Palladium-catalyzed Sonogashira Reaction Research Articles

Machine learning directed multi-objective optimization of mixed variable chemical systems

The consideration of discrete variables (e.g. catalyst, ligand, solvent) in experimental self-optimization approaches remains a significant challenge. Herein we report the application of a new mixed variable multi-objective optimization (MVMOO) algorithm for the self-optimization of chemical reactions. Coupling of the MVMOO algorithm with an automated continuous flow platform enabled identification of the trade-off curves for different performance criteria by optimizing the continuous and discrete variables concurrently. This approach utilizes a Bayesian methodology to provide high optimization efficiency, enhances process understanding by considering key interactions between the mixed variables, and requires no prior knowledge of the reaction. Nucleophilic aromatic substitution (SNAr) and palladium catalyzed Sonogashira reactions were investigated, where the effect of solvent and ligand selection on the regioselectivity and process efficiency were determined respectively whilst simultaneously determining the optimum continuous parameters in each case.

Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu

An efficient method is developed for the synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines via palladium-catalyzed Sonogashira reactions of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine with electron-poor aryl iodides in acetonitrile at room temperature. Excellent yields of the products were obtained in reaction times of 9–11 h.

An Efficient Synthesis of 5-Aminopropargyl-Pyrimidine-5'-O-Triphosphates Through Palladium-Catalyzed Sonogashira Coupling.

The utilization of 5-aminopropargyl nucleotide serves as a versatile molecular biology tool for the introduction of functional groups into a nucleic acid target of interest by using in-vitro enzymatic incorporation method. This article describes a simple, reliable, general, and efficient two-step chemical method for the synthesis of 5-(3-aminopropargyl)-2'-deoxycytidine-5'-O-triphosphate, 5-(3-aminopropargyl)-cytidine-5'-O-triphosphate, 5-(3-aminopropargyl)-2'-deoxyuridine-5'-O-triphosphate, and 5-(3-aminopropargyl)-uridine-5'-O-triphosphate, starting from the corresponding pyrimidine triphosphate. The first step involves regioselective C-5 iodination of pyrimidine triphosphate using N-iodosuccinimide and sodium azide. In the second step, propargylamine is coupled to the iodo-pyrimidine using the palladium-catalyzed Sonogashira reaction, producing good yields of highly pure (>99.5% HPLC) 5-aminopropargyl-pyrimidine-5'-O-triphosphate. In this approach, the palladium-catalyzed Sonogashira coupling reaction is highly chemoselective and does not involve protection and deprotection. © 2019 by John Wiley & Sons, Inc.

Post-cationic Modification of a Pyrimidine-Based Conjugated Microporous Polymer for Enhancing the Removal Performance of Anionic Dyes in Water.

Ionic porous organic polymers have attracted much attention due to their broad applications in catalysis, energy storage/conversion, proton conduction, etc. In this paper, an ionic porous organic polymer, CMP-PM-Me, was synthesized through post-synthetic modification of a pyrimidine-based conjugated microporous polymer, CMP-PM, which was constructed by the palladium catalyzed Sonogashira reaction of 1,3,5-triethynylbenzen and 2,5-dibromopyrimidine. These two polymers are porous with Brunauer-Emmett-Teller surface areas of 416 and 241 m2 g-1 for CMP-PM and CMP-PM-Me, respectively. Due to the cationic framework, CMP-PM-Me exhibits a much faster and more efficient adsorption performance to anionic dyes such as Congo red (CR) and methyl orange (MO) than that of CMP-PM with a neutral framework. The uptakes for CR are 400.0 mg g-1 for CMP-PM-Me and 344.8 mg g-1 for CMP-PM, respectively. Furthermore, CMP-PM-Me could quickly and drastically separate anionic dyes from the binary mixed solution of anionic and nonanionic dyes within a short time. This work not only enriches the family of ionic organic porous polymers and widens their synthetic utility, but also demonstrates their applications in the adsorption and separation of anionic dyes in water.

ChemInform Abstract: Efficient Synthesis of 2‐Phenyl‐3‐substituted Furo/thieno[2,3‐b]quinoxalines via Sonogashira Coupling Reaction Followed by Iodocyclization and Subsequent Palladium‐Catalyzed Cross‐coupling Reactions.

