Multicomponent Reaction Of Isocyanides Research Articles

An Efficient Electrochemical Synthesis of Selenocarbamates from Isocyanates and Diselenides

AbstractA facile electrochemical synthesis of selenocarbamates from multicomponent reactions of isocyanides, diselenides, and water is developed here. This strategy provides a mild, direct, and complementary approach for synthesizing selenocarbamates in moderate to excellent yields with good substrate tolerance. The simple undivided cell setting with carbon/Pt electrodes proceeded smoothly. A radical pathway was proposed by preliminary mechanistic research.

Diversifying DNA-Tagged Amines by Isocyanide Multicomponent Reactions for DNA-Encoded Library Synthesis.

In DNA-encoded library synthesis, amine-substituted building blocks are prevalent. We explored isocyanide multicomponent reactions to diversify DNA-tagged amines and reported the Ugi-azide reaction with high yields and a good substrate scope. In addition, the Ugi-aza-Wittig reaction and the Ugi-4-center-3-component reaction, which used bifunctional carboxylic acids to provide lactams, were explored. Five-, six-, and seven-membered lactams were synthesized from solid support-coupled DNA-tagged amines and bifunctional building blocks, providing access to structurally diverse scaffolds.

Multicomponent Reaction of Isocyanide, Ditelluride, and Mn(III) Carboxylate: Synthesis of N-Acyl Tellurocarbamate.

A multicomponent reaction of isocyanides, ditellurides and manganese(III) carboxylates under mild reaction conditions leads to the synthesis of various N-acyl tellurocarbamates. This method demonstrates good functional tolerance and broad substrate scope and, as a result, is especially suitable for the postfunctionalization of complicated molecules such as drugs. The given method can be further extended to the synthesis of selenocarbamates.

Chemically Stabilized DNA Barcodes for DNA‐Encoded Chemistry

DNA‐encoded compound libraries are a widely used small molecule screening technology. One important aim in library design is the coverage of chemical space through structurally diverse molecules. Yet, the chemical reactivity of native DNA barcodes limits the toolbox of reactions for library design. Substituting the chemically vulnerable purines by 7‐deazaadenine, which exhibits tautomerization stability similar to natural adenine with respect to the formation of stable Watson–Crick pairs, yielded ligation‐competent, amplifiable, and readable DNA barcodes for encoded chemistry with enhanced stability against protic acid‐ and metal ion‐promoted depurination. The barcode stability allowed for straightforward translation of 16 exemplary reactions that included isocyanide multicomponent reactions, acid‐promoted Pictet–Spengler and Biginelli reactions, and metal‐promoted pyrazole syntheses on controlled pore glass‐coupled barcodes for diverse DEL design. The Boc protective group of reaction products offered a convenient handle for encoded compound purification.

Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines

A multicomponent reaction of isocyanides with aryl(indol-3-yl)methylium salts and amines has been found. A series of aryl(indol-3-yl)acetimidamides was obtained in up to 96% yields. In the case of ethyl isocyanoacetate, the reaction is followed by cyclization to form 3,5-dihydro-4H-imidazol-4-one derivatives.

Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application.

Drug discovery efforts largely depend on access to structural diversity. Multicomponent reactions allow for time-efficient chemical transformations and provide advanced intermediates with three or four points of diversification for further expansion to a structural variety of organic molecules. This review is aimed at solid-phase syntheses of small molecules involving isocyanide-based multicomponent reactions. The majority of all reported syntheses employ the Ugi four-component reaction. The review also covers the Passerini and Groebke-Blackburn-Bienaymé reactions. To date, the main advantages of the solid-phase approach are the ability to prepare chemical libraries intended for biological screening and elimination of the isocyanide odor. However, the potential of multicomponent reactions has not been fully exploited. The unexplored avenues of these reactions, including chiral frameworks, DNA-encoded libraries, eco-friendly synthesis, and chiral auxiliary reactions, are briefly outlined.

Direct Assembly of Polysubstituted Propiolamidinates via Palladium-Catalyzed Multicomponent Reaction of Isocyanides.

A straightforward approach for the assembly of different polysubstituted propiolamidnates via palladium-catalyzed multicomponent reaction of isocyanides, haloalkynes, and amines has been reported in which the C(sp)-C(sp2) and C(sp2)═N bonds were constructed in one pot. This reaction featured in high efficiency, excellent chemoselectivity, and good functional group compatibility. The synthetic utility of this method was also demonstrated.

Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis.

Isocyanide multicomponent reactions play a prominent role in drug discovery. This chemistry has hardly been investigated for compatibility with DNA-encoded combinatorial synthesis. The Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions are well-tolerated by DNA on the solid phase and show a broad scope. However, an oxadiazole-forming variant of the Ugi reaction caused DNA depurination, requiring a more stable hexathymidine DNA for encoded library synthesis. Cheminformatic analysis revealed that isocyanide multicomponent-reaction-based encoded libraries cover a diverse chemical space.

