Three-component Coupling Strategy Research Articles

Photoinduced Decatungstate Anion-Catalyzed 1,4-Difunctionalization of 1,3-Butadienes via C-H Activation.

This paper outlines an innovative three-component coupling strategy for the 1,4-difunctionalization of 1,3-butadiene, utilizing sodium decatungstate (NaDT) as a hydrogen atom transfer (HAT) photocatalyst. The photoinduced process efficiently generates homoallylic amino acid esters with 100% atom economy, employing readily available components under mild reaction conditions. This light-induced protocol eliminates the need for an additional transition metal catalysts, additives, or equivalent reducing agents. The study explored various C(sp3)-H bearing partners, butadienes, and α-iminoesters, demonstrating the versatility and synthetic utility of this method.

Rational design of functionalized near-infrared absorbing phthalocyanines by three-component coupling strategy

Near-infrared (NIR) dyes are used in various applications such as organic solar cells and photodynamic therapy sensitizers. One example of a class of dyes, octa-arylthio-substituted phthalocyanines (Pcs), can effectively absorb NIR light above 800 nm. The substitution of the Pc’s peripheral sulfur effectively introduces extra functions without significant perturbation of the optical properties. However, the synthesis of phthalonitrile precursors containing various functionalized arylthio groups has been limited. Herein, we provide the three-component-type coupling reactions for synthesizing phthalonitriles with various functionalized chalcogen-aryl groups. Organometallic reagents were prepared from aryl halides, elemental chalcogen, and 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile can lead to functionalized phthalonitriles in a one-pot procedure. Commonly used methods were utilized to prepare the corresponding Pcs. This reaction can be extended to other group-16 elements, chemoselective organomagnesium, and organozincate reagents. The NIR absorption and fluorescence properties of Pcs were also revealed and rationalized under substitution effects.

Development of Kilogram-Scale Synthesis of EGFR Inhibitor EAI045

Herein, we report a synthetic route for an EGFR inhibitor, 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl) acetic acid (EAI045), using a three-step approach. This short and efficient route is the first report of a scalable process for EAI045, which employs a convergent three-component coupling strategy as the key step, producing EAI045 in good yield on kilogram scale.

Visible-Light-Induced, Copper-Catalyzed Three-Component Coupling of Alkyl Halides, Olefins, and Trifluoromethylthiolate to Generate Trifluoromethyl Thioethers.

Photoinduced, copper-catalyzed coupling reactions are emerging as a powerful method for generating Csp3-Y (Y = C or heteroatom) bonds from alkyl electrophiles and nucleophiles. Corresponding three-component couplings of alkyl electrophiles, olefins, and nucleophiles have the potential to generate an additional Csp3-Y bond and to efficiently add functional groups to both carbons of an olefin, which serves as a readily available linchpin. In this report, we establish that a variety of electrophiles and a trifluoromethylthiolate nucleophile can add across an array of olefins (including styrenes and electron-poor olefins) in the presence of CuI/binap and blue-LED irradiation, thereby generating trifluoromethyl thioethers in good yield. The process tolerates a wide range of functional groups, and an initial survey of other nucleophiles (i.e., bromide, cyanide, and azide) suggests that this three-component coupling strategy is versatile. Mechanistic studies are consistent with a photoexcited Cu(I)/binap/SCF3 complex serving as a reductant to generate an alkyl radical from the electrophile, which likely reacts in turn with the olefin and a Cu(II)/SCF3 complex to afford the coupling product.

Morita-Baylis-Hillman enal-based triple cascade strategy for anti-selective synthesis of highly functionalized tetrahydropyridines using iminium-enamine catalysis

A novel and efficient three-component coupling strategy for stereoselective synthesis of highly substituted tetrahydropyridines (THP) is reported in high yield (83–94%) with excellent diastereoselectivity (95–99%) in favor of anti-isomer. The reaction proceeds via sequential iminium-iminium-enamine mediated formation of three consecutive CC, CC and CN bonds in one-pot through reaction of [E]-α-cyano/nitro unsaturated aldehyde, activated methylene and aldimine/phenyl-N-tosyl-methanimine and opens up a new aspect for the utility of Morita-Baylis-Hillman (MBH) adducts in THP synthesis.

