Organics

Open AccessArticle

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

by

Mar Ríos-Gutiérrez

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Assem Barakat

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Luis R. Domingo

Organics 2022, 3(2), 122-136; https://doi.org/10.3390/org3020010 - 06 Jun 2022

Abstract

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY), derived from isatin and L-proline, with phenyl vinyl sulphone has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. ELF topological analysis of AY classifies it as a pseudo(mono)radical [...] Read more.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY), derived from isatin and L-proline, with phenyl vinyl sulphone has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. ELF topological analysis of AY classifies it as a pseudo(mono)radical species with two monosynaptic basins at the C1 carbon, integrating a total of 0.76 e. While vinyl sulphone has a strong electrophilic character, AY is a supernucleophile, suggesting a high polar character and low activation energy for the reaction. The nucleophilic Parr functions indicate that the pseudoradical C1 carbon is the most nucleophilic center. The 32CA reaction presents an activation Gibbs free energy of 13.1 kcal·mol⁻¹ and is exergonic by −26.8 kcal·mol⁻¹. This reaction presents high endo stereoselectivity and high meta regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable meta/endo TS, 0.31 e, accounts for the high polar character of this 32CA reaction, classified by forward electron density flux (FEDF). A Bonding Evolution Theory (BET) study along the most favorable meta/endo reaction path characterizes this 32CA reaction, taking place through a non-concerted two-stage one-step mechanism, as a pseudo(mono)radical-type 32CA reaction, in agreement with the ELF analysis of the AY. Full article

(This article belongs to the Special Issue Chemistry of Heterocycles)

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Open AccessArticle

Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates

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Rowan I. L. Meador

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Nilamber A. Mate

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John D. Chisholm

Organics 2022, 3(2), 111-121; https://doi.org/10.3390/org3020009 - 24 May 2022

Abstract

N-Alkyl pyrazoles are important heterocycles in organic and medicinal chemistry, demonstrating a wide range of biological activity. A new method for the N-alkylation of pyrazoles has been developed using trichloroacetimidate electrophiles and a Brønsted acid catalyst. These reactions provide ready access [...] Read more.

N-Alkyl pyrazoles are important heterocycles in organic and medicinal chemistry, demonstrating a wide range of biological activity. A new method for the N-alkylation of pyrazoles has been developed using trichloroacetimidate electrophiles and a Brønsted acid catalyst. These reactions provide ready access to N-alkyl pyrazoles which are present in a variety of medicinally relevant lead structures. Benzylic, phenethyl and benzhydryl trichloroacetimidates provide good yields of the N-alkyl pyrazole products. Unsymmetrical pyrazoles provide a mixture of the two possible regioisomers, with the major product being controlled by sterics. This methodology provides an alternative to other alkylation methods that require strong base or high temperature. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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Open AccessReview

Diels–Alder Polar Reactions of Azaheterocycles: A Theoretical and Experimental Study

by

Carla M. Ormachea

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María Nélida Kneeteman

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Pedro M. E. Mancini

Organics 2022, 3(2), 102-110; https://doi.org/10.3390/org3020008 - 22 May 2022

Abstract

A number of azaheterocycles (pyridines, pyrroles and indoles) have been properly functionalized so that they can act as dienophiles in cycloaddition Diels–Alder processes. This work analyzed the reactive behavior of these molecules through mechanistic analysis and the regioselectivity of the process using computational [...] Read more.

A number of azaheterocycles (pyridines, pyrroles and indoles) have been properly functionalized so that they can act as dienophiles in cycloaddition Diels–Alder processes. This work analyzed the reactive behavior of these molecules through mechanistic analysis and the regioselectivity of the process using computational calculation tools. Based on this knowledge, a study was conducted on the influences of reaction variables, in particular solvent, catalyst and microwave irradiation, to achieve favorable changes—shorter reaction times, more acceptable temperatures and better yields. Theoretical calculations allowed the development of predictive approaches, which were later experimentally corroborated. This analysis allowed us to make reasonable assumptions related to reaction mechanisms, which allowed—through the analysis of corresponding transition states—us to consider such reactions at the boundary between pericyclic and polar processes. Full article

(This article belongs to the Special Issue Chemistry of Heterocycles)

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Open AccessArticle

A Theoretical Study on the Photochemical Isomerization of 2,6-Dimethylpyrazine

by

Maurizio D’Auria

Organics 2022, 3(2), 95-101; https://doi.org/10.3390/org3020007 - 12 May 2022

Abstract

DFT calculations on the photoisomerization of 2,6-dimethylpyrazine allowed us to confirm the role of benzvalene isomers in the isomerization of hexatomic heterocyclic compounds. 2,6-Dimethylpyrazine in the excited singlet states can be converted into the corresponding Dewar isomers. If the S₂ state is [...] Read more.