In this paper, we report the successful synthesis of new 2-phenyl-3-substituted furo/thieno[2,3-b]quinoxaline derivatives from 2-chloro-3-methoxyquinoxaline and 2-chloro-3-(methylthio)quinoxaline by a three-step approach. The Sonogashira coupling reaction of the title compounds with terminal alkynes afforded 2-methoxy-3-(phenylethynyl)quinoxaline and 2-(methylthio)-3-(phenylethynyl)quinoxaline in good to excellent yields. The iodocyclization of the resulting compounds using ICl in CH2Cl2 afforded 3-iodo-2-phenylfuro[2,3-b]quinoxaline and 3-iodo-2-phenylthieno[2,3-b]quinoxaline. The subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodo compounds led to the formation of 2,3-disubstituded furo/thieno[2,3-b]quinoxaline in high yields. All compounds were fully characterized by FT-IR, mass, 1H NMR, and 13C NMR spectral data. The synthesized quinoxaline derivatives were also screened against the two bacterial strains Escherichia coli and Micrococcus luteus.

ChemInform Abstract: CuI Assisted Desulfurative Sonogashira Reaction of Mercapto N‐Heterocyclic Derivatives with Alkynes.

A palladium catalyzed Sonogashira reaction of mercapto N-heterocyclic derivatives with terminal alkynes by using CuI as the desulfurative reagent was described in this report. It provided an effective strategy for obtaining sp–sp2 cross-coupling products in good yields. The reaction mechanism was also investigated by density functional theory (DFT) calculation.

CuI assisted desulfurative Sonogashira reaction of mercapto N-heterocyclic derivatives with alkynes

A palladium catalyzed Sonogashira reaction of mercapto N-heterocyclic derivatives with terminal alkynes by using CuI as the desulfurative reagent was described in this report.

Synthesis of functionalized alkynes via palladium-catalyzed Sonogashira reactions

A highly efficient protocol for the copper and phosphine free Sonogashira cross-coupling reactions of aryl iodides with terminal alkynes under aerobic conditions has been developed. Using 1mol% of the palladium-bis(oxazoline) complex, Pd-BOX A, in the presence of KOH, and a CH3CN–H2O solvent system allowed for the cross-coupling reactions to proceed at room temperature or 60°C. This new catalytic system was found to be highly active for the cross-coupling reaction of aryl diiodo substrates with unactivated alkyl alkynes to produce various symmetrical dialkynes, as well as for the cross-coupling of terminal dialkynes with aryl iodides to generate symmetrical disubstituted internal alkynes.

Synthesis of the ortho/meta/para Isomers of Relevant Pharmaceutical Compounds by Coupling a Sonogashira Reaction with a Regioselective Hydration

Aryl ketones substituted in ortho, meta, and para position are prepared by a palladium-catalyzed Sonogashira reaction followed by a regioselective hydration of the so-formed alkyne with triflimidic acid or a gold catalyst, under catalytic conditions. This methodology opens a way to obtain substituted aryl alkyl ketones from readily available starting materials, haloarenes, and terminal alkynes. The syntheses of the different regioisomers of haloperidol, melperone, pipamperone, and ibuprofen are presented. Structure–activity relationships for these compounds are studied with dopaminergic and cyclooxigenase binding assays.

N-heterocyclic carbenes: VII. Abietane-based adamantylimidazolium salts

Adamantyl-substituted imidazolium salts were synthesized on the basis of abietane derivatives. The products were tested as N-heterocyclic carbene ligands in the palladium-catalyzed Sonogashira reaction.

Facile synthesis of 2-iodo-spiro[indene-1,1′-isobenzofuran]-3′-ones via iodine-promoted cascade cyclization

A novel and efficient synthetic approach to substituted 2-iodo-spiro[indene-1,1'-isobenzofuran]-3'-ones has been developed via an iodine-promoted cascade cyclization of 2-(3-hydroxy-3,3-diarylprop-1-yn-1-yl)benzoates. This sequential cascade process is concisely conducted at room temperature. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodides proceed smoothly in good yields.

Copper and amine free Sonogashira cross-coupling reaction catalyzed by efficient diphosphane–palladium catalyst

Abstract The commercially available diphosphane ligand MeO-BIPHEP was first investigated in the palladium-catalyzed Sonogashira reaction in the absence of copper and amine. The coupling of various aryl bromides and aryl chlorides with phenylacetylene gave moderate to excellent yields.

Unexpected formation of ( Z)-3-(halomethylene)isoindolinones from gem-dihalovinylbenzonitriles: efficient synthesis of enyne-containing isoindolinones

An efficient one-pot procedure for the regioselective synthesis of ( Z)-3-(halomethylene)-isoindolin-1-ones was developed from easily accessible 2-(2,2-dihalovinyl)benzonitriles. From this key intermediate, a variety of isoindolinones containing an enyne moiety were synthesized in good to excellent yields via palladium-catalyzed Sonogashira reaction. The generated enyne-containing isoindolinones could be further manipulated by iodide induced cyclization reaction to afford a versatile synthetic intermediate 5 H-pyrrolo[2,1- a]isoindolol-5-one in high yield and could be further elaborated.

