Base-promoted Cascade Research Articles

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids.

For the first time, recyclization of allomaltol derivatives with an amide fragment in the side chain were investigated. It was shown that the studied process leads to substituted tetronic acids bearing a pyrrolidinone moiety. The application of 1,1'-carbonyldiimidazole and DBU is necessary for implementation of the considered reaction. Based on the performed research a general method for the synthesis of a wide range of (3E,5E)-3-(1-hydroxyethylidene)-5-(5-oxopyrrolidin-2-ylidene)furan-2,4(3H,5H)-diones was elaborated. The advantages of the presented protocol are easily available starting compounds and simple isolation of the target products without chromatographic purification. The synthetic utility of the prepared tetronic acids was demonstrated by further transformations at the hydroxyethylidene fragment. The structures of one obtained tetronic acid and one product of derivatization were confirmed by X-ray analysis.

Base-promoted cascade vinylogous Michael/Michael addition of alkylidene succinimides for the construction of penta-substituted cyclopentanes.

Herein, an efficient, base catalyzed cascade vinylogous Michael/Michael cycloaddition reaction of α-alkylidene succinimides and oxindole-derived pyrazolones has been successfully developed. A variety of highly functionalized cyclopentanes fused with spirooxindoles were obtained in good yields, with excellent diastereoselectivities and exclusive vinylogous site-selectivities. This strategy represents the first example of α-alkylidene succinimides serving as nucleophilic reagents to trigger a vinylogous cascade reaction.

The Chameleonic Nature of the Nitro Group Applied to a Base-Promoted Cascade Reaction To Afford Indane-Fused Dihydrofurans.

We disclose a Michael/Conia-ene/SN2 cascade reaction for the synthesis of Indane-fused dihydrofurans from 1,3-dicarbonyl compounds and 2-alkynylnitrostyrenes promoted by potassium carbonate in DMSO at room temperature. In this reaction, the nitro group has a chameleonic role, first as an electron-withdrawing group for the Michael addition, then the nitronate behaves as a nucleophile, and finally, the allylic nitro acts as a leaving group. The product is obtained as a single diastereomer, affording up to 82% with 1,3-keto esters and 58% with 1,3-diketones. Furthermore, DFT calculations of the reaction mechanism explained the chemoselective addition of the nitronate over the enolate to the unactivated triple bond, with the enolate addition being highly endothermic.

DMAP-Promoted Cascade Reaction of α-Ketoester with Benzylidene- Malononitrile: Access Polyfunctionalized 2-Amino-3-Cyano-4H-Pyran Containing Ester Motifs

Abstract: A base-promoted cascade reaction of α-ketoester with benzylidene-malononitrile was developed under mild reaction conditions, which enabled the synthesis of polyfunctionalized 2-amino- 3-cyano-4H-pyrans containing ester motifs at 6-position with good to excellent yields. These transformations not only construct various polyfunctionalized 4H-pyrans, which add a new member to the family of 4H-pyrans, but also provide an efficient approach for the synthesis of fully substituted 4Hpyran derivatives.

Synthesis of Novel DPPH-Free Radical Scavenger Se-Containing Fused Chalcogenophenes: 2-Alkyl-7-Cyano-4-Imino-3-Phenyl-6-(pyrrolidin-1-yl)-3,4-Dihydroselenopheno[3,2-d]Pyrimidines

A straightforward and effective strategy for the synthesis of novel 7-cyano-4-imino-3-phenyl-6-(pyrrolidin-1-yl)-2-substituted-3,4-dihydroselenopheno[3,2-d]pyrimidines have been accomplished through a base-promoted cascade addition/cyclization sequence employing phenyl isothiocyanate followed by the S-alkylation of the obtained fused Se-containing heterocyclic framework with various alkyl halides. Free radical scavenging activity of the synthesized selenium-containing structures was studied against DPPH, as well. Antioxidant activities as IC50 values were ranged from 12.19 to 91.08 µM. Unfused 3-amino-2,4-dicyano-5-(pyrrolidin-1-yl)selenophene was much more powerful antioxidant agent than ascorbic acid. Moreover, the promising antioxidant potentials were observed with selenopheno[3,2-d]pyrimidines. Taking into account the best antioxidant activity of S-benzylated derivative amongst pyrimidine-fused heterocycles and significant relationship between antioxidant activity of compounds and many of their biological potencies, using benzyl halides bearing electron donating groups on phenyl ring can probably improve their antioxidant capacities to make them more effective anti-cancer, anti-diabetic, anti-inflammatory and anti-neurodegenerative agents.

Base-promoted cascade radical difluoroalkylation/cyclization of acrylamides for the synthesis of CF2-containing oxindoles and isoquinoline-1,3-diones

A base-promoted cascade radical difluoroalkylation/cyclization of acrylamides with ICF2COOEt to synthesize CF2-containing oxindoles and isoquinoline-1,3-diones in moderate to excellent yields was developed under transition metal-free and catalyst-free conditions. This reaction tolerated a variety of functional groups and provided an alternative and mild method for the preparation of difluoroester-substituted five- and six-membered nitrogen-containing heterocyclic products.

Base-promoted cascade β-F-elimination/electrocyclization/Diels-Alder/retro-Diels-Alder reaction: efficient access to δ-carboline derivatives.

A serendipitous and highly efficient approach for the construction of a variety of δ-carboline derivatives was developed through base-promoted cascade β-F-elimination/electrocyclization/Diels–Alder/retro-Diels–Alder reaction of N-2,2,2-trifluoroethylisatin ketoimine esters with alkynes in good to high yields with excellent regio-/chemoselectivity control. Moreover, a reasonable reaction pathway was proposed, which was in accordance with the prepared reaction intermediate and control experiment results. The δ-carboline product could be easily converted into a new chiral Py-box-type ligand through simple synthetic transformations. This salient strategy featured the advantages of metal-free conditions, excellent regio-/chemoselectivity, good to high yields, and outstanding substrate tolerance. Importantly, the potential application of these fascinating δ-carboline derivative products is well demonstrated in the recognition of ferric ions.

Base-Promoted Cascade Radical Difluoroacetylation/Cyclization of Acrylamides for the Synthesis of Cf2-Containing Oxindoles and Isoquinoline-1,3-Diones

Base-Promoted Cascade Radical Difluoroacetylation/Cyclization of Acrylamides for the Synthesis of Cf2-Containing Oxindoles and Isoquinoline-1,3-Diones

Synthesis of Alicyclic 2-Methylenethiazolo[2,3-b]quinazolinone Derivatives via Base-Promoted Cascade Reactions

AbstractThe synthesis of alicyclic 2-methylenethiazolo[2,3-b]quinazo­l­inones is performed via base-promoted cascade reactions, starting from either alicyclic β-amino propargylamides using carbon disulfide, or from alicyclic ethyl 2-isothiocyanatocarboxylates by addition of propargylamine. In both cases the cascade reaction proceeds by way of a favoured 5-exo-dig process during the second ring closure, as confirmed by full NMR spectroscopic assignments. Moreover, a high-yielding retro­-Diels–Alder (RDA) reaction is performed on the norbornene derivatives leading to 2-methylene-2H-thiazolo[3,2-a]pyrimidin-5(3H)-ones. The obtained compounds exert modest antiproliferative activities against a panel of human gynaecological cancer cell lines.

Direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines from propargyl sulfonylamides and allenamides.

Multisubstituted pyrroles are important fragments that appear in many bioactive small molecule scaffolds. Efficient synthesis of multisubstituted pyrroles with different substituents from easily accessible starting materials is challenging. Herein, we describe a metal-free method for the preparation of pentasubstituted pyrroles and hexasubstituted pyrrolines with different substituents and a free amino group by a base-promoted cascade addition–cyclization of propargylamides or allenamides with trimethylsilyl cyanide. This method would complement previous methods and support expansion of the toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines. Mechanistic studies to elucidate the reaction pathway have been conducted.