DFT calculations on the photoisomerization of 2,6-dimethylpyrazine allowed us to confirm the role of benzvalene isomers in the isomerization of hexatomic heterocyclic compounds. 2,6-Dimethylpyrazine in the excited singlet states can be converted into the corresponding Dewar isomers. If the S₂ state is populated, two Dewar isomers can be obtained, while the S₁ state allows the formation of only one of the possible Dewar isomers. Both Dewar isomers can be converted into the benzvalene isomer, that is, the precursor of 4,5-dimethylpyrimidine, the reaction product. In fact, the benzvalene isomer can be obtained from the Dewar isomers in processes that occur without an activation energy, and it is the more stable benzvalene isomers that can be obtained from the Dewar isomers. CASSCF study indicates the presence of a conical intersection allowing the direct formation of the benzvalene isomer. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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Open AccessArticle

Stabilized Arylzinc Iodides in Negishi Acylative Cross-Coupling: A Modular Synthesis of Chalcones

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Organics 2022, 3(2), 87-94; https://doi.org/10.3390/org3020006 - 23 Apr 2022

Abstract

Stabilized arylzinc iodides, synthesized by direct insertion of zinc into the corresponding halides, were used as nucleophiles into an acylative Negishi coupling reaction to synthesize chalcones. The reaction conditions were optimized to afford optimal results on a model reaction and then applied to [...] Read more.

Stabilized arylzinc iodides, synthesized by direct insertion of zinc into the corresponding halides, were used as nucleophiles into an acylative Negishi coupling reaction to synthesize chalcones. The reaction conditions were optimized to afford optimal results on a model reaction and then applied to synthesize nine compounds. Esters, chlorides, electron-rich, electron-poor and sterically hindered substrates are well tolerated and even heteroaryl derivatives can be synthesized. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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Open AccessArticle

β-Cyclodextrin Supramolecular Recognition of bis-Cationic Dithienylethenes

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Organics 2022, 3(2), 77-86; https://doi.org/10.3390/org3020005 - 06 Apr 2022

Abstract

The supramolecular interactions in water between β-cyclodextrin and the open and closed photochromic forms of two bis-cationic dithienylethenes, characterized by different electronic properties, were investigated aiming at underlying the key aspects of the recognition process. The dithienylethene equipped with the cyclopentenyl [...] Read more.

The supramolecular interactions in water between β-cyclodextrin and the open and closed photochromic forms of two bis-cationic dithienylethenes, characterized by different electronic properties, were investigated aiming at underlying the key aspects of the recognition process. The dithienylethene equipped with the cyclopentenyl unit showed a difference in binding free energies to the β-cyclodextrin between the open and closed photochromic forms of about 1 kJ/mol. Conversely, the dithienylethene equipped with the perfluorinated cyclopentenyl unit not only was a better guest but showed a three times higher difference in the binding of free energies between the open and closed isomers. Full article

(This article belongs to the Special Issue Supramolecular Organic Chemistry)

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Open AccessArticle

On the Mechanism of the Synthesis of Nitrofunctionalised Δ²-Pyrazolines via [3+2] Cycloaddition Reactions between α-EWG-Activated Nitroethenes and Nitrylimine TAC Systems

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Agnieszka �?apczuk-Krygier

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Radomir Jasiński

Organics 2022, 3(1), 59-76; https://doi.org/10.3390/org3010004 - 01 Mar 2022

Cited by 1

Abstract

We investigated the reactivity of different substituted nitrylimine-type three atom components (TACs) in [3+2] cycloaddition (32CAs) reactions with electrophilically activated nitroethenes within molecular electron density theory (MEDT). In parallel research, the molecular mechanism of the considered transformation was examined through analysis of all [...] Read more.