One‐pot synthesis of highly functionalized benzo [1,3] thiazine from isocyanides, aniline, and heterocumulene via Cu‐catalyzed intramolecular C‐H activation reactions

AbstractA one‐pot synthesis of functionalized benzo thiazine derivatives via a Cu‐catalyzed, multicomponent reaction of isocyanides, aniline, and heterocumulenes in acetonitrile at room temperature was developed. Transition metal‐catalyzed activation of C‐H bonds under mild copper‐catalytic reaction conditions, using simple and available starting materials, also obtaining a pure product with high yield without applying column chromatography are the major advantages of the applied method among the other ones used for this purpose. The structures are confirmed spectroscopically (1H‐ and 13C‐NMR, IR, and EI‐MS) and through elemental analyses.

Radical Cyanotrifluoromethylation of Isocyanides: Step-Economical Access to CF3-Containing Nitriles, Amines, and Imines.

A novel copper-catalyzed radical cyanotrifluoromethylation has been achieved through a multicomponent reaction of isocyanides, Togni's reagent, and trimethylsilyl cyanides, affording trifluoroacetimidoyl nitriles in good yields. This reaction demonstrates a unique feature of merging two valuable functional groups-trifluoromethyl (CF3) and cyan (CN)-onto the same C atom. The transformation proceeds by the initial addition of the CF3 radical to isocyanide and the subsequent intermolecular C-CN formation. The products can be successfully transformed to a series of CF3-containing amines and imines that may serve in the synthesis of valuable pharmaceuticals and agrochemicals.

Diversity Driven Decoration and Ligation of Fullerene by Ugi and Passerini Multicomponent Reactions.

Aiming at providing an efficient and versatile method for the diversity-oriented decoration and ligation of fullerenes, we report the first C60 derivatization strategy based on isocyanide-multicomponent reactions (I-MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo-peptidic scaffolds (i.e., N-alkylated and depsipeptides, peptoids) on carboxylic acid-functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60 , as well as for the construction of bis-antennary as well as PEG-tethered dimeric fullerenes. The quantum yields for the formation of 1 O2 was remarkable for the selected compounds analyzed.

TEMPO-Catalyzed Aerobic Oxidative Selenium Insertion Reaction: Synthesis of 3-Selenylindole Derivatives by Multicomponent Reaction of Isocyanides, Selenium Powder, Amines, and Indoles under Transition-Metal-Free Conditions.

A novel and efficient approach for the selenium functionalization of indoles was developed with selenium powder as the selenium source, catalyzed by 2,2,6,6-tetramethylpiperidinooxy (TEMPO) and employing O2 as the green oxidant. This protocol provides a practical route for the synthesis of 3-selenylindole derivatives and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates. Electron spin-resonance (ESR) studies reveal that the approach involves the formation of nitrogen-centered radicals and selenium radicals via oxidation of in situ generated selenoates.

One-pot three component isocyanide-based reaction: Synthesis of novel tetracyclic fused furo[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole

A rapid, efficient and benign protocol has been developed for the construction of potentially biologically active furo[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole derivatives as major products along with (3E)-3-[(alkylamino)methylene]-2H-pyrimido[2,1-b][1,3]benzothiazole-2,4(3H)-dione derivatives as minor products using a one-pot, multi-component reaction of isocyanides, aromatic aldehydes and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one. The significant features of this protocol are the readily available and low-cost starting materials, short reaction time, mild reaction conditions, high yield of products and avoidance of toxic solvents and catalysts. Structures of compounds 4b and 5a were confirmed from single crystal X-ray studies.

Synthesis of 2-(3-chromonyl)-2-acyloxycarboxamides via multicomponent reactions of isocyanides

A three-component reaction between a 3-formylchromone, an alkyl isocyanide, and a carboxylic acid which affords novel 2-(3-chromonyl)-2-acyloxycarboxamide derivatives is reported. This cascade reaction sequence represents an atom-economic route to biologically interesting molecules.

Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold.

A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.

ChemInform Abstract: Multicomponent Reactions of Isocyanides and Dialkyl Acetylenedicarboxylate in the Presence of 2‐Hydroxy‐3‐methyl‐2‐cyclopentene‐1‐one: One‐Pot Synthesis of 1‐Azadienes in Water.

AbstractA green, simple, and efficient method for the synthesis of 1‐azadienes (IV) under neutral conditions is presented.

Synthesis of 4‐Aminoxanthones by an Uncatalyzed, Multicomponent Reaction

AbstractThe synthesis of xanthones via a multicomponent reaction of isocyanides is described for the first time. In this one‐pot process, a tandem [4+1] plus [4+2] cycloaddition leads to polysubstituted 4‐aminoxanthones in excellent to quantitative yields at room temperature in a non‐catalyzed reaction.magnified image

Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60–0.75 μM) and 12h (IC50: 1.12–2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >20 μM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

Multicomponent Reactions of Isocyanides and Dialkyl Acetylenedicarboxylate in the Presence of 2-Hydroxy-3-Methyl-2-Cyclopentene-1-One: One-Pot Synthesis of 1-Azadienes in Water

The 1: 1 reactive intermediate generated by the addition of alkyl isocyanides to dialkyl acetylenedicarboxylates was trapped by 2-Hydroxy-3-methyl-2-cyclopentene-1-one as OH-acid to yield highly functionalised 1-azadienes in water.

Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions