Regioselective Nucleophilic Addition Research Articles

Nucleophilic Addition of Amides to Haloalkynes: Synthesis of (Z)-β-Halovinyl Amides as Dual Precursors of Alkylidene Carbenes and Allyl Halides.

Toward a regioselective method for the synthesis of β-halovinyl amides, we developed a transition-metal-free nucleophilic addition reaction of amides to haloalkynes. The regioselective nucleophilic addition was achieved under solvent-free conditions using phosphonates to protonate the intermediate alkylidene carbenoids, thus suppressing their decomposition. Furthermore, we demonstrate that β-halovinyl amides can serve as dual precursors of allyl halides and alkylidene carbenes to obtain functionalized indoles and pyrrolidones.

Regioselective Addition of Sulfur and Amine Nucleophiles To Assemble S═C-S, S-N, and Umpolung C-N Bonds: Exploration of the -CBr3 Group as a Synthetic Equivalent of S═C-S.

The regioselective addition of sulfur and amine nucleophiles to a -CBr3 unit and nitromethyl moiety in a molecule with the installation of a five-diverse bond structure to novel isothiazole-5(2H)-thione is demonstrated. Umpolung of the nitromethyl group leads to a novel scaffold with selective C-N bond formation. Consequently, differentiating reactive centers by sulfur and amine nucleophiles has been proposed to create unique S-N bonds in conjunction with the dithioate (S═C-S-) moiety. This protocol allows for exploration of the -CBr3 moiety as a synthetic equivalent of the dithioate (S═C-S-) unit during the reaction.

Oxidative Functionalization of Catechol Derivatives Substituted with Electron-Withdrawing Groups.

Catechols possessing electron-withdrawing groups at the C3 position effectively underwent oxidative functionalization at the C4 position in the presence of phenyliodine(III) diacetate (PIDA) and heteroarene nucleophiles (e.g., indole, indazole, and benzotriazole) to produce the corresponding biaryl products. The PIDA-mediated oxidation of catechol derivatives afforded the ortho-benzoquinone intermediate, which subsequently underwent regioselective nucleophilic addition to the α,β-unsaturated carbonyl moiety of ortho-benzoquinone using indole, indazole, and benzotriazole to give 4-substituted catechol derivatives in a one-pot manner. Notably, the nucleophilic substitution positions of indazole and benzotriazole were perfectly controlled. Additionally, the reaction using N-methylaniline as the nucleophile afforded a tertiary amine product.

Catalyst-Controlled Enantioselective and Regiodivergent Addition of Aryl Boron Nucleophiles to N-Alkyl Nicotinate Salts.

Dihydropyridines are versatile building blocks for the synthesis of pyridines, tetrahydropyridines, and piperidines. Addition of nucleophiles to activated pyridinium salts allows synthesis of 1,2-, 1,4-, or 1,6-dihydropyridines; however, this process often leads to a mixture of constitutional isomers. Catalyst-controlled regioselective addition of nucleophiles to pyridiniums has the potential to solve this problem. Herein, we report that the regioselective addition of boron-based nucleophiles to pyridinium salts can be accomplished by the choice of a Rh catalyst.

Divergent Synthesis of Fluorinated Alkenes, Allenes, and Enynes via Reaction of 2-Trifluoromethyl-1,3-enynes with Carbon Nucleophiles.

Herein, inorganic base K3PO4 promoted divergent synthesis of CF3-substituted allenes, cyclopentenes, alkynes, and fluorinated enynes via regioselective nucleophilic addition of carbon nucleophiles to 2-trifluoromethyl-1,3-enynes was developed. With the choice of different carbon nucleophiles, various fluorinated compounds could be obtained under K3PO4/DMF reaction system. When malononitriles were used as nucleophiles, CF3-substituted allenes, cyclopentenes, and alkynes could be obtained, respectively. By using 1,3-dicarbonyl compounds as nucleophiles, ring-monofluorinated 4H-pyrans could be prepared, and 1,1-difluoro-1,3-enynes could be furnished with the participation of diethyl malonate. Moreover, these five kinds of fluorinated allenes, alkenes, and enynes are valuable building blocks.

Aryne 1,4-Disubstitution and Remote Diastereoselective 1,2,4-Trisubstitution via a Nucleophilic Annulation-[5,5]-Sigmatropic Rearrangement Process.

Both aryne 1,4-disubstitution and 1,2,4-trifunctionalization were accomplished from tertiary amines bearing a penta-2,4-dien-1-yl moiety. These transformations could directly incorporate a C-N and a C-C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]-sigmatropic rearrangement. When arynes bearing 3-tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]-sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen-bonding interactions between two C-H hydrogens on the penta-2,4-dien-1-yl chain and the oxygen anion generated upon N-nucleophilic annulation reaction in the [5,5]-sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

Aryne 1,4‐Disubstitution and Remote Diastereoselective 1,2,4‐Trisubstitution via a Nucleophilic Annulation‐[5,5]‐Sigmatropic Rearrangement Process

AbstractBoth aryne 1,4‐disubstitution and 1,2,4‐trifunctionalization were accomplished from tertiary amines bearing a penta‐2,4‐dien‐1‐yl moiety. These transformations could directly incorporate a C−N and a C−C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]‐sigmatropic rearrangement. When arynes bearing 3‐tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]‐sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen‐bonding interactions between two C−H hydrogens on the penta‐2,4‐dien‐1‐yl chain and the oxygen anion generated upon N‐nucleophilic annulation reaction in the [5,5]‐sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

3-Hydroxy-3-alkylindolin-2-ones: regioselective synthesis, molecular docking and nematicidal studies against Meloidogyne incognita

Regioselective nucleophilic addition of unsubstituted isatin (1) was carried out for the synthesis of pharmaceutically and to be agrochemically important 3-hydroxy-3-akylindolin-2-ones (3a-f) using discrete nucleophiles via generation of Grignard reagent. The synthesized derivatives were characterized by spectral techniques and were evaluated for nematicidal activity against Meloidogyne incognita. The nematicidal assay revealed that 1-ethyl-3-hydroxyindolin-2-one (3a) exhibited potent nematicidal activity against M. incognita. The most active member (3a) exhibited reasonably good ovicidal (LC50 = 0.077 mg/mL) and larvicidal activity (LC50 = 0.058 mg/mL), respectively. In support of the nematicidal activity, molecular docking of isatin (1) and its derivatives (3a-f) was performed using three parasitic proteins viz., carboxylic ester hydrolase, cytochrome c oxidase and aspartyl protease which revealed maximum interaction with amino acid residues Tyr 356, Tyr 170, Glu 238, Glu 327, Arg 271, Arg 112, Ser 29, Ser 31, Ser 368, Asn 115, Leu 326 and His 51 which act as supporting factors for compounds to curb the parasite.

Copper(I)-Catalyzed Synthesis of Unsymmetrical All-Carbon Bis-Quaternary Centers at the Opposing α-Carbons of Cyclohexanones.

We describe a new synthetic reaction that generates all-carbon bis-quaternary centers at the opposing side of α-carbons in cyclohexanone with four different substituents in a controlled manner. Catalyzed by Cu(MeCN)4BF4 salt, this chemistry is proposed to proceed via an intermediacy of unsymmetrical O-allyl oxyallyl cations, which undergo a sequence of regioselective nucleophilic addition with substituted indoles and diastereoselective Claisen rearrangement in a single synthetic operation. The stereochemical outcome of the products features the cis diastereorelationship between the two aryl groups at the α,α′-positions.

Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies.

The possibility to form new C–B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report experimental and computational data that allows the individuation of the structural requisites and of reaction conditions necessary to open alkyl aziridines using bis(pinacolate)diboron (B2pin2) in a regioselective nucleophilic addition reaction under copper catalysis.

An environmentally benign multi-component reaction: Highly regioselective synthesis of functionalized 2-(diarylphosphoryl)-1,2-dihydro-pyridine derivatives

A novel protocol was developed for the construction of highly functionalized 2-(diarylphosphoryl)-1,2-dihydropyridine derivatives (DAPDHPs) from 3-formylchromones (1), heterocyclic ketene aminals (HKAs, 2), and phosphine oxides (R2P(O)H, 3) via a novel, one-pot cascade reaction. Optimization of the reaction conditions determined that refluxing the mixture of the 3-formylchromones, HKAs, and various R2P(O)H in propylene carbonate (PC) in the presence of triethylamine as a base facilitated the highest yields of the DAPDHP products. This cascade reaction, which involved the cleavage of one C–O bond in the 3-formylchromone substrates and the formation of three new bonds (one C–C, one C–N, and one C–P bond), enabled the synthesis of a small library of DAPDHP products. The dearomatized DAPDHP products were formed by the regioselective nucleophilic addition of the R2P(O)H reagents to the intermediate pyridinium salts 8. This approach has several advantages such as the use of an environmentally-friendly solvent, simple and practical operation (with filtration and washing without column chromatography separation), good yields, and a product with potential biological activity.

Total synthesis of acronycine and noracronycine: An aryne amination approach

Acronycine and noracronycine are chromene-containing alkaloids with significant biological activity. We have accomplished a concise total synthesis of acronycine and noracronycine. The key step, regioselective nucleophilic addition of anthranilate to chromene-type arynes under mild and transition-metal-free conditions was achieved. In addition, further modifications of nucleophilic addition products, such as hydrogenation, O-functionalization and palladium-catalyzed coupling reactions have also been developed, providing a concise procedure for these alkaloids and their derivatives.