We investigated the reactivity of different substituted nitrylimine-type three atom components (TACs) in [3+2] cycloaddition (32CAs) reactions with electrophilically activated nitroethenes within molecular electron density theory (MEDT). In parallel research, the molecular mechanism of the considered transformation was examined through analysis of all possible reaction channels and full optimization of all critical structures. In particular, the existence of zwitterionic intermediates on reaction paths was verified. On the basis of the bonding evolution theory (BET), the mechanism of the 32CA reaction between C,N-diphenylnitrylimine and (E)-2-phenyl-1-cyano-1-nitroethene should be treated as a one-step two-stage mechanism. Full article

(This article belongs to the Special Issue Chemistry of Heterocycles)

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Open AccessArticle

¹³C NMR Spectroscopic Studies of Intra- and Intermolecular Interactions of Amino Acid Derivatives and Peptide Derivatives in Solutions

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Organics 2022, 3(1), 38-58; https://doi.org/10.3390/org3010003 - 09 Feb 2022

Abstract

¹³C NMR spectroscopic investigations were conducted for various amino acid derivatives and peptides. It was observed that ¹³C NMR chemical shifts of the carbonyl carbons are correlated with the solvent polarities, but the extent depends on the structures. The size of [...] Read more.

¹³C NMR spectroscopic investigations were conducted for various amino acid derivatives and peptides. It was observed that ¹³C NMR chemical shifts of the carbonyl carbons are correlated with the solvent polarities, but the extent depends on the structures. The size of the functional groups and inter- and intra-molecular hydrogen bonding appear to be the major contributors for this tendency. Full article

(This article belongs to the Special Issue Feature Papers in Organics)

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Open AccessArticle

De Novo Synthesis of Bacteriochlorins Bearing Four Trideuteriomethyl Groups

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Organics 2022, 3(1), 22-37; https://doi.org/10.3390/org3010002 - 07 Feb 2022

Abstract

Site-specific introduction of isotopes in tetrapyrrole macrocycles provides the foundation for probing physicochemical features germane to photosynthetic energy-transduction processes, but has chiefly been done with porphyrins rather than the more biologically relevant hydroporphyrin analogues of native photosynthetic pigments. A prior study incorporated pairwise [...] Read more.

Site-specific introduction of isotopes in tetrapyrrole macrocycles provides the foundation for probing physicochemical features germane to photosynthetic energy-transduction processes, but has chiefly been done with porphyrins rather than the more biologically relevant hydroporphyrin analogues of native photosynthetic pigments. A prior study incorporated pairwise ¹³C or ¹⁵N atoms in the skeleton of a bacteriochlorin containing a gem-dimethyl group in each pyrroline ring. Here, a complementary effort is reported that installs deuterium atoms in substituents at the perimeter of a bacteriochlorin. Thus, perdeuteriated 3-methyl-2,4-pentanedione was converted in an 8-step synthesis via the intermediacy of tert-butyl 5-formyl-3,4-bis(trideuteriomethyl)pyrrole-2-carboxylate to the 2,3,12,13-tetrakis(trideuteriomethyl)-8,8,18,18-tetramethylbacteriochlorin (BC-2). The fidelity of isotope substitution was maintained throughout the synthesis. Resonance Raman spectroscopy of the copper chelate (CuBC-2) revealed that addition of the four β-pyrrolic substituents alone is not sufficient to account for the vibronic complexity observed for the copper chelate of bacteriochlorophyll a (CuBChl a). The increased vibronic activity exhibited by the natural pigments and CuBChl a must arise from the increased structural complexity of the macrocycle. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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Open AccessReview

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

by

Balaram S. Takale

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Fan-Yi Kong

and

Ruchita R. Thakore

Organics 2022, 3(1), 1-21; https://doi.org/10.3390/org3010001 - 18 Jan 2022

Abstract

Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process [...] Read more.

Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process chemistry. On the one hand, these reactions have given medicinal chemists a resource to derivatize the core compound to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross-coupling reactions is broad. This review will specifically focus on their real (pharma) world applications in large-scale synthesis appearing in the last three years. Full article

(This article belongs to the Special Issue New Reactions and Strategies for Natural Product Synthesis)

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Open AccessArticle

Micellar Suzuki Cross-Coupling between Thiophene and Aniline in Water and under Air

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Organics 2021, 2(4), 415-423; https://doi.org/10.3390/org2040025 - 16 Dec 2021

Abstract

The Suzuki–Miyaura cross-coupling reaction plays a fundamental role in modern synthetic organic chemistry, both in academia and industry. For this reason, scientists continue to search for new, more effective, cheaper and environmentally friendly procedures. Recently, micellar synthetic chemistry has been demonstrated to be [...] Read more.

The Suzuki–Miyaura cross-coupling reaction plays a fundamental role in modern synthetic organic chemistry, both in academia and industry. For this reason, scientists continue to search for new, more effective, cheaper and environmentally friendly procedures. Recently, micellar synthetic chemistry has been demonstrated to be an excellent strategy for achieving chemical transformations in a more efficient way, thanks to the creation of nanoreactors in aqueous environments using selected surfactants. In particular, the cheap and commercially available surfactant Kolliphor EL (a polyethoxylated castor oil derivative) has been used with success to achieve metal-catalyzed transformations in water with high yields and short reaction times, with the advantage of using air-sensitive catalysts without the need for inert atmosphere. In this work, the Kolliphor EL methodology was applied to the Suzuki cross-coupling reaction between thiophene and aniline, using the highly effective catalyst Pd(dtbpf)Cl₂. The cross-coupling products were achieved at up to 98% yield, with reaction times of up to only 15 min, working at room temperature and without the need for inert atmosphere. Full article

(This article belongs to the Special Issue Feature Papers in Organics)

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Open AccessCommunication

1-(4-Nitrophenyl)-1H-1,2,3-Triazole-4-carbaldehyde: Scalable Synthesis and Its Use in the Preparation of 1-Alkyl-4-Formyl-1,2,3-triazoles

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Organics 2021, 2(4), 404-414; https://doi.org/10.3390/org2040024 - 06 Dec 2021

Cited by 1

Abstract

1,2,3-Triazole-4-carbaldehydes are useful synthetic intermediates which may play an important role in the discovery of novel applications of the 1,2,3-triazole moiety. In this work, a one-step multigram scale synthesis of 4-formyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (FNPT) as a preferred reagent for the synthesis of 1-alkyl-4-formyltriazoles [...] Read more.

1,2,3-Triazole-4-carbaldehydes are useful synthetic intermediates which may play an important role in the discovery of novel applications of the 1,2,3-triazole moiety. In this work, a one-step multigram scale synthesis of 4-formyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (FNPT) as a preferred reagent for the synthesis of 1-alkyl-4-formyltriazoles is described, making use of the commercially available 3-dimethylaminoacrolein and 4-nitrophenyl azide. Next, the earlier reported reaction of FNPT with alkylamines is further explored, and for hexylamine, the one-pot sequential cycloaddition and Cornforth rearrangement is demonstrated. In addition, a useful protocol for the in situ diazotization of 4-nitroaniline is provided. This facilitated the complete hydrolysis of rearranged 4-iminomethyl-1,2,3-triazoles and allowed for the recycling of 4-nitrophenyl azide. Full article

(This article belongs to the Special Issue New Reactions and Strategies for Natural Product Synthesis)

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Open AccessArticle

Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes

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Organics 2021, 2(4), 395-403; https://doi.org/10.3390/org2040023 - 16 Nov 2021

Cited by 1

Abstract

Organophosphorus compounds with stereogenic phosphorus and carbon atoms have received increasing attention. In this regards, primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom were synthesized by the reduction in phosphonates and phosphonoselenoates with a binaphthyl group. Their oxidized products, [...] Read more.

Organophosphorus compounds with stereogenic phosphorus and carbon atoms have received increasing attention. In this regards, primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom were synthesized by the reduction in phosphonates and phosphonoselenoates with a binaphthyl group. Their oxidized products, i.e., phosphine oxides with a stereogenic tetrasubstituted carbon atom, were found to undergo BEt₃-mediated radical addition to cyclohexene to give P-stereogenic secondary phosphine oxides with a diastereoselectivity of 91:9. The products were characterized by ordinary analytical methods, such as Fourier transform infrared spectroscopy; ¹H, ¹³C, and ³¹P NMR spectroscopies; and mass spectroscopy. Computational studies on the phosphorus-centered radical species and the obtained product implied that the thermodynamically stable radical and the adduct may be formed as a major diastereomer. The radical addition to a range of alkenes took place in an anti-Markovnikov fashion to give P-stereogenic secondary phosphine oxides. A variety of functional groups in the alkenes were tolerated under the reaction conditions to afford secondary phosphine oxides in moderate yields. Primary phosphines with an alkenyl group, which were generated in situ, underwent intramolecular cyclization to give five- and six-membered cyclic phosphines in high yields after protection by BH₃. Full article

