Efficient Traceless Solid-Phase Synthesis of 3,4-Dihydropyrazino[1,2-<i>b</i>]indazoles and Their 6-Oxides

Pudelová, Naděžda; Krchňák, Viktor

doi:10.1021/cc800181y

Cited by 26 publications

(22 citation statements)

References 18 publications

(31 reference statements)

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“…Among the various methods for iminium ion synthesis, the condensation of secondary amides/amines with aldehydes/ketones is regarded as one of the most versatile 6,13–15. All polymer‐supported acyclic precursors were synthesized using standard solid‐phase chemistry16–21 and individual synthetic steps will be portrayed for each particular reaction sequence.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Vaňková

Brulíková

et al. 2012

Eur J Org Chem

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Trisubstituted piperazinones, piperazines, tetrahydropyrazines, and dihydropyrazinones were prepared in a one‐step procedure from easily accessible polymer‐supported acyclic precursors containing either a masked aldehyde or ketone group. Acid‐mediated unmasking of the aldehyde triggered cyclic iminium formation followed by reduction with triethylsilane present in the cleavage cocktail. The effect of the substituent at the iminium‐forming nitrogen was evaluated: whereas complete conversion to the target compounds was observed with N‐alkyl, aryl, and phenylsulfonamido derivatives, the N‐acyl compound suffered from a partial reduction of the aldehyde to an alcohol. Similarly, ketones readily provided cyclic iminiums with N‐alkyl compounds, whereas their cyclization with N‐acyl precursors proceeded unwillingly. Interestingly, cleavage of the resin‐bound acyclic precursor at 60 °C in the presence of triethylsilane resulted in the decomposition of the amide bond and formation of a lactone. An analogous synthetic route was also successfully used for the preparation of piperazines and tested as an alternative route for the synthesis of diazepanones.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Vaňková

Brulíková

et al. 2012

Eur J Org Chem

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“…Each alkylation product was individually advanced through the base-promoted cyclization reaction. A limited survey of bases and solvents revealed that Cs 2 CO 3 was the best choice, but more importantly, the reaction had to be carried out in a nonpolar solvent, either DCM or DCE, to minimize the formation of the Smiles rearrangement product 27 (see the Supporting Information for the mechanism of this reaction). − Higher-polarity solvents such as DMF or ACN gave no cyclization product, instead exclusively yielding 27 . Even in DCM, yields of piperazines 25e cis and 26e trans never exceeded 40%.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

et al. 2019

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The piperazine heterocycle is housed within a large number of FDA-approved drugs and biological probe compounds. Structurally, however, these compounds are mostly confined to substitutions on the two ring nitrogen atoms, rationalizing the expansion of piperazine chemical diversity through carbon substitutions. On the basis of the concept of systematic chemical diversity, a divergent six-step synthesis was developed in which chiral amino acids were transformed, with high diastereoselectivity, into either cis or trans 5-substituted piperazine-2-acetic acid esters that could be chromatographically rendered diastereomerically homogeneous. Starting from six commercially available amino acids or their respective amino alcohols (both antipodes), we obtained a complete set of 24 protected chiral 2,5-disubstituted piperazines, as single stereoisomers in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as starting materials for parallel library synthesis and as intermediates for the targeted production of more complex C-substituted piperazine compounds.

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“…3,4-Dihydropyrazino[1,2-b]indazoles and their 6-oxides were synthesized based on tandem carbon−carbon bond formation followed by nitrogen−nitrogen bond formation. 347 The synthesis started with the regioselective immobilization of substituted ethylenediamines onto Wang resin 2 via a carbamate linker, and resulting resin 1261 was sulfonated with 2-NsCl and acylated with α-bromoketones or bromoacetate (intermediates 1262, Scheme 227). Subsequent treatment with DBU in DMF led to the formation of 2H-indazole N-oxide 1263 via tandem carbon−carbon followed by nitrogen−nitrogen bond formation.…”

Section: Condensationmentioning

confidence: 99%

Traceless Solid-Phase Organic Synthesis

2019

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Traceless solid-phase synthesis represents an ultimate sophisticated synthetic strategy on insoluble supports. Compounds synthesized on solid supports can be released without a trace of the linker that was used to tether the intermediates during the synthesis. Thus, the target products are composed only of the components (atoms, functional groups) inherent to the target core structure. A wide variety of synthetic strategies have been developed to prepare products in a traceless manner, and this review is dedicated to all aspects of traceless solid-phase organic synthesis. Importantly, the synthesis does not need to be carried out on a linker designed for traceless synthesis; most of the synthetic approaches described herein were developed using standard, commercially available linkers (originally devised for solid-phase peptide synthesis). The type of structure prepared in a traceless fashion is not restricted. The individual synthetic approaches are divided into eight sections, each devoted to a different methodology for traceless synthesis. Each section consists of a brief outline of the synthetic strategy followed by a description of individual reported syntheses.

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Efficient Traceless Solid-Phase Synthesis of 3,4-Dihydropyrazino[1,2-b]indazoles and Their 6-Oxides

Cited by 26 publications

References 18 publications

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

Traceless Solid-Phase Organic Synthesis

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Efficient Traceless Solid-Phase Synthesis of 3,4-Dihydropyrazino[1,2-b]indazoles and Their 6-Oxides

Cited by 26 publications

References 18 publications

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyl­iminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyl­iminiums

Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

Traceless Solid-Phase Organic Synthesis

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Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums