Intramolecular Nucleophilic Cyclization Research Articles

Total Synthesis of Thaxtomin A and Its Stereoisomers and Findings of Their Biological Activities

The first and facile total synthesis of thaxtomin A and its three stereoisomers has been achieved. The synthetic approach involves intramolecular nucleophilic cyclization of an amide toward a ketoamide group to produce a C-hydroxydiketopiperazine scaffold. The most amazing discovery was that each of the four stereoisomers of TA exhibits different phytotoxic, fungicidal, and antiviral activities.

DFT-Assisted Mechanism Evolution of the Carbonylation of Ethylene Glycol to Ethylene Carbonate by Urea over Zn(NCO)2·2NH3 Catalyst

Zn(NCO)2·2NH3 catalyst has been synthesized, characterized by X-ray diffraction and IR spectroscopy, and used as a catalyst for the cyclization of urea and ethylene glycol (EG) to ethylene carbonate (EC) for the first time. A maximum yield of 40% has been obtained with a urea/EG mole ratio of 1:1.5 and a temperature of 150 ± 2 °C. An attempt has been made to predict the mechanism of the reaction with the help of density functional theory calculations. Our calculations suggest the reaction to be a consecutive one. In the first step, urea decomposes to ammonia and isocyanic acid (HNCO). HNCO reacts with EG to produce 2-hydroxyethyl carbamate (2-HEC). At the last step, 2-HEC cyclizes over Zn(NCO)2·2NH3 to EC. Calculations suggest the cyclization of 2-HEC to follow a charge-controlled intramolecular nucleophilic elimination cyclization path.

A novel domino condensation–intramolecular nucleophilic cyclization approach towards annulated thiochromenes

A one-pot protocol towards previously unreported derivatives of thiochromeno [2′,3′:4,5] imidazo[2,1-a]isoquinoline via a domino reaction of isoquinoline-derived iminium salts and α-mercapto benzaldehydes is elaborated.

PPA-Mediated C–C Bond Formation: A Synthetic Route to Substituted Indeno[2,1-c]quinolin-6(7H)-ones

A facile and efficient synthesis of substituted indeno[2,1-c]quinolin-6(7H)-ones from a variety of α-acyl N-arylcinnamamides mediated by polyphosphoric acid (PPA) is described, and a mechanism involving the formation of a dicationic superelectrophile and subsequent double intramolecular nucleophilic cyclization reactions is proposed.

ChemInform Abstract: Facile and Efficient Synthesis of Quinolin‐2(1H)‐ones via Cyclization of Penta‐2,4‐dienamides Mediated by H2SO4.

AbstractThe reaction proceeds via formation of a dicationic superelectrophile followed by intramolecular nucleophilic cyclization.

遷移金属触媒による高効率かつ新規な変換反応

Rhenium and manganese-catalyzed regioselective insertion of unsaturated molecules into aromatic and olefinic C-H bonds have been achieved. In some cases, successive intramolecular nucleophilic cyclization proceeded. We have also succeeded in regioselective insertion of alkynes into a non-strained C-C single bond of 1,3-dicarbonyl compounds using a rhenium or manganese catalyst. In addition, we have succeeded in regio- and stereo-defined cycloaddition reactions. By using a rhodium or palladium catalyst, we have achieved direct and efficient carbon-heteroatom bond formations via C-H bond activation.

Mechanism of cysteine-dependent inactivation of aspartate/glutamate/cysteine sulfinic acid α-decarboxylases

Animal aspartate decarboxylase (ADC), glutamate decarboxylase (GDC) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of aspartate, glutamate and cysteine sulfinic acid to β-alanine, γ-aminobutyric acid and hypotaurine, respectively. Each enzymatic product has been implicated in different physiological functions. These decarboxylases use pyridoxal 5-phosphate (PLP) as cofactor and share high sequence homology. Analysis of the activity of ADC in the presence of different amino determined that beta-alanine production from aspartate was diminished in the presence of cysteine. Comparative analysis established that cysteine also inhibited GDC and CSADC in a concentration-dependent manner. Spectral comparisons of free PLP and cysteine, together with ADC and cysteine, result in comparable spectral shifts. Such spectral shifts indicate that cysteine is able to enter the active site of the enzyme, interact with the PLP-lysine internal aldimine, form a cysteine-PLP aldimine and undergo intramolecular nucleophilic cyclization through its sulfhydryl group, leading to irreversible ADC inactivation. Cysteine is the building block for protein synthesis and a precursor of cysteine sulfinic acid that is the substrate of CSADC and therefore is present in many cells, but the presence of cysteine (at comparable concentrations to their natural substrates) apparently could severely inhibit ADC, CSADC and GDC activity. This raises an essential question as to how animal species prevent these enzymes from cysteine-mediated inactivation. Disorders of cysteine metabolism have been implicated in several neurodegenerative diseases. The results of our study should promote research in terms of mechanism by which animals maintain their cysteine homeostasis and possible relationship of cysteine-mediated GDC and CSADC inhibition in neurodegenerative disease development.

Rhenium-Catalyzed Regioselective Synthesis of Multisubstituted Pyridines from β-Enamino Ketones and Alkynes via C–C Bond Cleavage

A new method is described for the regioselective synthesis of multisubstituted pyridine derivatives. Treatment of N-acetyl β-enamino ketones with alkynes in the presence of the rhenium catalyst, Re(2)(CO)(10), gives multisubstituted pyridines regioselectively. In this reaction, the N-acetyl moieties are important for the selective formation of the multisubstituted pyridines. This reaction proceeds via insertion of alkynes into a carbon-carbon single bond of β-enamino ketones, intramolecular nucleophilic cyclization, and elimination of acetic acid.

An unusual Me3SiI-promoted [4+2] annulation and reduction: an efficient approach to construct 4H-benzopyrans

Me(3)SiI-promoted reaction of salicylic aldehydes with β-dicarbonyl compounds provided a facile way to construct 4H-benzopyrans in moderate to good yields. This tandem reaction proceeds with high efficiency through nucleophilic addition, silyl enol ether formation, substitution, reduction, and intramolecular nucleophilic cyclization.

Palladium(0)-catalyzed cyclization of 1,6-diyn-3-yl carbonates with a nucleophilic functionality: efficient synthesis of polycyclic benzo[b]fluorene derivatives via allene intermediates

We report in this paper an interesting tandem reaction involving sequential palladium(0)-catalyzed decarboxylation of diynylic carbonates, intramolecular nucleophilic cyclization and Schmittel reaction, which provides a facile method for the synthesis of a variety of polycyclic benzo[b]fluorene derivatives from easily accessible starting materials.

Facile and efficient synthesis of quinolin-2(1H)-ones via cyclization of penta-2,4-dienamides mediated by H2SO4

A facile and efficient synthesis of substituted quinolin-2(1H)-ones is developed via intramolecular cyclization of penta-2,4-dienamides mediated by concentrated H(2)SO(4) (98%), and a mechanism involving the formation of a dicationic superelectrophile, and subsequent intramolecular nucleophilic cyclization reactions is proposed.

Synthesis and Crystal Structure of 1-(3-Fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

The base catalyzed intramolecular nucleophilic cyclization of 1-(2-bromobenzoyl)-3-(2-fluorophenyl)thiourea (1) in the presence of N,N-dimethyl formamide (DMF) afforded the 1-(3-fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2) by an intramolecular nucleophilic substitution SNAr mechanism. The structure was supported by the spectroscopic data and unambiguously confirmed by the single crystal X-ray diffraction data. It crystallizes in the orthorhombic space group P na21 with unit cell dimensions a = 22.430(4), b = 8.1478(16), c = 13.522(3) Å, V = 2471.2(9) Å3. There are two independent molecules per asymmetric unit that are linked to centrosymmetric AB-dimers via intermolecular N-H…S bonds.

Vilsmeier Reaction of 3-Aminopropenamides: One-Pot Synthesis of Pyrimidin-4(3H)-ones

A facile one-pot synthesis of pyrimidin-4(3H)-ones was developed via reactions of a series of readily available 3-aminopropenamides with varied Vilsmeier reagents, and a mechanism involving sequential halogenation, formylation, and intramolecular nucleophilic cyclization is proposed.

Rhenium-Catalyzed Synthesis of Indenones by Novel Dehydrative Trimerization of Aryl Aldehydes via C−H Bond Activation

By heating aryl aldehydes with catalytic amounts of a rhenium complex, ReBr(CO)(5), and N-phenylacetamide in toluene, indenone derivatives are obtained in good to excellent yields. This reaction proceeds via (1) the formation of an isobenzofuran derivative by the insertion of an aldehyde into the C-H bond of another aldehyde (C-H bond activation) and successive intramolecular nucleophilic cyclization, (2) nucleophilic addition of the formed isobenzofuran derivative to the third aldehyde, (3) isomerization, and (4) intramolecular aldol condensation.

