to incorporate aromatic or heteroaromatic groups by means of SuzukiÀMiyaura coupling reactions in order to generate a library of α7 nicotinic ligands.…”

Section: ' Introductionmentioning

confidence: 99%

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Synthesis of Bridgehead-Substituted Azabicyclo[2.2.1]heptane and -[3.3.1]nonane Derivatives for the Elaboration of α7 Nicotinic Ligands

Slowinski¹,

Ayad²,

Vache³

et al. 2011

J. Org. Chem.

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Azabicyclo[2.2.1]heptane and -[3.3.1]nonane scaffolds (X = Cl, Br) containing a pyridinyl substituent at the bridgehead position were prepared via two complementary chemical pathways, either by the transformation of a methoxy group into a synthetically valuable chlorine atom at the C-6 position of the pyridine moiety or by means of a regioselective C-6 deprotonation/halogenation process of the pyridine moiety exemplified by chlorination or bromination. These newly generated scaffolds were then engaged in Suzuki-Miyaura coupling reactions to provide α7 nicotinic ligands. Both chemical series were evaluated in vitro for their affinity at α7 nicotinic receptors, revealing nanomolar potency with significant selectivity over the α4β2 nicotinic subtype. These approaches offer a general access to these α7 nicotinic scaffolds and ligands.

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Synthesis of New Bridgehead Substituted Azabicyclo-[2.2.1]heptane and -[3.3.1]nonane Derivatives as Potent and Selective α7 Nicotinic Ligands

Cited by 8 publications

References 17 publications

β-SiH-Containing Tris(silazido) Rare-Earth Complexes as Homogeneous and Grafted Single-Site Catalyst Precursors for Hydroamination

β-SiH-Containing Tris(silazido) Rare-Earth Complexes as Homogeneous and Grafted Single-Site Catalyst Precursors for Hydroamination

Noncryogenic Synthesis of Functionalized 2-Methoxypyridines by Halogen-Magnesium Exchange Using Lithium Dibutyl(isopropyl)magnesate(1-) and Lithium Chloride

Synthesis of Bridgehead-Substituted Azabicyclo[2.2.1]heptane and -[3.3.1]nonane Derivatives for the Elaboration of α7 Nicotinic Ligands

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