(This article belongs to the Special Issue Progress in Synthesis and Applications of Phosphorus-Containing Compounds)

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Open AccessCommunication

Adamantane-Functionalized Phthalimide Scaffold: Pathways to Supramolecular Interactions and Drug Discovery

by

Hamidou Keita

Organics 2021, 2(4), 388-394; https://doi.org/10.3390/org2040022 - 11 Nov 2021

Cited by 1

Abstract

Herein, the synthesis of a novel adamantanyl-functionalized phthalimide scaffold is demonstrated. The novel compound could be used as a precursor for various synthetic pathways owing to the generic use of adamantane substituents as the driving force for supramolecular interactions with macrocycles and N-substituted [...] Read more.

Herein, the synthesis of a novel adamantanyl-functionalized phthalimide scaffold is demonstrated. The novel compound could be used as a precursor for various synthetic pathways owing to the generic use of adamantane substituents as the driving force for supramolecular interactions with macrocycles and N-substituted phthalimide derivatives as a core structure in numerous drugs. The adamantanyl-functionalized phthalimide scaffold contains bromide groups on the C4 and C5 positions of the benzene ring, effectively allowing further facile modifications of the scaffold. The structure was fully characterized including single-crystal X-ray crystallography. The crystal structure shows an adamantane moiety at an angle of 115.57(7)° to the phthalimide core, hence sterically freeing the adamantane unit for host–guest interactions. Full article

(This article belongs to the Special Issue New Reactions and Strategies for Natural Product Synthesis)

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Open AccessReview

Recent Advances in Oxa-6π Electrocyclization Reactivity for the Synthesis of Privileged Natural Product Scaffolds

by

Stéphane P. Roche

Organics 2021, 2(4), 376-387; https://doi.org/10.3390/org2040021 - 26 Oct 2021

Abstract

The stunning advances in understanding the reactivity and selectivity principles of asymmetric pericyclic reactions have had a profound impact on the synthetic planning of complex natural products. Indeed, electrocyclizations, cycloadditions, and sigmatropic rearrangements enable synthetic chemists to craft highly functionalized scaffolds that would [...] Read more.

The stunning advances in understanding the reactivity and selectivity principles of asymmetric pericyclic reactions have had a profound impact on the synthetic planning of complex natural products. Indeed, electrocyclizations, cycloadditions, and sigmatropic rearrangements enable synthetic chemists to craft highly functionalized scaffolds that would not otherwise be possible with a similar atom-, step-, and redox-economy. In this review, selected examples from the last two decades of research (2003–2020) on tandem processes combining oxa-6π electrocyclic reactions are discussed in terms of reactivity challenges, inherent reversibility, and key structural bond formation in the assembly of natural products. A particular emphasis is given to the electrocyclic ring-closures in the tandem processes featuring Knoevenagel-type condensations, Diels–Alder cycloadditions, Stille couplings, and oxidative dearomatizations. The synthetic manifolds reviewed here illustrate how oxa-6π electrocyclizations are intimately linked to the construction of complex natural product scaffolds and have inspired a number of biomimetic syntheses in the laboratory. Full article

(This article belongs to the Special Issue Pericyclic Reactions in Organic Synthesis)

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Open AccessReview

Boranils: Versatile Multifunctional Organic Fluorophores for Innovative Applications

by

Julien Massue

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Denis Jacquemin

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Gilles Ulrich

Organics 2021, 2(4), 365-375; https://doi.org/10.3390/org2040020 - 12 Oct 2021

Cited by 3

Abstract

Multifunctional stimuli-responsive fluorophores showing bright environment-sensitive emissions have fueled intense research due to their innovative applications in the fields of biotechnologies, optoelectronics, and materials. A strong structural diversity is observed among molecular materials, which has been enriched over the years with a growing [...] Read more.

