Aromatic Nucleophiles Research Articles

N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides.

Concerted nucleophilic aromatic substitution (CSN Ar) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSN Ar reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CSN Ar reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (Cipso -Cβ )→ σ*(Cipso -F) interaction critically contributes to the stabilization of the transition state for the cyclization.

Acid‐Catalyzed Cascade Reaction of 4‐Aminobutanal Derivatives with (Hetero)aromatic Nucleophiles: A Versatile One‐Pot Access to 2‐(Hetero)arylpyrrolidines.

Abstract2‐(Hetero)arylpyrrolidine fragment is found in a diverse array of biologically active molecules, both natural and unnatural. In recent years, a substantial increase in number of approved drugs featuring this scaffold is observed. Developing methods for the synthesis of such compounds has been essential for making progress in this field. Most of these methods require usage of metal catalysts and introduce additional chemical steps to obtain appropriately substituted starting compounds. This microreview details the one‐pot approach for the synthesis of pyrrolidine derivatives possessing (hetero)aromatic substituent at the second position of pyrrolidine ring based on usage of readily available N‐substituted 4,4‐diethoxybutan‐1‐amines and (hetero)aromatics as starting compounds and Bronsted acids as catalysts.

Sodium-Catalyzed Friedel–Crafts Reactions and Mechanistic Insight

Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) demonstrates catalytic activity for Friedel-Crafts addition reactions of phenolic and other aromatic nucleophiles to trans-β-nitrostyrene. Solubility studies demonstrate a chelating effect between the Na+ cation and the nitro group of trans-β-nitrostyrene as the basis for catalytic activation. Mechanistic studies are presented, including a comparison with other sodium salts, additive effects, and reaction progress kinetics analysis using 19F NMR spectroscopy.

Addition–cyclization reactions of furan-2-carbonyl isothiocyanate with nitrogen nucleophiles as a synthetic route to novel azines and azoles of potential biological activity

Heterocyclization of furan-2-carbonyl isothiocyanate 1 with a variety of aliphatic and aromatic nitrogen nucleophiles resulted in the formation of a new series of heterocycles including triazines, pyrimidines, oxadiazines, imidazolidines, thiadiazoles and their condensed candidates. The antibacterial screening for a group of the newly synthesized compounds showed that they possess moderate antibacterial activities against examples of Gram-positive and Gram-negative bacteria.

Controlled-Coupling of Quinone Monoacetals by New Activation Methods: Regioselective Synthesis of Phenol-Derived Compounds

We have studied for a long time the reaction of quinone acetal type compounds, such as quinone monoacetals, quinone O,S-acetals, and iminoquinone monoacetals, and have reported the regioselective introduction of various nucleophiles. Quinone monoacetals show various types of reactivities toward nucleophiles due to their unique structures. In this study, we found that aromatic and alkene nucleophiles can be regioselectively introduced into the α-position of the carbonyl group on quinone monoacetals by specific activation of the acetal moiety. These reactions enabled the metal-free synthesis of highly functionalized aromatic compounds by the regioselective introduction of nucleophiles. In this account, we describe our recent studies of the coupling of quinone monoacetals.1 Introduction2 Regioselective Introduction of Aromatic Nucleophiles into α-Position of Carbonyl2.1 Biaryl Synthesis by Introduction of Aromatic Nucleophiles2.2 Synthesis of Terphenyls and Oligoarenes by Iterative Coupling2.3 Synthesis of Phenol Cross-Coupling Products3 [3+2] Coupling with Alkene Nucleophiles3.1 Development of Efficient [3+2] Coupling3.2 Improvement of Brønsted Acid Promotor4 Synthesis of α-Aryl Carbonyl Compounds Triggered by Silyl Transfer5 Utilization of o-Quinone Monoacetals6 Application to Iminoquinone Monoacetals7 Conclusion

DBU-mediated annulation of 2-aryl-3-nitro-2H-chromenes with 1,3-cyclohexanediones for the synthesis of benzofuro[2,3-c]chromenone derivatives.