A three-component coupling approach to the ACE-ring substructure of C19-diterpene alkaloids.

C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component coupling strategy. A radical-polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an aldehyde was realized by the actions of Et3B and O2, resulting in the installation of three new stereocenters and extension of the carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons, 4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.

Evolution of a Polyene Cyclization Cascade for the Total Synthesis of (-)-Cyclosmenospongine.

We report a full account on the development of a unique cationic polyene cyclization for the total synthesis of the tetracyclic meroterpenoid (-)-cyclosmenospongine. A highly convergent three-component coupling strategy enabled rapid access to individual cyclization precursors that were tested for their reactivity. The successful transformation generates three rings and sets four consecutive stereocenters in a single operation proceeding in a highly efficient manner to give exclusively the trans-decalin framework. In addition, we found that the enol ether geometry and the relative configuration of C3 and C8 are crucial for the success of the polyene cyclization.

Development of a Palladium-Catalyzed Carbonylative Coupling Strategy to 1,4-Diketones

We report on a three-component palladium-catalyzed coupling strategy for accessing a wide range of 1,4-diketones, which represent important precursors to heterocycles. Our method relies on a carbonylative Heck reaction employing substituted allylic alcohols, aryl iodides, and carbon monoxide. The reaction conditions are mild and do not require high CO pressure, and a wide functional group tolerance is revealed, providing the desired 1,4-diketones in moderate to good yields. Furthermore, the methodology is adaptable to the selective installment of 13C-carbon isotopes at either one or both of the carbonyl positions.

The first NHC-induced regioselective introduction of C- and N-nucleophiles in to Baylis–Hillman enals

The first direct conversion of [E]-α-cyanocinnamaldehyde in to corresponding functionalized amide is reported. The reaction involves three-component coupling strategy and proceeds via NHC-catalyzed regioselective introduction of carbon and nitrogen nucleophiles in to Baylis–Hillman enals. The functionalized amide scaffold further underwent iodine-catalyzed ring transformation to afford δ-lactam in excellent yields (85–92%) and high diastereoselectivities (96–99%) in favor of trans isomer. The reported method is novel and efficient application of Baylis–Hillman chemistry in δ-lactam synthesis and has advantage of its operational simplicity, no by-product formation, and ambient reaction conditions.

Copper(II) Catalyzed Expeditious Synthesis of Furoquinoxalines through a One-Pot Three-Component Coupling Strategy

Microwave assisted one-pot transformation has been developed for the synthesis of biologically significant polysubstituted furoquinoxalines in good to excellent yields through a copper(II) catalyzed three-component coupling of o-phenylenediamine, ethylglyoxalate, and terminal alkyne, known as A(3)-coupling, followed by 5-endo-dig cyclization.

Zinc Mediated Azide–Alkyne Ligation to 1,5- and 1,4,5-Substituted 1,2,3-Triazoles

A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.

ChemInform Abstract: A Three-Component Coupling Strategy for Tetrahydrofuran Synthesis: Application of the Diisopropyl Tartrate, Modified (E)-γ-(Dimethylphenylsilyl)allylboronate as an α,γ-Allyl Dianion Equivalent.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Glycocinnasperimicin†D

The first total synthesis of amino sugar antibiotic glycocinnasperimicin D (1) has been achieved by a convergent, three-component coupling strategy. The key steps involve the Heck-Mizoroki reaction by using the iodophenyl glycoside 50 and acryl amide 32 to furnish the right core structure of 1, and the construction of the urea glycoside employing the reaction of glycosyl isocyanate 8 with amino sugar 9. Glycosyl isocyanate 8 was prepared by the oxidation of isonitrile 10, which displayed excellent reactivity in the coupling event. Synthetic roadblocks, encountered during this synthetic effort, have led to the development of the alpha-selective, Lewis acid catalyzed phenyl glycosylation process with 2-amino-hexopyranose and a procedure for acetonide deprotection without affecting the silyl ethers.