Palladium-catalyzed Sonogashira reactions of aryl amines with alkynes via in situ formation of arenediazonium salts

A general and convenient palladium-catalyzed Sonogashira reaction of in situ generated arenediazonium salts has been developed and various internal arylalkynes are produced in good yields under mild conditions.

Efficient Synthesis of Biologically Interesting 3,4‐Diaryl‐Substituted Succinimides and Maleimides: Application of Iron‐Catalyzed Carbonylations

A straightforward two-step synthesis of trans-3,4-disubstituted succinimides through a palladium-catalyzed Sonogashira reaction and an iron-catalyzed double carbonylation is described. In situ oxidative dehydrogenation gave the corresponding 3,4-diarylmaleimides. By starting from readily available aryl and heteroaryl halides, a variety of new analogues and derivatives of bioactive 3,4-bisindolylmaleimides are obtained in good yield and selectivity.

ChemInform Abstract: Transition Metal-Catalyzed Syntheses of “Rod-Like” Thioglycoside Dimers.

Abstract Using copper(I)-catalyzed Glaser reaction and palladium-catalyzed Sonogashira reaction, divalent ‘rod-like’ thiomanno-, gluco, galacto, and lactoside clusters were prepared in high yields.

One-Pot Synthesis of Diarylalkynes Using Palladium-Catalyzed Sonogashira Reaction and Decarboxylative Coupling of sp Carbon and sp2 Carbon

Decarboxylative coupling of sp-sp2 carbons is possible by palladium catalyst. Employing propiolic acid (1) as a difunctional alkyne, and using the consecutive reactions of the Sonogashira reaction and the decarboxylative coupling, unsymmetrically substituted diaryl alkynes were obtained in moderate to good yield.

Regio- and stereo-specific preparation of ( E)-1-aryl-3,3,3-trifluoro-1-iodo-propenes and their palladium-catalyzed reaction with terminal alkynes

A new type of iodo-containing trifluoromethylated building blocks were synthesized. The reaction of 1-aryl-3,3,3-trifluoropropynes 1 with lithium iodide in acetic acid at 75 °C gave ( E)-1-aryl-3,3,3-trifluoro-1-iodo-propenes 2 in high yield, which undergo the palladium-catalyzed Sonogashira reaction with terminal alkynes afforded trifluoromethyl-containing 1,3-enynes in high yield.

Palladium-Catalyzed Copper-Free Sonogashira Coupling Reaction in Water and Acetone

An efficient palladium-catalyzed copper-free Sono­gashira reaction in water and acetone has been developed under mild conditions. The results showed that the aryl iodides could carry out the cross-coupling reaction with a variety of terminal alkynes in high yields in water-acetone in the absence of amine, copper(I) salts, or phosphine ligands at 60 °C for one hour, and good yields were obtained for aryl bromides at 60 °C for 12-24 hours in the presence of triphenylphosphine and piperidine. The method could be used to synthesize polyethynyl aromatic compounds in a one-pot reaction.

Mechanism of the Copper‐Free Palladium‐Catalyzed Sonagashira Reactions: Multiple Role of Amines

Amines used as bases in copper-free, palladium-catalyzed Sonogashira reactions play a multiple role. The oxidative addition of iodobenzene with [Pd(0)(PPh(3))(4)] is faster when performed in the presence of amines (piperidine>morpholine). Amines also substitute one ligand L in trans-[PdI(Ph)(L)(2)] (L=PPh(3), AsPh(3)) formed in the oxidative addition. This reversible reaction, which gives [PdI(Ph)L(R(2)NH)], is favored in the order AsPh(3)>PPh(3) and piperidine>morpholine. Two mechanisms are proposed for Sonogashira reactions, depending on the ligand and the amine. When L=PPh(3), its substitution by the amine in trans-[PdI(Ph)(PPh(3))(2)] is less favored than that of the alkyne. A mechanism involving prior coordination of the alkyne is suggested, followed by deprotonation of the ligated alkyne by the amine. When L=AsPh(3), its substitution in trans-[PdI(Ph)(AsPh(3))(2)] by the piperidine is easier than that by the alkyne, leading to a different mechanism: substitution of AsPh(3) by the amine is followed by substitution of the second AsPh(3) by the alkyne to generate [PdI(Ph)(amine)(alkyne)]. Deprotonation of the ligated alkyne by an external amine leads to the coupling product. This explains why the catalytic reactions are less efficient with AsPh(3) than with PPh(3) as ligand.