Diastereoselective direct amidation/aza-Michael cascade reaction to synthesize cis-1,3-disubstituted isoindolines

A convenient and efficient base-promoted cascade reaction for the synthesis of cis-1,3-disubstituted isoindolines has been reported herein. We discovered that various N-protected imines bearing a Michael acceptor react smoothly with several nitrogenous nucleophiles in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene under mild conditions. cis-1,3-Disubstituted isoindolines bearing aminal functionality were assembled as a single diastereomer in moderate to good yields (52%–94%). This cascade process features the direct amidation of imines followed by the intramolecular aza-Michael reaction.

New efficient design and synthesis of novel antioxidant and antifungal 7-imino[1,3]selenazolo[4,5-d]pyrimidine-5(4H)-thiones utilizing a base-promoted cascade addition/cyclization sequence

A straightforward strategy for the efficient synthesis of multi-functionalized 7-imino[1,3]selenazolo[4,5-d]pyrimidine-5(4H)-thiones bearing an incorporated N-phenylmethanethioamide fragment from the heteroannulation of several 2,4,5-trisubstituted 1,3-selenazoles with readily accessible phenyl isothiocyanates was established in boiling pyridine. To enrich the biological profile of the newly synthesized fused heterocyclic scaffold, some noted pharmacophores such as pyrrolidine, piperidine, morpholine, fluorine, and bromine were inserted into the framework. Inhibitory activities of the selenium-containing heterocycles were assessed against DPPH and Candida albicans. Antioxidant activities as IC50 values were observed in the range of 0.010–0.063 mM. Results revealed that 6-phenyl-substituted selenazolopyrimidines bearing C2-pyrrolidine and C2-piperidine both with IC50 value of 0.010 mM were superlative amongst others. Being far superior to ascorbic acid (IC50 = 0.022 mM), 4-fluorophenyl-substituted compounds bearing 2-morpholine residual (IC50 = 0.014 mM), and 2-piperidine (IC50 = 0.019 mM) were ranked in the second place and third place of antioxidant efficacy, respectively. Moreover, para-bromo and fluoro substituted N-phenylselenazolo[4,5-d]pyrimidines containing pyrrolidine moiety exhibited similar and six times higher potency for death and blocking of Candida albicans fungus than ketoconazole, respectively. Consequently, some of these selenazolopyrimidines are promising anti-Candida albicans as well as antioxidant lead compounds which can be used in the treatment of candidiasis, cancer, and neurodegenerative and diabetes diseases.

Base-Promoted Cascade Reactions of 3-(1-Alkynyl)chromones with Pyridinium Ylides to Chromeno[2,3- d]azepine Derivatives.

A base-promoted cascade reaction of 3-(1-alkynyl)chromones with pyridinium ylides has been developed to afford a novel chromeno[2,3- d]azepine scaffold in an efficient and economic manner. This tandem process involves multiple reactions including a Michael addition/deprotonation/alkyne-allene isomerization/cyclization and the subsequent 1,2-addition under mild conditions without a transition metal catalyst.

Three-Component Cascade Reaction of 1,1-Enediamines, N,N-Dimethylformamide Dimethyl Acetal, and 1,3-Dicarbonyl Compounds: Selective Synthesis of Diverse 2-Aminopyridine Derivatives.

A novel approach has been developed for the synthesis of three kinds of highly functionalized 2-aminopyridine derivatives (APDs) through a three-component reaction of 1,1-enediamines (EDAMs) 1, N,N-dimethylformamide dimethyl acetal (DMF-DMA) 2, and 1,3-dicarbonyl compounds 3–5 via a base-promoted cascade reaction, producing the desired products in good to excellent yields. This method represents a route to obtain a novel class of APDs in a concise, rapid, and practical manner. This approach is particularly attractive because of the following features: low cost, mild temperature, atom economy, high yields, and potential biological activity of the product.

