Anionic Ring Closure Research Articles

Photoredox Radical/Polar Crossover Enables Construction of Saturated Nitrogen Heterocycles.

Photoredox-mediated radical/polar crossover (RPC) processes offer new avenues for the synthesis of cyclic molecules. This process has been realized for the construction of medium-sized saturated nitrogen heterocycles. Photocatalytically generated alkyl radicals possessing pendant leaving groups engage imines in C-C bond formation, and subsequent reduction of the intermediate nitrogen-centered radical triggers anionic ring closure. With the aid of visible light irradiation, substituted pyrrolidines, piperidines, and azepanes can be prepared under mild, redox-neutral conditions.

N-Arylazetidines: Preparation through Anionic Ring Closure

We report herein an efficient synthesis of diversely substituted N-aryl-2-cyanoazetidines based on an anionic ring-closure reaction. These compounds can be prepared from β-amino alcohols in enantiomerically pure form through a three-step sequence involving (i) copper-catalyzed N-arylation, (ii) N-cyanomethylation of the secondary aniline, and (iii) one-pot mesylation followed by ring closure induced by a base. This high-yielding sequence gives access to azetidines with a predictable and adjustable substitution pattern and also with predictable diastereoselectivity. These compounds are susceptible to multiple further derivatizations through Suzuki coupling or nitrile transformation, thus appearing as valuable new scaffolds for medicinal chemistry. Their rigid shape, featuring an almost planar N-arylamine and a planar four-membered ring, was revealed by both AM1 calculations and X-ray crystallography.

ChemInform Abstract: Synthesis of Pyridoacridines Through Anionic Cascade Ring Closure.

AbstractA short synthetic strategy for the construction of pentacyclic heterocycles trough anionic cascade ring closure is developed.

Synthesis of Pyridoacridines through Anionic Cascade Ring Closure

A new synthesis of 13-deazaascididemin (AK-37) based on a recently developed anionic cascade ring closure is presented. Although the isolated yields are modest, the approach provides ready access to new substituted derivatives of 13-deazaascididemin.

ChemInform Abstract: Synthesis of Substituted Diazino[c]quinolin‐5(6H)‐ones, Diazino[c]isoquinolin‐6(5H)‐ones, Diazino[c]naphthyridin‐6(5H)‐ones and Diazino[c]naphthyridin‐5(6H)‐ones

Abstractvia one‐pot cross‐coupling/cyclization or two‐step cross‐coupling/KOH‐mediated anionic ring closure reactions

Synthesis of substituted diazino[c]quinolin-5(6H)-ones, diazino[c]isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)-ones and diazino[c]naphthyridin-5(6H)-ones

Substituted diazino[c]quinolin-5(6H)-ones and -isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)- and -5(6H)-ones were obtained using two synthetic routes: one-pot cross-coupling/cyclisation and two-step cross-coupling/KOH-mediated anionic ring closure. The two strategies gave yields in the same order of magnitude and their choice depends on the availability of the starting material.

Total synthesis of ascididemin via anionic cascade ring closure

A new and convergent synthesis of ascididemin is presented. Using an anionic cascade ring closure as the key step, this natural product is obtained in 45% overall yield in just 6 steps starting from 2'-fluoroacetophenone. This new approach was extended to the synthesis of a new isomer of ascididemin.

Rules for Anionic and Radical Ring Closure of Alkynes

This work reexamined the stereoelectronic basis for the "favored attack trajectories" regarding the nucleophilic and radical cyclizations of alkynes. In contrast to the original Baldwin rules, the acute attack angle of a nucleophile leading to the proposed endo-dig preference for the formation of small cycles is less favorable stereoelectronically than the alternative obtuse trajectory leading to the formation of exo-dig products. For smaller cycles, this intrinsic stereoelectronic preference can be masked by the greater thermodynamic stability of the less strained endo-products. Unbiased comparison of competing cyclization attacks has been accomplished via dissection of the activation barrier into the intrinsic barrier and thermodynamic component via Marcus theory. Intrinsic barriers of thermoneutral reactions strongly favor exo-dig closures, in full accord with the greater magnitude of two-electron bond forming interactions for the obtuse trajectory. This analysis agrees very well with experimental observations of efficient 3-exo-dig and 4-exo-dig cyclizations predicted to be unfavorable by the Baldwin rules and with the calculated 3-exo-/4-endo-, 4-exo-/5-endo-, and 5-exo-/6-endo-dig selectivities in the cyclizations of carbon-, nitrogen-, and oxygen-centered nucleophiles. The generality of these predictions is confirmed by analogous trends for the related radical cyclizations where the stereoelectronically favorable exo-closures are also preferred kinetically, with a few exceptions where a large difference in product stability skews the intrinsic stereoelectronic trends.

ChemInform Abstract: General Method for the Synthesis of Substituted Phenanthridin‐6(5H)‐ones Using a KOH‐Mediated Anionic Ring Closure as the Key Step.

