Intermediates In Synthetic Organic Chemistry Research Articles

5-(1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Multicomponent reactions have been demonstrated as a promising tool for the creation of diverse molecular structures with enhanced efficiency, reduced waste, and a high atom economy. Arylglyoxal monohydrates with two different carbonyl groups are well known as worthwhile synthons in organic synthesis. 2-Pyrone and pyrimidine-2,4,6-trione are versatile building blocks for the synthesis of key intermediates in synthetic organic chemistry as well as in medicinal chemistry. A simple and efficient tandem Knoevenagel–Michael protocol for the synthesis of the previously unknown 5-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimet-hylpyrimidine-2,4,6(1H,3H,5H)-trione was elaborated. The suggested method is based on the multicomponent reaction of phenylglyoxal hydrate, 1,3-dimethylbarbituric acid, and 4-hydroxy-6-methyl-2H-pyran-2-one. The structure of the synthesized compound was proven by 1H, 13C-NMR, and IR spectroscopy, mass spectrometry, and elemental analysis. A procedure for predicting the possible types of its biological activity was carried out for the title compound.

The chemistry of 2-hydroxy-β-nitrostyrenes: versatile intermediates in synthetic organic chemistry.

The applications of 2-hydroxy-β-nitrostyrenes as efficient bifunctional intermediates in organic synthesis are investigated in this review. For this purpose, reactions of 2-hydroxy-β-nitrostyrenes with diverse molecules, including carbonyl compounds, 1,3-dicarbonyl compounds, α,β-unsaturated carbonyl compounds, hemiacetals, nitroalkenes, γ-butenolides, tetronic acid, azalactones, pyrazolones, enamines, malononitrile, methyleneindolinones, ylides, etc., were investigated to construct interesting biologically active scaffolds such as chromans, chromenes, coumarins, benzofurans and their fused and spiro rings, natural products, and other useful cyclic and acyclic compounds. The main focus is on the asymmetric synthesis of these compounds via cascade/domino/tandem reactions catalyzed by chiral organocatalysts. In this review, around 60 papers reported between the years 2000 and 2022 are presented.

Catalytic Enantioselective Dihalogenation of Alkenes

AbstractVicinal dihalides not only emerge as reactive intermediates in synthetic organic chemistry, but also are extensively existing in bioactive marine natural products. The dihalogenation of alkenes is the most direct and effective method for the synthesis of vicinal dihalides. Because there is always an exchange process between the chiral haloniums and the unreacted olefins to cause racemization, the development of catalytic enantioselective dihalogenation of alkenes is of great difficulty. Recently, great progress has been made in catalytic asymmetric manner. However, there is a lack of related review of discussions of the mechanisms and reaction systems. This review is aimed at summarizing enantioselective dihalogenation of alkenes, including 1,2-dichlorination, 1,2-dibromination, and 1,2-difluorination, which is expected to encourage more researchers to participate in this field.1 Introduction2 Enantioselective 1,2-Dichlorination and 1,2-Dibromination of Alkenes2.1 Chiral-Boron-Complex-Promoted Enantioselective 1,2-Dichlorination2.2 Organocatalytic Asymmetric 1,2-Dichlorination and 1,2-Dibromination2.3 Chiral-Titanium-Complex-Catalyzed 1,2-Dihalogenation3 Chiral-Iodide-Catalyzed Enantioselective Oxidative 1,2-Difluorination4 Summary and Outlook

Recent advances in catalysts for the Henry reaction

The Henry reaction, the coupling of a nitro alkane and a carbonyl group, is an important C–C bond-forming reaction giving nitro alkanols, which are useful, versatile intermediates in synthetic organic chemistry and for the pharmaceutical industry. Among the catalysts employed in the Henry reaction, transition metal complex catalysts play an important role. Transition metal complexes, including small molecules and nanoparticles, catalyze the asymmetric Henry reaction efficiently and in most of the cases give chiral nitro alkanol products in good yield and enantiomeric excess. This review summarizes transition metal complex catalysts, metal-free organic catalysts and nanoparticle catalysts for the Henry reaction.

Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Chlorobenzenesulfonates.

Aryl sulfonate esters are versatile synthetic intermediates in organic chemistry as well as attractive architectures due to their bioactive properties. Herein, we report the synthesis of alkyl-substituted benzenesulfonate esters by iron-catalyzed C(sp2)–C(sp3) cross-coupling of Grignard reagents with aryl chlorides. The method operates using an environmentally benign and sustainable iron catalytic system, employing benign urea ligands. A broad range of chlorobenzenesulfonates as well as challenging alkyl organometallics containing β-hydrogens are compatible with these conditions, affording alkylated products in high to excellent yields. The study reveals that aryl sulfonate esters are the most reactive activating groups for iron-catalyzed alkylative C(sp2)–C(sp3) cross-coupling of aryl chlorides with Grignard reagents.

Vicinal halo-trifluoromethylation of alkenes.

Both trifluoromethyl and halide groups are widely found in medicinally and pharmaceutically important compounds and, moreover, organohalides are commonly used as versatile intermediates in synthetic organic chemistry. Due to their prevalence and easy accessibility, alkene halo-trifluoromethylation provides a convenient way to install these valuable functionalities in complex targets. In this review, we summarize recent advances and achievements in this fast-growing research field. For clarity, the reactions were classified according to the type of halogen atom.

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization.

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

Maltol- and Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions.

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

ONE POT MULTICOMPONENT SYNTHESIS OF HIGHLY FUNCTIONALIZED PYRIDINES USING MORPHOLINE ORGANOBASE CATALYST

An atom efficient synthesis of polysubstituted dihydropyridine derivatives was accomplished by the one-pot four-component condensation of aldehydes, amines, dialkyl acetylene dicarboxylates and active methylene group-containing compounds such as malononitrile or ethyl cyanoacetate using morpholine as a catalyst at ambient temperature. Broad substrate scope, non-chromatographic purification, good yields of the products makes it be a useful and valuable methodology for employing the 1,4-dipolar intermediates in synthetic organic chemistry. Use of organobase as a single catalyst, room temperature conditions renders the method protocol as a significant addition to the existing methods for the synthesis of multifunctionalized dihydropyridines.

Gold Vinylidenes as Useful Intermediates in Synthetic Organic Chemistry

Gold vinylidenes have recently emerged as useful intermediates in synthetic organic chemistry. These species, which can principally be accessed by a 1,2-migration process from a gold-activated alkyne or by dual gold catalysis on a diyne substrate, can react with nucleophilic partners or by C–H insertion to produce a variety of functionalized (poly)cyclic compounds. This short review covers the synthetic approaches developed so far to access gold vinylidenes and the different reactivities these species can exhibit.1 Introduction2 1,2-Migration Processes3 Dual Gold Catalysis4 Other Processes5 Conclusion

Iodine-catalyzed diazo activation to access radical reactivity

Transition-metal-catalyzed diazo activation is a classical way to generate metal carbene, which are valuable intermediates in synthetic organic chemistry. An alternative iodine-catalyzed diazo activation is disclosed herein under either photo-initiated or thermal-initiated conditions, which represents an approach to enable carbene radical reactivity. This metal-free diazo activation strategy were successfully applied into olefin cyclopropanation and epoxidation, and applying this method to pyrrole synthesis under thermal-initiated conditions further demonstrates the unique reactivity using this method over typical metal-catalyzed conditions.

Recent Advances in the Synthesis of Aryl Nitrile Compounds

AbstractAryl nitriles are widely found in natural products, pharmaceuticals, agrochemicals, dyes, and herbicides. Moreover, because the cyano group can be easily converted into various functional groups, aryl nitriles are important intermediates in synthetic organic chemistry. Consequently, the development of new methodologies for the synthesis of aryl nitriles is of significant interest. The traditional methods for their synthesis include Sandmeyer reactions, Rosenmund–von Braun reactions, as well as dehydration reactions of aldoximes and amides. In recent years, numerous efforts have been devoted to transition metal‐catalyzed cyanation reactions of aryl (pseudo)halides, organometallic reagents and aryl C–H bonds. A number of cyanating reagents have been explored for such transformations, including metal cyanides and organic cyano group sources. In addition, styrenes and aryl‐substituted alkynes are successfully converted into aryl nitriles through carbon‐carbon double or triple bond cleavage. Various benzylic compounds have also been used for the synthesis of aryl nitriles, such as benzylic halides, alcohols, amines and azides. Furthermore, the direct conversion of the methyl group of toluene derivatives into a cyano group has also drawn attention. In this critical review, we summarize the recent developments and useful applications in this field and reaction mechanisms are also briefly discussed.magnified image

Copper(I)-Catalyzed Regio- and Stereoselective Intramolecular Alkylboration of Propargyl Ethers and Amines.

The copper(I)-catalyzed regio- and stereoselective intramolecular alkylation of propargyl ethers and amines bearing an alkyl electrophilic moiety has been developed. The reaction showed high functional group tolerance and gave highly functionalized alkenylboronates bearing heterocyclic rings, which are versatile synthetic intermediates in organic chemistry. The borylation products can be transformed into multisubstituted alkenes through stereospecific transformations. Mechanistic studies showed that the chemo- and stereoselectivity of copper(I)-catalyzed borylation depends on the type of leaving group. Density functional theory calculations suggested that the regioselectivity of the borylcupration of the alkyne is controlled by the electronic effect of the oxygen atom of the propargyl ether in combination with the steric congestion between the boryl group and the substituent at the propargylic position.

Chiral Alkyl Halides: Underexplored Motifs in Medicine.

While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.

NbCl5 as an Expeditious Catalyst for the Synthesis of Quinoxalinyl and Dibenzodioxepinyl Phosphonates/Phosphinates via Michaelis-Arbuzov Reaction and their Biological Evaluation

Background: Michaelis-Arbuzov reaction is one of the well studied reaction in phosphorus chemistry and used for the synthesis of phosphonates, phosphinates and phosphine oxides. Phosphonates are not only versatile intermediates in synthetic organic chemistry but also plays a vital role in biological activity. The usage of niobium(V) chloride as a catalyst has attracted the considerable attention due to its low hygroscopic character, high stability, cost effective, low loading and ease of handling. Methods: The present study describes the synthesis of a series of various aryl/heterocyclic substituted phosphonates/ phosphinates of 2-chloroquinoxaline 3(a-e) and 6-iododibenzo[d,f][1,3]dioxepine 5(a-e) using an expeditious catalyst, niobium(V) chloride by Michaelis-Arbuzov reaction and evaluated their antimicrobial and antioxidant activities. Results: A simple, efficient and new synthetic protocol was developed for the synthesis of quinoxalinyl and dibenzodioxepinyl phosphonate/phosphinate derivatives (3a-e/5a-e) in good yields using niobium(V) chloride as a catalyst. Biological data revealed that compound 5c exhibited potent antimicrobial activity and the compounds 3e and 5e good antioxidant activity. Conclusion: From the results it was concluded that niobium(V) chloride was an efficient catalyst for the synthesis of quinoxalinyl and dibenzodioxepinyl phosphonate/phosphinate derivatives and also exhibited good antimicrobial and antioxidant activities. Keywords: 2-chloroquinoxaline, 6-iododibenzo[d, f][1, 3]dioxepine, antimicrobial activity, antioxidant activity, aryl/heterocylic phosphonates, Michaelis-Arbuzov reaction, niobium(V) chloride catalyst.

Iodine-mediated synthesis of heterocycles via electrophilic cyclization of alkynes

Iodine has been recognized as an efficient, non-toxic, readily available and easy-to-handle electrophilic reagent to favour halocyclization reactions for the synthesis of novel iodofunctionalized heterocyclic molecules that serve as versatile intermediates in synthetic organic chemistry. This review presents numerous useful methodologies for the synthesis of O, N, S, and Se-heterocycles through electrophilic cyclization via the attack of an electrophile on the C(sp) bond of alkynes. The cyclization proceeds under mild reaction conditions and tolerates a wide variety of functional groups.

ChemInform Abstract: Metal‐Catalyzed Carbonylation of Alkynes: Key Aspects and Recent Development

AbstractReview: 198 refs.

Effective Nitration of Anilides and Acrylamides by tert‐Butyl Nitrite

AbstractNitro compounds are important intermediates in synthetic organic chemistry and the chemical industry. Herein, the efficient copper‐catalyzed [10 % Cu(NO3)2·3H2O] nitration of anilides was developed by using TBN (tert‐butyl nitrite) as a nitrating reagent to give the corresponding nitro‐substituted aromatic products in good to excellent yields. The use of TBN also led to the selective nitration of acrylamides at room temperature to afford only the (E) isomer of the nitration product. A series of anilides and acrylamides with a broad array of functional groups were well‐tolerated by this procedure. This synthetic method has many advantages, which include inexpensive starting materials, mild reaction conditions, a fast reaction rate, and high yields. A mechanistic investigation indicates that a nitro radical, which is generated from the thermal homolysis of TBN, is involved in the two nitration processes.

Recent Advances in Catalytic Functionalization of N‐Oxide Compounds via CH Bond Activation

AbstractN‐Oxide compounds are very important intermediates in synthetic organic chemistry as well as in the chemical industry. Numerous efforts have been devoted to the development of efficient approaches for the CH bond activation and functionalization of N‐oxides in recent years, including arylation, alkenylation, alkylation, acyloxylation, amination, amidation and sulfonylation. In this review, recent advances in this area are summarized and their mechanisms are discussed.magnified image

Reaction between (Z)-arylchlorooximes and α-isocyanoacetamides: a procedure for the synthesis of aryl-α-ketoamide amides.

(Z)-Arylchlorooximes and α-isocyanoacetamides undergo a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in good yields. Opening of the oxazole ring and deoximation reaction give a facile access to aryl-α-ketoamide amides, a class of privileged scaffolds in medicinal chemistry and important synthetic intermediates in organic chemistry.