Rh(II)‐Catalyzed Denitrogenative Reaction of 1,2,3‐Triazolyl Esters with Indoles or Arenes: Efficient Synthesis of Homotryptamines or Allylamines

AbstractAn efficient strategy for the synthesis of structurally diverse homotryptamines and allyl amines via a Rh(II)‐catalyzed tandem reaction of 1,2,3‐triazolyl esters with either indoles or 1,3,5‐trimethoxybenzene has been developed. The reaction proceeds via Rh(II)‐catalyzed intramolecular rearrangement of triazoles into 1‐azadienes followed by regioselective nucleophilic addition. The efficiency of the current protocol was illustrated by broad substrate scope, gram scale synthesis and further functionalization of homotryptamines into other biologically relevant heterocycles.magnified image

Catalytic Enantio- and Regioselective Addition of Nucleophiles in the Intermolecular Hydrofunctionalization of 1,3-Dienes

Catalytic enantioselective synthesis of small-molecule building blocks with allylic stereogenic centers is an important objective in organic synthesis, but preparing this motif wherein the adjacent...

TBuLi‐Promoted Intermolecular Regioselective Nucleophilic Addition of Arenes to Diazo Compounds as N‐Terminal Electrophiles: Efficient Synthesis of Hydrazine Derivatives

The tBuLi‐promoted intermolecular direct nucleophilic addition of arenes to diazo compounds as the N‐terminal electrophiles has been developed. This reaction proceeds in a completely regioselective manner and is an efficient method for the preparation of hydrazine derivatives in high to excellent yields. This transformation not only provides an efficient approach for aromatic C–N bond formation under transition‐metal‐free and oxidant‐free conditions but also represents a strategy for the 3‐amination of pyridines and the dearomatization of indoles.

Palladium-Catalyzed Sequential Nucleophilic Addition/Oxidative Annulation of Bromoalkynes with Benzoic Acids To Construct Functionalized Isocoumarins.

An efficient and robust protocol for the preparation of 3-substituted isocoumarins via palladium-catalyzed nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids has been developed. Remarkably, preliminary mechanistic studies indicated that the transformation might proceed via a stereo- and regioselective nucleophilic addition and C-H functionalization procedure.

Three Component Divergent Reactions: Base-Controlled Amphiphilic Synthesis of Benzimidazole-Linked Thiazetidines and Fused Thiadiazines.

A divergent reaction of 2-aminobenzimidazole with isothiocyanates and dihalomethanes has been developed for the selective synthesis of benzoimidazothiazetidine and benzoimidazothiadiazine. A single-pot reaction of 2-aminobenzimidazole in the presence of sodium hydride delivers benzoimidazothiazetidine, whereas triethylamine promotes the formation of benzoimidazothiadiazine via a sequential stepwise fashion. The reaction sequence involves the initial formation of thiourea followed by regioselective nucleophilic addition and intramolecular ring-closing with dihalo electrophiles. The observed regioselectivity of this reaction is governed by the nature of bases and the reaction sequence.

ChemInform Abstract: Lewis Acid and Fluoroalcohol Mediated Nucleophilic Addition to the C2 Position of Indoles.

AbstractThe formation of indolium is described allowing for the 2‐selective inter‐ as well as intramolecular highly regioselective nucleophilic addition of electron rich aromatic compounds.

Radical reactivity of α,β,β-trifluoroacrylic ester: Facile approach to γ-silyloxy-α,β,β-trifluorobutyric acid derivatives involving regioselective nucleophilic radical addition reaction

In this paper are disclosed new aspects for chemical reactivity of benzyl α,β,β-trifluoroacrylate, which is already known to undergo CC bond formation reactions via nucleophilic addition-elimination reaction or Diels-Alder cycloaddition reaction. The α,β,β-trifluoroacrylate reacted well with nucleophilic radical species, generated from cyclic ethers, to afford the corresponding radical adducts in good to excellent yield as a diastereomeric mixture. The radical addition protocol is successfully evolved into the new synthetic approach to γ-silyloxy-α,β,β-trifluorobutanoic acid derivatives, which fascinates as promising precursors for medicinally as well as pharmaceutically-important organic molecules.

Carbazole Annulation via Cascade Nucleophilic Addition-Cyclization Involving 2-(Silyloxy)pentadienyl Cation.

We report a new strategy toward the synthesis of highly functionalized carbazoles via 2-(silyloxy)pentadienyl cation intermediates, which were generated upon ionization of vinyl-substituted α-hydroxy silyl enol ethers under Brønsted acid catalysis. These electrophilic species were found to readily undergo cascade reactions with substituted indoles to generate carbazole molecular scaffolds in good yields via a sequence of regioselective nucleophilic addition, followed by intramolecular dehydrative cyclization.