A novel cascade Kröhnke condensation—an intramolecular nucleophilic cyclization approach toward annulated chromenes

Abstract A one-pot protocol toward previously unreported derivatives of chromeno[2′,2′:4,5]imidazo[2,1-a]isoquinoline via a cascade reaction of isoquinoline-derived immonium salts and α-hydroxy aromatic aldehydes is elaborated.

Synthesis, Characterization and Crystal Structure of Some Novel 1‐Aryl‐2‐Thioxo‐2,3‐Dihydro‐1H‐Quinazolin‐4‐Ones

AbstractThe base catalyzed intramolecular nucleophilic cyclization of 1‐(2‐haloaroyl)‐3‐aryl thioureas (1a‐i), in the presence of DMF afforded the 1‐aryl‐2‐thioxo‐2,3‐dihydro‐1H‐quinazolin‐4‐ones (2a‐i). The structures were confirmed by spectroscopic data, elemental analyses and in case of the 2c by single crystal X‐ray diffraction data. The mechanistic studies support an intramolecular nucleophilic substitution (SNAr mechanism) rather than intramolecular aromatic substitution (SRN1 mechanism).

Synthesis of highly functionalized oxazines by Vilsmeier cyclization of amidoalkyl naphthols

The intramolecular cyclization of amidoalkyl naphthols by Vilsmeier reagent produced 1,3-oxazines. The Vilsmeier reagent (chloromethylenedimethylammonium chloride) has been used as an efficient and cheap acid activator for the one-step synthesis of oxazine derivatives. A mechanism involving sequential haloformylation and intramolecular nucleophilic cyclization is proposed.

Conformationally Restricted Nonchiral Pipecolic Acid Analogues

Practical syntheses of 2-azabicyclo[3.1.1]heptane-1-carboxylic (2,4-methanopipecolic), 2-azabicyclo[2.2.2]octane-1-carboxylic (2,5-ethanopipecolic), and 9-azabicyclo[3.3.1]nonane-1-carboxylic (2,6-propanopipecolic) acids are reported. The synthetic schemes are short (five, seven, and five steps, respectively) and result in reasonably high yields of the title compounds. The key step in the syntheses is the tandem Strecker reaction and intramolecular nucleophilic cyclization of ketones possessing a leaving group at the delta-position.

Regioselective Syntheses of 2- and 4-Formylpyrido[2,1-b]benzoxazoles

o-Acetaminophenols (2) reacted with Vilsmeier reagent under Meth-Cohn conditions to yield 2-formylpyrido[2,1-b]benzoxazoles (5) unexpectedly besides the known compounds 2-(benzoxazol-2'-yl)-3-dimethylaminoacroleins (4). Refluxing 4 in acetic anhydride gave 4-formylpyrido[2,1-b]benzoxazoles (6), an isomer of 5. Both 5a and 6a were structurally characterized by X-ray crystallography. A mechanism for the formation of 5 involving sequential chlorination, dimerization, intramolecular elimination of HCl to form the oxazole ring, formylation twice, and regioselective intramolecular nucleophilic cyclization to construct the pyridone ring is proposed.

Reactions and Mechanistic Studies of Rhenium-Catalyzed Insertion of α,β-Unsaturated Carbonyl Compounds into a C–H Bond

Abstract A rhenium complex, [ReBr(CO)3(thf)]2, catalyzes the insertion of α,β-unsaturated carbonyl compounds into a C–H bond of aromatic compounds having nitrogen-containing directing groups. In this reaction, Re2(CO)10 can also be used as a catalyst. When imines are employed as the aromatic substrates, sequential cyclization proceeds and indene derivatives are obtained in good to excellent yields. This reactivity is in contrast to those of ruthenium and rhodium complexes, which are usually used as catalysts in the insertion reactions of unsaturated molecules into a C–H bond. Investigations on the reaction mechanism indicate that the rhenium catalyst promotes C–H bond activation of aromatic compounds, the insertion of α,β-unsaturated carbonyl compounds into a Re–C bond, and intramolecular nucleophilic cyclization followed by reductive elimination and the elimination of an amine.