AbstractThe cyclization proceeds with both 2′‐fluorobiphenyl‐2‐carbonitriles bearing electron‐withdrawing and electron‐donating groups.

General method for the synthesis of substituted phenanthridin-6(5 H)-ones using a KOH-mediated anionic ring closure as the key step

Substituted phenanthridin-6(5 H)-ones were obtained in a two-step procedure involving a Suzuki cross-coupling reaction followed by a KOH-mediated anionic ring closure. The influence of the nature and the position of the substituents on the cyclization step were studied. This methodology offers a general and practical route to diversely substituted phenanthridin-6(5 H)-ones.

The Synthesis of Three New Heterocycles: The Pyrido[4,3 or 3,4 or 2,3‐c]‐1,5‐naphthyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

A straightforward synthesis of 3-substituted azetidinic amino acids

A series of enantiomerically pure N,N-disubstituted β-amino alcohols were chlorinated by treatment with thionyl chloride. This reaction afforded a mixture of regioisomeric β-amino chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The secondary chlorides thus obtained were engaged in an intramolecular anionic ring-closure to give access to fully protected enantioand diastereoisomerically pure 2,3-cis-disubstituted azetidinic amino acid. One of the latter was deprotected for inclusion in a tripeptide sequence. This synthetic methodology was applied for N,N-disubstituted γ-amino alcohols, leading to 3or 5substituted proline derivatives but with a low 2,3or 2,5diastereoselectivity.

The synthesis of three new heterocycles: the pyrido[4,3 or 3,4 or 2,3- c]-1,5-naphthyridines

Pyrido[4,3 or 3,4 or 2,3- c]-1,5-naphthyridines were obtained with good yields after chlorodehydroxylation and dehalogenation reactions starting from the parent pyridonaphthyridinones. These pyridonaphthyridinones were synthesized in a two-step procedure using a Suzuki cross-coupling reaction between 2-chloro-3-fluoropyridine and orthocyanopyridylboronic esters followed by a KOH-mediated anionic ring closure.

A new, direct, and efficient synthesis of benzonaphthyridin-5-ones

Microwave-assisted Suzuki cross-coupling reaction of 2-fluorophenylboronic acid with all orthochlorocyanopyridine isomers allowed the rapid syntheses of key intermediates for anionic ring closure, which was performed using potassium hydroxide under microwave irradiation to give benzonaphthyridin-5-ones in high yields.

Synthesis of Azaphenanthridines (V), (IX) via Anionic Ring Closure.

Synthesis of Azaphenanthridines (V), (IX) via Anionic Ring Closure.

Stereocontrolled Synthesis of 3-Substituted Azetidinic Amino Acids

A set of enantiomerically pure N-disubstituted β-amino alcohols was chlorinated by treatment with thionyl chloride. This reaction gave a mixture of regioisomeric chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The chlorides thus obtained were engaged in an intramolecular anionic ring-closure and gave access to fully protected enantio- and dia­stereomerically pure 2,3-cis-disubstituted azetidinic amino acids. One of the latter was deprotected and included in a short peptide ­sequence.

Synthesis of azaphenanthridines via anionic ring closure

A new and convergent synthesis of azaphenanthridines via an anionic ring closure is reported. Ortho-lithiation/in situ borylation of cyanopyridines produces the corresponding cyanopyridylboronic esters, which undergo a Suzuki–Miyaura cross-coupling to give the key intermediates. Addition of lithium morpholide produces the azaphenanthridines.

Convergent synthesis of 6-substituted phenanthridines via anionic ring closure.

[reaction: see text] The addition of organometallic derivatives to the cyano group of 2-(2-fluorophenyl)benzonitrile followed by intramolecular nucleophilic substitution produces 6-substituted phenanthridines. Alkyllithiums, aryllithiums, and sterically nondemanding lithium amides reacted at -78 degrees C to produce the 6-substituted phenanthridines in 82-98% yield upon warming to room temperature. The addition of the corresponding Grignard reagents requires an excess of the organometallic reagent and extented reaction times at elevated temperature.

Efficient Enantioselective Synthesis of Sertraline, a Potent Antidepressant, via a Novel Intramolecular Nucleophilic Addition to Imine

[formula: see text] An efficient enantioselective synthesis of sertraline, an antidepressant, utilizing anionic imine ring closure is described.

Dopamine autoreceptor agonists: computational studies, synthesis and biological investigations

Based on molecular modeling studies on the electronic properties of dopamine and dopamine agonists the pyrazolo[1,5-a]pyridine structure has been evaluated as a catechol surrogate. The azaergoline analogue 6, including this moiety has been synthesized via 1,3-dipolar cycloaddition, anionic ring closure and electrophilic amination. The target compounds ( 6) exhibit DA autoreceptor agonistic activity.