The DBU-mediated annulations of 2-aryl-3-nitro-2H-chromenes with 1,3-cyclohexanediones have been developed. This reaction involves a highly efficient domino sequence consisting of regioselective intermolecular Michael addition, intramolecular nucleophilic addition and aromatization as key unit steps. The reaction appears to be general for a variety of 2-aryl-3-nitro-2H-chromenes and tolerates the presence of aromatic moieties with electron-withdrawing and electron-donating substituents. This transformation provides a straightforward synthetic protocol for constructing benzofuro[2,3-c]chromenone derivatives.

Highly Functionalized Cyclohexenes Derived from Benzene: Sequential Tandem Addition Reactions Promoted by Tungsten.

The dihapto-coordination of benzene to the π-basic fragment {TpW(NO)(PMe3)} (Tp = hydridotris(pyrazolyl)-borate) enhances the basicity of the arene ligand to the point that it can be protonated with a mild Brønsted acid (diphenylammonium triflate; p Ka ∼ 1). The resulting η2-benzenium complex reacts with a wide range of nucleophiles including protected enolates, cyanide, amines, methoxide, and aromatic nucleophiles to form 5-substituted 3,4-η2-1,3-cyclohexadiene complexes in good yield (42-70%). These coordinated dienes were successfully taken through a second protonation and nucleophilic addition with a similar scope of nucleophiles (54-80%). The resulting cis-3,4- and cis-3,6-disubstituted η2-cyclohexene complexes were prepared with high regio- and stereocontrol, as governed by the asymmetric nature of π-allyl intermediates. In some cases, a diene linkage isomerization from 3,4-η2 to 1,2-η2 could be effected with a redox catalyst, and reactions of the latter species led to cis-3,5-disubstituted cyclohexene products exclusively. Oxidative decomplexation afforded the free cyclohexene products in moderate yield (37-68%). Additionally, when a single enantiomer of the chiral dearomatization agent was used, the elaborated cyclohexenes were able to be synthesized in enantioenriched forms (86-90% enantiomeric excess). Full characterization of 40 new compounds is provided that includes two-dimensional NMR, IR, electrochemical and in some cases crystallographic data.

Efficient Green Synthesis and Computational Chemical Study of Some Interesting Heterocyclic Derivatives as Insecticidal Agents

A series of 5,5‐diarylhydantoin (Dilantin) 3, 4, and 7, imidazole 1, 2, 5, 6, 8, and 9, thiazole 10–12, triazinthione 13, 15, 16, and 17, and thiadiazine 14 derivatives, containing diverse hydrophobic groups, were green synthesized through one‐pot stepwise reaction of aromatic aldehydes, vitamin B1, and nitrogen nucleophiles, for example, urea, thiourea, and thiosemicarbazide using grinding technique as well as conventional thermal methods. Such synthesized compounds have potent insecticidal activities; for example, compounds 4, 6, and 17 exhibited the highest insecticidal activity against both Plutella xylostella and Helicoverpa armigera with minimum inhibitory concentration values at 500 μg/mL and LD50 activities at 50 μg/mL. The density functional theory was then applied to explore the structural and electronic characteristics of these compounds. All the synthesized compounds have been characterized based on their elemental analyses and spectral data.

Mechanistic study of the direct oxidative photocatalytic aerobic C[sbnd]H/C[sbnd]H coupling of azines with heteroarenes

Experimental facts on the mechanism of the direct oxidative photocatalytic CH/CH coupling of azines with (hetero)aromatic nucleophiles, proceeding in the presence of TiO2 as a photocatalyst, have been obtained by using EPR spectroscopy and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)-2-methylpropanamide (TMT-H), as spin trap reagent and spin probe, respectively. The formation of the superoxide radical anion (O2−) and N-centered radicals has been detected for the first time for the SNH transformations.

Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of the natural maslinic acid

Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic…) have been reported for maslinic acid (MA) and MA-based compounds. In continuation of our previous work on MA, herbicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semisynthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were synthesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (propargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trapping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)3, by aromatic nucleophiles. The cycloaddition reaction afforded regiospecifically 1,4-disubstituted triazoles in good yields. The latter hybrid compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step in development of potent herbicides since one of the final semisynthesized structures can serve as a promising lead candidate for further studies.

Metal- and Reagent-Free Dehydrogenative Formal Benzyl-Aryl Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol.

