Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview.

This review collects the synthetic modifications performed on andrographolide, a natural molecule derived from , for oncology applications. Various pharmacomodulations were carried out, and the products were tested on different cancer cell lines. The impact of these modifications was analyzed with the aim of mapping the positions essential for activity to facilitate future research in this field.

Copper-catalyzed transformation of alkyl nitriles to -arylacetamide using diaryliodonium salts.

This work reports a simple and efficient method for the copper-catalyzed redox-neutral transformation of alkyl nitriles using eco-friendly diaryliodonium salts and leading to -arylacetamides. The method features high efficiency, broad substrate scope and good functional group tolerance.

Electrophile promoted cyclization of -aryl substituted ynamides: construction of 3-amino-4-halo- or 4 seleno-isocoumarin derivatives.

Isocoumarins are important building blocks in medicinal chemistry. They are widespread in the core structure of biologically active compounds. Here we report the development of an efficient and highly reactive electrophilic cyclization of ortho-ynamidyl benzoate esters providing access to 3-amino-4-halo- or 4-seleno-isocoumarins in a short time (<1 min) with good yields.

Chan-Evans-Lam 1-(het)arylation and 1-alkеnylation of 4-fluoroalkylpyrimidin-2(1)-ones.

The Chan-Evans-Lam reaction of 1-unsubstituted 4-fluoroalkylpyrimidin-2(1)-ones with arylboronic acids is reported as a facile synthetic route to hitherto unavailable 1-(het)aryl and 1-alkenyl derivatives of the corresponding pyrimidines. An efficient C-N bond-forming process is also observed by using boronic acid pinacol esters as coupling partners in the presence of Cu(II) acetate and boric acid. The 4-fluoroalkyl group on the pyrimidine ring significantly assists in the formation of the target 1-substituted products, in contrast to the 4-methyl and 4-unsubstituted substrates which do not undergo 1-arylation under similar reaction conditions.

Rapid synthesis of 3-amino-1-isochromene from -ynamidyl het(aryl) aldehyde derivatives.

A simple and original efficient synthesis of 3-amino-1-isochromene bearing a bromine atom at the C-1 position a 6-endo-cyclization approach from generated -ynamidyl het(aryl) aldehyde derivatives is achieved under mild reaction conditions and with good yields. Original -ynamidyl benzaldehyde compounds were also successfully obtained.

Regioselective Pd-Catalyzed Carbopalladation/Decarboxylative Allylic Alkynylation of -Iodoallenamides with Alkynyl Carboxylic Acids.

A regioselective Pd-catalyzed domino carbopalladation/decarboxylative allylic alkynylation of -iodoallenamides with alkynyl carboxylic acids was studied. This domino process, based on the consecutive formation of C(sp)-C(sp) and C(sp)-C(sp) bonds, was originally achieved for the design of a novel library of prop-2-ynyl isoquinolinones and then extended to indoles. Finally, a general three-step one-pot strategy involving in situ generation of allenamide, π-allyl-Pd complex formation, and decarboxylative allylic alkynylation was subsequently set up.

Diphenyliodonium Ion/EtN Promoted Csp2-H Radical Phosphorylation of Enamides.

This work reports a simple and efficient method for the direct phosphorylation of enamide under metal-free conditions. The P-centered radicals, derived from secondary phosphine oxides, are generated under mild reaction conditions in the presence of diphenyliodonium salt and EtN and are introduced onto a range of enamides in good isolated yields. The method features broad substrate scope, good functional group tolerance, and efficient scale-up.

Access to Unprotected β-Fluoroalkyl β-Amino Acids and Their α-Hydroxy Derivatives.

Unprotected β-(het)aryl-β-fluoroalkyl β-amino acids and their α-hydroxy derivatives can be readily obtained using a decarboxylative Mannich-type reaction without protection/deprotection steps. This protocol utilizes lithium hexamethyldisilazide and (het)arylfluoroalkyl ketones to generate NH-ketimine intermediates. The mild reaction conditions allow the preparation of original fluorinated β-amino acids as useful building blocks in a practical and scalable manner.

Near-infrared emitting lanthanide(iii) complexes as prototypes of optical imaging agents with peptide targeting ability: a methodological approach.

A methodological approach to design prototypes of specific near-infrared emitting imaging agents based on a small molecular compound combining a lanthanide(iii) ion, the cyclen derivative as a coordinating unit and the azo-dye as a sensitizer with a Arg-Gly-Asp cyclopeptide as a targeting moiety, is presented here.

Rapid synthesis of 3-amino isocoumarin derivatives from ynamides.

A novel and efficient fast synthesis of 3-amino isocoumarins in good to excellent yields is reported. These interesting scaffolds can be obtained either in a single step from readily available ynamides or in a two-step sequence from the corresponding alkynyl bromide after C-N cross-coupling. This protocol, which only requires a Brønsted or Lewis acid as a promoter, offers an alternative approach toward synthesizing 3-substituted isocoumarins under smooth and fast conditions.

Palladium-Catalyzed Domino Allenamide Carbopalladation/Direct C-H Allylation of Heteroarenes: Synthesis of Primprinine and Papaverine Analogues.

Palladium-catalyzed intramolecular carbopalladation onto allenamides completed by direct C-H allylation of heterocycles is studied. The domino construction/heteroarylation of isoquinolone process is first achieved. A general three-step one-pot strategy, involving in situ generation of allenamide, π-allyl-Pd complex generation, and interception with heteroarenes, has been subsequently set up.

