A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.

Several halo-substituted alkoxypyridines were prepared and subjected to directed metalation and metalhalogen exchange reactions. The studies resulted in useful methods for synthesis of numerous substituted pyridines via regioselective lithiation, magnesation and halogen dance reactions.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTEditorial for the Special Issue on HeterocyclesDaniel Comins and Dawei MaView Author Information Department of Chemistry, North Carolina State University Shanghai Institute of Organic ChemistryCite this: J. Org. Chem. 2016, 81, 21, 10107–10108Publication Date (Web):November 4, 2016Publication History Published online4 November 2016Published inissue 4 November 2016https://pubs.acs.org/doi/10.1021/acs.joc.6b02488https://doi.org/10.1021/acs.joc.6b02488editorialACS PublicationsCopyright © 2016 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1068Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (254 KB) Get e-AlertscloseSUBJECTS:Addition reactions,Chemical synthesis,Heterocyclic compounds,Organic compounds,Pharmaceuticals Get e-Alerts

The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.

Herein is described an original approach to access a tricyclic framework of the lepadiformine-type alkaloids. A Grignard/N-acylpyridinium salt reaction of a 4-methoxytetrahydroquinoline is the key carbon-carbon bond-forming step that was used to establish the desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features an allylation reaction with an N-acyliminium ion to set the C10 quaternary stereocenter, a mild dissolving-metal cleavage of hindered phenyl carbamates, and an aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct C10 stereochemistry, it showcases an efficient method to build analogues with the ring system of this class of alkaloids in 11 steps overall.

A racemic and asymmetric synthesis of cermizine D (1) was accomplished in six steps from 4-methoxypyridine or 4-methoxy-3-TIPS-pyridine in 12% and 13% overall yield, respectively. A key step is a stereoselective 1,4-addition of a 2-((trimethylsilyl)methyl)pyridine-derived cuprate to a bicyclic 2,3-dihydro-4-pyridone. Racemic and (−)-cermizine D failed to exhibit cytotoxicity against four different cell lines.

A dihydropyridone-mediated approach to the morphine skeleton was investigated. The hexahydroisoquinoline 2 was synthesized in nine steps using N-acylpyridinium chemistry and dihydropyridone functionalization methods. This new approach should be useful in the design of more efficient syntheses of morphine and its derivatives.

A strategy for the synthesis of the lycopodium alkaloid dihydrolycolucine (1) has been investigated. Synthetic routes were developed based on N-acylpyridinium salt chemistry to prepare target fragments 3 and 4 that could ultimately converge to the natural product. Key reactions include IMDA cycloadditions and retro-Mannich ring-openings to form both the AB and the EF ring fragments. The ring C precursor was prepared using pyridine substitution and directed lithiation chemistry. A Suzuki cross-coupling of rings C and EF led to the CEF ring fragment. Initial attempts at closure of the seven-membered D ring were unsuccessful.

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin-Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride).

Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji-Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton-McCombie reaction in the presence of a catalytic amount of diphenyl diselenide.

This chapter describes total syntheses from Professor Comins' laboratories using chiral N -acylpyridinium salt chemistry and N -acyl-2,3-dihydro-4-pyridone building blocks. These dihydropyridones are ideal synthetic intermediates due to their facile preparation from pyridine derivatives, the useful functionality present, their availability as either enantiomerically pure isomer, good air and acid stability, ease of introducing ring substituents in a regio- and stereocontrolled fashion, and their potential for use in alkaloid synthesis. Application of this chemistry towards the concise, asymmetric total syntheses of twenty four alkaloids of various types are included along with mechanistic explanations for the observed stereoselectivity of many key reactions.

The preparation and application of dihydropyridines continue to attract considerable interest in organic synthesis and medicinal chemistry. The biological activities and synthetic utility of these heterocycles have prompted the development of new routes to their construction. The Hantzsch synthesis of dihydropyridines and pyridines has been well-studied and is now a very reliable method for preparing numerous symmetrical and asymmetrical derivatives. A widely used method to prepare 1,2- and 1,4-dihydropyridines involves the addition of nucleophiles to N-activated pyridines. The regioselectivity of this reaction has been shown to be dependent upon the pyridine-activating reagent and the nucleophile. Numerous catalytic methods for the construction of dihydropyridines have been developed.This review covers recent contributions to the preparation of dihydropyridines and pyridines via acyclic and cyclic precursors, the conversion of dihydropyridine intermediates to pyridines, and the synthetic utility of dihydropyridines as synthetic intermediates in organic synthesis.

ABC and EF ring fragments of spirolucidine have been prepared via asymmetric synthesis using chiral N-acylpyridinium salt chemistry. Model studies have been carried out to support further progress toward the completion of this complex alkaloid.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Hoch stereokontrolliert verlief die Totalsynthese der Titelverbindung, in der eine Reaktion mit einem chiralen N-Acylpyridinium-Salz, eine neuartige, durch Trifluoressigsäureanhydrid vermittelte Addition eines Allylstannans an ein vinyloges Amid sowie eine allylische Tsuji-Trost-Aminierung und eine Ringschlussmetathese für den Aufbau des zentralen Gerüsts genutzt wurden. TIPS = Triisopropylsilyl. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.