A selective dehydrogenative electrochemical functionalization of benzylic positions that employs 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) has been developed. The electrogenerated products are versatile intermediates for subsequent functionalizations as they act as masked benzylic cations that can be easily activated. Herein, we report a sustainable, scalable, and reagent- and metal-free dehydrogenative formal benzyl-aryl cross-coupling. Liberation of the benzylic cation was accomplished through the use of acid. Valuable diarylmethanes are accessible in the presence of aromatic nucleophiles. The direct application of electricity enables a safe and environmentally benign chemical transformation as oxidizers are replaced by electrons. A broad variety of different substrates and nucleophiles can be employed.

Porphyrin Co(III)-Nitrene Radical Mediated Pathway for Synthesis of o-Aminoazobenzenes.

Azobenzenes are versatile compounds with a range of applications, including dyes and pigments, food additives, indicators, radical reaction initiators, molecular switches, etc. In this context, we report a general method for synthesizing o-aminoazobenzenes using the commercially available cobalt(II) tetraphenyl porphyrin [CoII(TPP)]. The net reaction is a formal dimerization of two phenyl azides with concomitant loss of two molecules of dinitrogen. The most commonly used methodology to synthesize azobenzenes is based on the initial diazotization of an aromatic primary amine at low temperatures, which then reacts with an electron rich aromatic nucleophile. As such, this limits the synthesis of azobenzenes with an amine functionality. In contrast, the method we report here relies heavily on the o-amine moiety and retains it in the product. The reaction is metal catalyzed and proceeds through a porphyrin Co(III)-nitrene radical intermediate, which is known to form on activation of organic azides at the cobalt center. The synthesized o-aminoazobenzenes are bathochromatically shifted, as compared to azobenzenes without amine substituents. Based on the crystal structure of one of the products, strong H-bonding between the N-atom of the azo functionality and the H of the NH2 substituent is shown to stabilize the trans isomeric form of the product. The NH2 substituents offers possibilities for further functionalization of the synthesized azo compounds.

A Heteroarylamine Library: Indium‐Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines

AbstractUnder indium Lewis acid catalysis, electron‐rich five‐membered heteroaryl electrophiles fused with/without a benzene ring were found to couple with amines to produce heteroarylamines with broad structural diversity. The heteroarylamine formation proceeds through the cleavage of a heteroaryl−OMe bond by the nucleophilic attack of the amine based on the nucleophilic aromatic substitution (SNAr) reaction. In contrast to the corresponding traditional SNAr amination, the present SNAr‐based heteroaryl amination can be performed without relying on both heteroaryl electrophiles with electron‐withdrawing groups and nucleophilicity‐enhanced metal amides. High compatibility towards the functional groups such as NO2, Br, I, CF3, CN, CO2Et, pyridyl, thiazolyl, C=C, and OH groups was observed, thus showing the practicality and reliability of this method. Mechanistic studies indicated that a carbon−indium bond is likely to be formed on the heteroaryl ring during the process.magnified image

Buchwald-Hartwig amination using Pd(i) dimer precatalysts supported by biaryl phosphine ligands.

We report the synthesis of air-stable Pd(i) dimer complexes featuring biaryl phosphine ligands. Catalytic experiments suggest that these complexes are competent precatalysts that can mediate cross-coupling amination reactions between aryl halides with both aliphatic and aromatic amine nucleophiles. This work represents an expansion of the air-stable precatalyst toolbox for Pd-catalyzed cross-coupling transformations.

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

AbstractAn efficient and sustainable one‐step procedure for the synthesis of new asymmetric phenazines and phenoxazinones from commercially available ortho‐substituted diamines and ortho‐substituted hydroxyamines is reported. In this study we have expanded the substrate scope of CotA‐laccase‐catalyzed aerobic oxidations through the use of aromatic amines presenting variable functional groups, including N‐substitution, contributing to the rational synthesis of different heterocyclic scaffolds. The transformations proceed smoothly through a cascade of oxidative reactions to the benzoquinonediimine intermediates followed by nucleophilic addition, intramolecular cyclization and aromatization, all performed in mild conditions.magnified image

Alkyne Hydroheteroarylation: Enantioselective Coupling of Indoles and Alkynes via Rh-Hydride Catalysis.

We report an enantioselective coupling between alkynes and indoles. A Rh-hydride catalyst isomerizes alkynes to generate a metal-allyl species that can be trapped with both aromatic and heteroaromatic nucleophiles.