Regio- and Stereoselective Iron-Catalyzed Oxyazidation of Enamides Using a Hypervalent Iodine Reagent.

A novel regio- and diastereoselective iron-catalyzed intermolecular oxyazidation of enamides using various azidobenziodoxolone (ABX) derivatives is presented. A variety of α-N amino derivatives and of α-N piperidines were synthesized in good yields and under mild reaction conditions. The reaction involves a radical process using cheap FeCl as the initiator.

Reaction of Ynamides with Iminoiodinane-Derived Nitrenes: Formation of Oxazolones and Polyfunctionalized Oxazolidinones.

This article describes the reaction of ynamides with metallanitrenes generated in the presence of an iodine(III) oxidant. N-(Boc)-Ynamides are converted to oxazolones via a cyclization reaction. The reaction is mediated by a catalytic dirhodium-bound nitrene species that first behaves as a Lewis acid.

Cobalt-Catalyzed Carbozincation of Ynamides.

An original cobalt-catalyzed ynamide carbozincation leading mainly to diverse 3-aryl enamides with mild reaction conditions and good functional-group tolerance has been developed. This reaction displays an excellent regio- and total stereoselectivity and opens the way to appealing synthetic applications. Moreover, this approach allows the selective synthesis of biologically relevant 3,5-disubstituted oxazolone frameworks.

Iron-catalyzed trifluoromethylation of enamide.

Herein the first example of the iron(II)-catalyzed trifluoromethylation of enamide using mild and simple reaction conditions is reported. The method is cost-effective and uses the easy-to-handle Togni's reagent as the electrophilic CF3 source. This transformation is totally regioselective at the C3 position of enamides and exhibits broad substrate scope, good functional group tolerance and thus demonstrates its useful application in a late-stage fluorination strategy.

Direct metal-catalyzed regioselective functionalization of enamides.

Enamides are stable enamine surrogates and provide key intermediates for the synthesis of small but complex nitrogen-containing compounds. Metal-catalyzed regioselective functionalization of enamides provides a rapid method to synthesize useful nitrogen containing heterocycles. This review discloses the recent progress made in the development of the C-H functionalization of enamides involving efficient and atom-economical routes.

Copper-catalyzed olefinic C-H difluoroacetylation of enamides.

Copper-catalyzed olefinic difluoroacetylation of enamides via direct C-H bond functionalization using BrCF2CO2Et is reported for the first time. It constitutes an efficient radical-free method for the regioselective synthesis of β-difluoroester substituted enamides which exhibits broad substrate scope, and thus demonstrates its potent application in a late stage fluorination strategy.

Enantiomeric separation of original heterocyclic organophosphorus compounds in supercritical fluid chromatography.

New and original heterocyclic α-enamido phosphine chiral solutes were prepared: four structurally similar racemates with the chirality center placed on the phosphorus atom, and four other related pairs of enantiomers with chirality borne by the carbon atoms of the phospholane ring. The structural variations were placed on an aliphatic heterocycle (six- or seven-member rings) and on the carbamate function (methyl or t-butyl). Their separation was achieved on a commercial cellulose tris-(3,5-dimethylphenylcarbamate) stationary phase (Lux Cellulose-1, Phenomenex) in supercritical fluid chromatography (SFC).

Direct site-selective arylation of enamides via a decarboxylative cross-coupling reaction.

An efficient Pd-catalyzed decarboxylative cross-coupling reaction of simple enamides was achieved. Depending on the choice of the nitrogen-protecting group, a site-selective synthesis of mono- or diarylated framework(s) was performed under mild conditions. This unprecedented reactivity could be applied to the synthesis of a range of 2- or 2,4-diarylated nitrogen-containing bioactive derivatives.

Copper-catalyzed direct arylation of cyclic enamides using diaryliodonium salts.

A convenient method for the copper(II)-catalyzed direct arylation of cyclic and nonaromatic enamides using diaryliodonium salts has been developed. The reaction demonstrates large functional group tolerance, good yields, and total regioselectivity with a C(3)-functionalization. The synthetic potential of this coupling was explored by using a range of readily accessible diaryliodonium salts and enamides.

Construction of nitrogen-fused tetrahydroquinolines via a domino reaction.

An efficient domino approach for the diastereoselective synthesis of polyfunctionalized nitrogen-fused tetrahydroquinoline frameworks under mild conditions has been developed. The scope and limitation of this transformation were investigated by using a range of readily accessible enamides and benzyl azides. This method is also applicable to the formation of 2,3-functionalized enamides.

Palladium(II)-catalyzed direct alkenylation of nonaromatic enamides.

A mild and efficient method for the direct alkenylation of nonaromatic enamides was achieved through a palladium(II)-catalyzed C-H functionalization. The reaction scope includes cyclic and acyclic enamides and a range of activated alkenes. This approach represents the first successful direct C(3)-functionalization of nonaromatic cyclic enamides.

Diversity-oriented synthesis of polycyclic diazinic scaffolds.

An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity.

Synthesis and biological evaluation of novel benzodioxinocarbazoles (BDCZs) as potential anticancer agents.

We report the efficient synthesis and biological evaluation of new benzodioxinoindolocarbazoles heterocycles (BDCZs) designed as potential anticancer agents. Indolic substitution and maleimide variations were performed to design a new library of BDCZs and their cytotoxicity were evaluated on two representative cancer cell lines. Several derivatives have shown a marked cytotoxicity with IC(50) values in the nanomolar range.