The first ionic liquid-promoted three-component coupling strategy for an expeditious synthesis of β-nitrocarbonitriles/thiocyanates

A novel and convenient three-component coupling reaction of nitromethane, aromatic aldehydes and trimethylsilyl cyanide (TMSCN) or ammonium thiocyanate has been developed for an expeditious synthesis of β-nitrocarbonitriles or β-nitrothiocyanates, respectively, via C–C and C–S bond-forming reactions. The synthetic protocol strategically involves a one-pot sequential Henry reaction and a Michael addition efficiently promoted by the same ionic liquid [bmim]OH. The main advantages of the present approach include the use of inexpensive simple substrates and an ionic liquid as an efficient reaction promoter for the mild synthesis in a one-pot procedure.

Three-Component Coupling Strategy to Benzoannulated N- or O-Heterocycles

Three-Component Coupling Strategy to Benzoannulated N- or O-Heterocycles

Green protocol for annulation of the s-triazine ring on thiazoles using a three-component coupling strategy

Novel three-component one-pot reactions of thiazole Schiff bases, ammonium acetate, and aromatic aldehydes under solvent-free microwave irradiation conditions expeditiously and diastereoselectively annulate the s-triazine ring on thiazoles to yield thiazolo-s-triazines.

Three-component coupling strategy for the expeditious synthesis of novel 4-aminobenzoxazinone N-nucleosides

One-pot montmorillonite K-10 clay-supported three-component reactions of substituted salicylaldehydes, ribosyl/deoxyribosylureas and ammonium acetate expeditiously yield the novel N-nucleosides, 4-amino-3,4-dihydro-3-(β- d-ribo- or β- d-2′-deoxyribofuranosyl)-2 H-benz[ e]-1,3-oxazin-2-ones, via cycloisomerisation of an aldimine intermediate under solvent-free microwave irradiation conditions.

A synthetic route to 11-(1 H-pyrrol-1-yl)-11 H-indeno[1,2- b]quinoxaline derivatives exploiting a three-component coupling strategy under microwave irradiation

11 H-Indeno[1,2- b]quinoxalin-11-ones generated in situ from ninhydrin and various 1,2-phenylenediamines, catalysed by montmorillonite K10 under microwave irradiation, condense with 4-hydroxyproline to produce 11-(1 H-pyrrol-1-yl)-11 H-indeno[1,2- b]quinoxaline derivatives in good yields.

Selective Lewis Acid Catalyzed Transformation (γ-Butyrolactone versus Cyclopropane) of 2-Methoxy-4-benzyltetrahydrofuran Derivatives. Efficient Synthesis of Lignan Lactones

[reaction: see text]. A short synthesis of lactone lignans exploiting a three-component coupling strategy is presented using a new Lewis acid catalyzed ring-opening/cyclization reaction of 2-methoxytetrahydrofuran derivatives 4 leading to gamma-butyrolactones as a key step. By simply changing the reaction conditions, it was possible, from the same substrates 4, to obtain selectively cyclopropane derivatives.

Three-Component Coupling Strategy for Expeditious Synthesis of 4-Aminobenzoxazinones on Mineral Support

Novel montmorillonite K-10 clay supported three-­component reactions of substituted salicylaldehydes, N-substituted ureas/carbamates and ammonium acetate or an amine expeditiously yield 3,4-dihydro-4-amino-2H-benz[e]-1,3-oxazin-2-ones via ­cycloisomerization of intermediate aldimines under solvent-free microwave irradiation in a one-pot procedure.