Synthesis of 6-Substituted Piperidin-3-ones via Rh(II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles with Electron-Rich Aromatic Nucleophiles.

A highly diastereoselective rhodium(II)-catalyzed transannulation of aldehyde-tethered N-sulfonyl triazoles with electron-rich aromatic nucleophiles is reported for the first time to afford functionalized 6-substituted piperidin-3-ones. The reaction has a broad substrate scope including both aliphatic and aromatic N-sulfonyl-1,2,3-triazoles together with various aromatic nucleophiles. The addition of a catalytic amount of Lewis acid has proven to be crucial for the yield improvement. By employing this methodology, hardly accessible piperidin-3-ones bearing quaternary carbons could be obtained.

Metal- and Oxidant-Free Benzylic C-H/Aromatic C-H Cross Coupling Based on the Stabilized Cation Pool Method

The cation pool method serves as a nice tool in electroorganic synthesis. Organic cations are electrochemically generated and accumulated in solution at low temperatures. Reactions with subsequently added nucleophiles give the desired products. However, the cation pool method cannot be applied to highly unstable cations that decompose during the course of the electrolysis. To expand the scope of the cation pool method, we have developed the stabilized cation pool method, in which organic cations stabilized by suitable stabilizing agents are electrochemically generated and accumulated in solution. The reactions of the stabilized organic cations with subsequently added nucleophiles give the desired products. In this paper we show that C−H/aromatic C−H cross-coupling can be achieved by the electrochemical generation and accumulation of stabilized benzyl cations followed by their reactions with subsequently added aromatic nucleophiles. Beznylaminosulfonium ions as stabilized benzyl cations are generated and accumulated in the electrochemical oxidation of toluene derivatives. In the next step, the reactions with subsequently added electron-rich aromatic compounds as nucleophiles give the corresponding cross-coupled product. The method has been successfully applied to the synthesis of TP27, an inhibitor of PTPase. The reactions of benzylaminosulfonium ions with other carbon nucleophiles such as acetylacetone, ketene silyl acetals, allyltrimethylsilane, and trimethylsilylacetylene will also be discussed in the presentation.

New chiral Mannich adducts of di-tert-butylphenols and a bicyclic imine – Synthesis and antiproliferative activity

Tests of antiproliferative activity of Mannich adducts of aromatic nucleophiles and a chiral bicyclic imine revealed a di-tert-butylphenol derivative as a promising compound for further exploration. To study the influence of substitution pattern and a configuration of stereogenic centers on the inhibition of cancer cell growth, a series of Mannich bases were obtained with a good to high diastereoselectivity from the reaction of the imine and three isomeric di-tert-butylphenols. Six new enantiopure adducts were isolated and fully characterized. Selected derivatives were shown to exhibit an interesting antiproliferative activity comparable to cisplatin.

Enantioselective Three-Component Amination of Enecarbamates Enables the Synthesis of Structurally Complex Small Molecules.

The control of asymmetric synthesis tools represents a major challenge, especially when it comes to the synthesis of bioactive molecules. In this context, the asymmetric synthesis of 1,2-diamines through amination of enecarbamates has been proposed as a highly efficient and tunable approach. Indeed, reactivity of the latter species could be exploited to realize a double functionalization via an electrophilic amination followed by nucleophilic trapping. Herein, we describe a chiral phosphoric acid catalyzed electrophilic amination of enecarbamates with dibenzyl azodicarboxylate and oxygenated or thiol-containing nucleophiles affording stable precursors of α-hydrazinoimines in high yields and with almost complete enantioselectivities (up to >99%). These precursors were successfully functionalized with various silylated nucleophiles without epimerization of the stereogenic center, giving access to a wide range of 1,2-disubstituted 1,2-diamines. We also show that the thiolated precursors were successfully engaged in a Friedel-Crafts reaction against a variety of aromatic and heteroaromatic nucleophiles, leading to various 1-(hetero)aryl-1,2-diamines without loss of enantioselectivity and with complete diastereoselectivity. Reductive N-N bond cleavage provided the N,N-diprotected 1,2-diamines with no loss in diastereo- or enantioselectivity. The protocol was successfully scaled up to a multigram scale and the catalyst was successfully recovered, demonstrating the potential applications of this new methodology.