Synthesis of thiazolo[2,3-b]quinazoline derivatives via base-promoted cascade bicyclization of o-alkenylphenyl isothiocyanates with propargylamines.

A highly efficient cascade bicyclization reaction of o-alkenylphenyl isothiocyanates with propargylamines has been developed, which affords a series of thiazolo[2,3-b]quinazolines in good to excellent yields by using K2CO3 as a base in MeCN at 80 °C. This method is transition-metal-free and operationally simple with broad functional group tolerance. Mechanistically, 6-exo-trig hydroamination followed by 5-exo-dig hydrothiolation was involved in this transformation.

A base-promoted cascade reaction of α,β-unsaturated N-tosylhydrazones with o-hydroxybenzyl alcohols: highly regioselective synthesis of N-sec-alkylpyrazoles.

An efficient method for the synthesis of N-sec-alkylpyrazoles through a base-promoted cascade cyclization/Michael addition reaction of α,β-unsaturated N-tosylhydrazones with ortho-hydroxybenzyl alcohols has been developed. The desired products containing di- or triaryl groups at the same carbon atom were afforded in good to excellent yields with excellent regioselectivities (>20 : 1). Moreover, a three-component reaction of ortho-hydroxybenzyl alcohols, α,β-unsaturated N-tosylhydrazones and saturated N-tosylhydrazones also took place to afford pyrazoles in good yields. This reaction offers a new route to triarylmethanes with a simple operation and is applicable for large-scale synthesis.

Synthesis of 2-Aminopyridines via a Base-Promoted Cascade Reaction of N-Propargylic β-Enaminones with Formamides

N-Substituted formamides as nucleophiles react with in situ-generated 1,4-oxazepines from N-propargylic β-enaminones followed by spontaneous N-deformylation to deliver densely substituted 2-aminopyridines in good yields (31-88%). The formyl group is found to be a superior traceless activating group of free amines and would ultimately be removed in situ. This reaction proceeds smoothly at room temperature, in the presence of NaOH as sole additive, without protection from the atmosphere and generates H2O and sodium formate as byproducts.

Base-Promoted Cascade C-C Coupling/N-α-sp3C-H Hydroxylation for the Regiospecific Synthesis of 3-Hydroxyisoindolinones.

A base-promoted cascade reaction for the regiospecific synthesis of substituted 3-hydroxyisoindolinones under transition-metal-free conditions is developed. The base-mediated C-C bond coupling and N-α-sp3C-H bond hydroxylation are involved in this procedure, which features high regioselectivity, efficiency, and environmental friendliness. Various substituted 3-hydroxyisoindolinones, including some bioactive molecules, were provided in up to 93% yield for 28 examples.

Base-Promoted Cascade Approach for the Preparation of Reduced Knoevenagel Adducts Using Hantzsch Esters as Reducing Agent in Water

A cascade Knoevenagel condensation–reduction approach, which was carried out in water, has been reported. Using Hantzsch esters as reducing agent, under the promotion of base, a variety of reduced Knoevenagel adducts could be easily prepared by direct alkyl­ation of malononitrile, ethyl 2-cyanoacetate, and 2-(4-nitrophenyl)acetonitrile, respectively. Meanwhile, a gram-scale synthesis of the protocol was also realized with excellent isolated yield.

Efficient three-component one-pot synthesis of steroidal polysubstituted anilines

An efficient and practical base-promoted cascade reaction has been developed to access steroidal polysubstituted anilines from simple precursors. The protocol reported herein achieved the formation of a benzene ring as well as three continuous C–C bonds in a single operation. The reaction mechanism was proposed on the basis of the key intermediate obtained. Besides, this method could be potentially employed for the synthesis of biphenyl compounds. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.