Multifunctional stimuli-responsive fluorophores showing bright environment-sensitive emissions have fueled intense research due to their innovative applications in the fields of biotechnologies, optoelectronics, and materials. A strong structural diversity is observed among molecular materials, which has been enriched over the years with a growing responsiveness to stimuli. Boron dipyrromethene (BODIPY) dyes have long been the flagship of emissive boron complexes due to their outstanding properties until a decade ago when analogues based on N^O, N^N, or N^C π-conjugated chelates emerged. The finality of developing borate dyes was to compensate for BODIPYs’ lack of solid-state fluorescence and small Stokes shifts while keeping their excellent optical properties in solution. Among them, the borate complexes based on a salicylaldimine ligand, called by the acronym boranils appear as the most promising, owing to their facile synthesis and dual-state emission properties. Boranil dyes have proven to be good alternatives to BODIPY dyes and have been applied in applications such as bioimaging, bioconjugation, and detection of biosubstrates. Meanwhile, ab initio calculations have rationalized experimental results and provided insightful feedback for future designs. This review article aims at providing a concise yet representative overview of the chemistry around the boranil core with the subsequent applications. Full article

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Open AccessReview

Synthesis of 1-Trifluorometylindanes and Close Structures: A Mini Review

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Olesya V. Khoroshilova

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Aleksander V. Vasilyev

Organics 2021, 2(4), 348-364; https://doi.org/10.3390/org2040019 - 08 Oct 2021

Cited by 2

Abstract

This review describes methods for the synthesis of 1-trifluomethylindanes and close structures, which are still quite rare and scarcely available compounds. There are two main approaches to obtain 1-CF₃-indanes. The first one is the construction of an indane system from CF [...] Read more.

This review describes methods for the synthesis of 1-trifluomethylindanes and close structures, which are still quite rare and scarcely available compounds. There are two main approaches to obtain 1-CF₃-indanes. The first one is the construction of an indane system from CF₃ precursors; the main methods are acid-mediated Friedel–Crafts cyclization, transition metal-catalyzed [3+2] annulation, and free-radical transformations. The second approach is the trifluoromethylation of a ready-made indane core by various CF₃ sources, such as Ruppert–Prakash or Togni reagents. Many of these synthetic procedures possess high regio- and stereo-selectivity, allowing the preparation of unique 1-CF₃-indane structures. In recent years, great attention has been paid to the synthesis of 1-CF₃-indanes, due to the discovery of important biologically active properties for these compounds. Full article

(This article belongs to the Special Issue Feature Papers in Organics)

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Open AccessReview

Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization

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Carolina Durand

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Michal Szostak

Organics 2021, 2(4), 337-347; https://doi.org/10.3390/org2040018 - 08 Oct 2021

Cited by 2

Abstract

Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural [...] Read more.

Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization. Full article

(This article belongs to the Special Issue Feature Papers in Organics)

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Open AccessReview

Electrocyclizations of Conjugated Azapolyenes Produced in Reactions of Azaheterocycles with Metal Carbenes

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Nikolai V. Rostovskii

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Mikhail S. Novikov

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Alexander F. Khlebnikov

Organics 2021, 2(3), 313-336; https://doi.org/10.3390/org2030017 - 14 Sep 2021

Cited by 1

Abstract

Conjugated azapolyenes (azabuta-1,3-dienes, aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes) are highly reactive in electrocyclization reactions, which makes them convenient precursors for the synthesis of a wide range of four-, five-, and six-membered nitrogen heterocycles that are of relevance for medicinal chemistry. Ring opening reactions of 2H-azirines [...] Read more.

Conjugated azapolyenes (azabuta-1,3-dienes, aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes) are highly reactive in electrocyclization reactions, which makes them convenient precursors for the synthesis of a wide range of four-, five-, and six-membered nitrogen heterocycles that are of relevance for medicinal chemistry. Ring opening reactions of 2H-azirines and azoles containing an N–N or N–O bond, initiated by a transition metal carbene, have become increasingly important in recent years, since they easily allow the generation of azapolyenes with different numbers of double bonds and heteroatoms in various positions. This review summarizes the literature, published mainly in the last decade, on the synthetic and mechanistic aspects of electrocyclizations of azapolyenes generated by the carbene method. Full article

(This article belongs to the Special Issue Pericyclic Reactions in Organic Synthesis)

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