Multicomponent Coupling Reaction Research Articles

Employing Arynes in Diels-Alder Reactions and Transition-Metal-Free Multicomponent Coupling and Arylation Reactions.

Arynes are highly reactive intermediates having several applications in organic synthesis for the construction of various ortho-disubstituted arenes. Traditionally, arynes are generated in solution from haloarenes under strongly basic conditions. However, the scopes of many of the aryne reactions are limited because of the harsh conditions used for their generation. The renaissance of interest in aryne chemistry is mainly due to the mild conditions for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. This Account is focused on the Diels-Alder reaction of arynes and their transition-metal-free application in multicomponent couplings as well as arylation reactions. The Diels-Alder reaction of arynes is a powerful tool for constructing benzo-fused carbocycles and heterocycles. In 2012, we developed an efficient, broad-scope, and scalable Diels-Alder reaction of pentafulvenes with arynes affording benzonorbornadiene derivatives. Subsequently, we accomplished the Diels-Alder reaction of arynes with dienes such as 1,2-benzoquinones and tropones. Moreover, we uncovered a transition-metal-free protocol for the synthesis of 9,10-dihydrophenanthrenes by the reaction of arynes with styrenes that proceeds via a Diels-Alder/ene-reaction cascade. In addition, we demonstrated the reaction of arynes with indene/benzofurans, which proceeds via a tandem [4 + 2]/[2 + 2] sequence. Multicomponent coupling (MCC) involving arynes mainly comprises the initial addition of a nucleophile to the aryne followed by interception of the aryl anion intermediate with an electrophile (provided the nucleophilic and electrophilic moieties do not belong to the same molecule). We have disclosed aryne MCCs initiated by N-heterocycles such as (iso)quinoline, pyridine, and aziridines. When (iso)quinoline is used as the nucleophilic trigger and N-substituted isatin as the third component, the reaction affords spirooxazino(iso)quinolines via 1,4-dipolar intermediates. Unexpectedly, using pyridine affords indolin-2-ones, where the reaction proceeds via the pyridylidene intermediate. Additionally, we developed the phosphine-triggered aryne MCCs for the synthesis of functionalized benzooxaphospholes. In another phase of our work, we studied the synthetic utility of CO2 as a one-carbon synthon in aryne MCCs for the synthesis of phthalimides. Engaging arynes as an aryl source is one of the transition-metal-free methods for arylation reactions. We have demonstrated the N-arylation of aromatic tertiary amines and O-arylation of aliphatic alcohols using arynes. It is anticipated that the chemistry of arynes will continue to prosper and will lead to surprising developments for the synthesis of various 1,2-disubstituted arenes of molecular complexity and structural diversity. Future challenges in this area include the utility of arynes in enantioselective transformations and the synthesis and reactions of exotic heterocyclic arynes.

Copper‐Catalyzed Multicomponent Synthesis of Fluorescent 2′‐Phenyl‐1′H‐spiro[fluorene‐9,4′‐naphtho[2,3‐h]quinoline]‐7′,12′‐dione Derivatives

Copper‐catalyzed multicomponent coupling reactions between ketones, alkynes, and amines (KA2 coupling) by using 9‐fluorenones 1a–1e, aryl alkynes 2a–2g, and amino anthraquinones 3a and 3b afforded the highly conjugated, fluorescent spirofluorenonaphthoquinoline derivatives 4a–4r in very good yields. The products obtained from 1‐aminoanthraquinone (3a) and 1,4‐diaminoanthraquinone (3b) appear different in color but both series of products show emission in the red region. An analogous reaction with 1‐aminopyrene (5) afforded the highly fluorescent hybrid pyrene‐fluorenone spirocycle derivative 6, which shows emission in the deep blue region.

Metal-Free, Multicomponent Synthesis of Pyrrole-Based π-Conjugated Polymers from Imines, Acid Chlorides, and Alkynes.

Multicomponent coupling reactions (MCRs) are becoming increasingly used in the synthesis of macromolecules, as they can allow the rapid generation of libraries of materials as a method to tune properties. MCRs could prove particularly useful in the synthesis of π-conjugated polymers in which structural changes are necessary for fine-tuning of electronic properties. We describe here the first metal-free multicomponent approach to conjugated polymers. This reaction exploits the coupling of imines, acid chlorides, and (catechyl)PPh to generate phospha-münchnone-containing polymers, which can be converted to poly(pyrroles) via cycloaddition. The platform allows for the efficient synthesis of families of high molecular weight polymers in one step from readily available monomers.

Phosphine/phenylacetylide-ligated Au clusters for multicomponent coupling reactions

Metal nanocatalysts with well-defined surface structures are fundamentally important for mechanistic investigations of chemical reactions and symmetric development of catalytic systems for higher specificity and efficiency. We investigate the catalytic activity of atomically precise phosphine/phenylacetylide-ligated Au25(PPh3)10(CCPh)5X2 (X=Cl/Br) clusters in the multicomponent coupling reaction of alkynes, aldehydes, and amines. The clusters are well characterized using UV–vis spectroscopy, scanning transmission electron microscopy, and matrix-assisted laser desorption ionization mass spectrometry. The TiO2-supported cluster in polar solvents is found to be an efficient and recyclable catalyst for remarkable conversion of the substrate. The Au25(PPh3)10(CCPh)5X2/TiO2 catalyst is tested for a range of alkyne, aldehyde and ketone, and amine derivatives. Aromatic aldehydes give rise to higher conversion than aliphatic counterparts. Interestingly, ketones are found to suppress the reaction completely, in contrast with that on conventional gold nanocatalysts. The reaction mechanism is investigated via kinetic studies and UV–vis spectroscopy as well as density functional theory calculations. Results show that ligand removal under reaction conditions is the first step in exposing surface gold atoms to the reactants, thereby providing catalytic sites for the activation of CH bonds of terminal alkynes. This work demonstrates the promise of Au25(PPh3)10(CCPh)5X2 cluster in the multicomponent coupling reaction, and a combined approach of experiment and theory leads to mechanistic understanding at the atomic level.

Cobalt-Catalyzed Multicomponent Coupling Reactions with Alkynes

Cobalt-Catalyzed Multicomponent Coupling Reactions with Alkynes

Multicomponent Coupling Reaction and Intramolecular Nitrile Oxide–Alkyne Cycloaddition towards Isoxazolo[3,4]‐pyrrolizines

AbstractThis study reports an efficient four‐step method to synthesize a series of new (4S,8aS)‐3,4‐diphenyl‐6,7,8,8a‐tetrahydro‐4H‐isoxazolo[3,4‐a]pyrrolizines. The first step involves a copper(II) acetylacetonate catalyzed three component coupling of aldehyde, (S)‐pyrrolidin‐2‐ylmethanol, and alkynes (A3 coupling) to form propargylamines (4 a–4 n). The coupling reaction is applicable to various aldehydes, amines, and alkynes and provides the propargylamines in good to excellent yields with excellent distereoselectivities. Products (4 a–4 n) were converted into aldehydes (5 a–5 n) by Swern oxidation, aldehydes (5 a–5 n) were reacted with hydroxyl amine hydrochloride to form aldoxime (6 a–6 n), respectively. Further aldoximes (6 a–6 n) underwent an intramolecular 1,3‐dipolar cycloaddition to form tricyclic‐fused isoxazoles (7 a–7 n). The 1,3‐dipolar cycloaddition reaction tolerates high structural diversity and generated desired products (7 a–7 n) in moderate to good yields and excellent diastereoselectivities. A proposed mechanism for synthesis of 7 a is reported.

ChemInform Abstract: Rhodium‐Catalyzed C—C Coupling Reactions via Double C—H Activation

AbstractReview: [61 refs.

Three-Component, Diastereoselective Prins–Ritter Reaction for cis-Fused 4-Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands

Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.

Substituted quinolines as noncovalent proteasome inhibitors

Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2‐a]indoles: A Remarkable Case of Enantioinversion

AbstractA new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2‐a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3′‐unsubstituted binaphthyl catalyst as a result of transition‐state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3‐ and 3′‐positions, the first reported example of this phenomenon in the context of binaphthalene‐derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2-a]indoles: A Remarkable Case of Enantioinversion.

A new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2-a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3'-unsubstituted binaphthyl catalyst as a result of transition-state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3- and 3'-positions, the first reported example of this phenomenon in the context of binaphthalene-derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.

ChemInform Abstract: Enantioselective Reductive Multicomponent Coupling Reactions Between Isatins and Aldehydes.

AbstractA new highly stereoselective and metal‐free multicomponent coupling reaction between isatins and aldehydes with dialkyl phosphite as an economical reductant is reported.

Copper(I)-Catalysed Multicomponent Reaction: Straightforward Access to 5-Hydroxy-1H-pyrrol-2(5H)-ones

A copper-catalysed multicomponent coupling reaction between readily available (Z)-3-iodoacrylic acids, terminal alkynes, and primary amines was developed to smoothly access a small library of 5-hydroxy-1H-pyrrol-2(5H)-ones in good yields. This practical and general process was applied to a short-steps synthesis of the natural product pulchellalactam.

Multi-component Reactions Based on Formal [2+2] Reaction of Benzyne with Formamide

Arynes, such as benzyne, are highly strained and kinetically unstable intermediates that have been widely employed in organic synthesis. In particular, since the initial report regarding the in situ generation of arynes under neutral conditions from ortho-(trimethylsilyl)aryl triflates and fluoride ions in 1983, numerous nucleophilic additions to arynes have been utilized in the synthesis of carbocycles, heterocycles, and multi-substituted arenes. Recently, we reported the insertion of arynes into the π-bond in formamides, as well as related cascade reactions. First, we synthesized salicylaldehydes and aminophenols via the insertion of arynes into the C=O bond of sterically less hindered N,N-dimethylformamide (DMF). Notably, computational studies revealed the generation of unstable benzoxetene and ortho-quinone methide as reactive intermediates. We also studied multi-component coupling reactions leading to 2H-chromenes, coumarins, and xanthen-1-ones under mild conditions through the stepwise release of the strain energy in arynes. Furthermore, we studied the synthesis of O-heterocycles such as dihydrobenzofuran, benzofuran, and 4H-chromene as an application of our method. In this review, we will describe these studies in detail.

CuI/CuBr2-catalyzed decarboxylative/A3 reaction of propiolic acids for the facile synthesis of 1,4-diheterocycle-2-butynes

A novel and efficient microwave-assisted protocol to 1,4-diheterocycle-2-butynes was successfully developed. The method is based on one-pot copper-catalyzed A3 reaction/decarboxylative coupling of a propiolic acid, a formaldehyde, and a 1,2- or 1,3-amino alcohol. This multicomponent coupling reaction provides a straight forward access to introduction oxazolidine or 1,3-oxazinane at the 1,4-position of a but-2-yne from readily available starting materials. 1,4-Diheterocycle-2-butynes with diverse substitution patterns are obtained in moderate to good yields.

ChemInform Abstract: Aza‐Nickelacycle Key Intermediate in Nickel(0)‐Catalyzed Transformation Reactions

AbstractReview: 92 refs.

ChemInform Abstract: Nickel Catalysis: Synergy Between Method Development and Total Synthesis

AbstractReview: 51 refs.

ChemInform Abstract: Metal‐Free Multicomponent Coupling Reaction of Aliphatic Amines, Formaldehyde, Organoboronic Acids, and Propiolic Acids for the Synthesis of Diverse Propargylamines.

Abstract A metal-free multicomponent coupling reaction of aliphatic amines, formaldehyde, organoboronic acids, and propiolic acids has been reported for the synthesis of diverse propargylamines. This transformation involves a MCR2 of PBM and decarboxylative three-component coupling reactions.

ChemInform Abstract: Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Catalytic Platform in the Development of Multicomponent Coupling Reactions.

A titanocene-catalyzed multicomponent coupling is described herein. Using catalytic titanocene, phosphine, and zinc dust, zinc acetylides can be generated from the corresponding iodoalkynes to affect sequential nucleophilic additions to aromatic aldehydes. The intermediate propargylic alkoxides are trapped in situ with acetic anhydride, which are susceptible to a second nucleophilic displacement upon treatment with a variety of electron-rich species, including acetylides, allyl silanes, electron-rich aromatics, silyl enol ethers, and silyl ketene acetals. Additionally, employing cyclopropane carboxaldehydes led to ring-opened products resulting from iodine incorporation. Taken together, these results form the basis for a new mode of three-component coupling reactions, which allows for rapid access to value added products in a single synthetic operation.

ChemInform Abstract: Acid‐Mediated Synthesis of Fully Substituted 1,2,3‐Triazoles: Multicomponent Coupling Reactions, Mechanistic Study, Synthesis of Serine Hydrolase Inhibitor and Its Derivatives.

AbstractSome results indicate that the reaction proceeds through methylenetriazolium intermediates.