Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Donor-Acceptor Cyclopropane Ring Expansion to 1,2-Dihydronaphthalenes. Access to Bridged Seven-Membered Lactones.

A Lewis-acid-promoted domino ring-opening cyclization of readily available donor-acceptor cyclopropanes with a preinstalled electrophilic center, embedded in a donor group, to functionalized 1,2-dihydronaphthalenes is reported herein. The obtained compounds are transformed to pharmacologically attractive bridged tricyclic esters in a diastereospecific manner.

Photoredox-Catalyzed Chlorotrifluoromethylation of Arylallenes: Synthesis of a Trifluoromethyl Building Block.

A new class of trifluoromethyl building blocks─2-trifluoromethyl allyl chlorides─have been obtained through a photoredox-catalyzed chlorotrifluoromethylation of aryl allenes. The reaction proceeded in a regio- and stereoselective manner. A trifluoromethylated analog of the flunarizine drug was synthesized.

Electrochemical Decarbonylative Aminosulfonylation of Alkynes with Sulfinates and N-(Formyl)anilides.

An unprecedented electrochemical three-component reaction of phenylacetylene, sulfinate, and N-(formyl)anilide was discovered. The transformation occurs in an undivided cell with a graphite anode and cathode in DMF in the presence of tetrabutylammonium iodide as an electrolyte. The addition of silver(I) oxide and catalytic amounts of iodine facilitated the reaction significantly. The transformation was also carried out under photoredox-catalyzed conditions.

Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor-Acceptor Cyclopropanes and Anilines/Benzylamines.

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives.

Chemoselective Divergent Transformations of N-(Propargyl)indole-2-carbonitriles with Nitrogen Nucleophiles: Alkyne Hydroamination or Domino Cyclizations.

Interactions of N-(propargyl)indole-2-carbonitriles with nitrogen nucleophiles were studied. It was found that lithium hexamethyldisilazane (LiHMDS)-promoted reactions give mixtures of two product types, originating from an initial attack onto carbon-carbon or carbon-nitrogen triple bonds. Performing the reaction at reduced temperature and in the presence of catalytic amounts of LiHMDS delivered alkyne hydroamination products exclusively. On the contrary, the one-pot reaction of N-(propargyl)indole-2-carbonitriles with methanol and LiHMDS on heating, followed by the addition of a nitrogen nucleophile, allowed a selective domino cyclization sequence toward 1-aminopyrazino[1,2-a]indoles. Anilines and nitrogen heterocycles could be employed as N-nucleophiles to obtain products of both types. Moreover, an alternative one-pot route toward a third product type has been developed. When N-(propargyl)indole-2-carbonitrile was first combined with aniline and LiHMDS at reduced temperature, further heating of the in situ generated hydroamination product led to the intramolecular cyclization into 1-imino-2-phenylpyrazino[1,2-a]indoles. Thus, chemodivergent transformations of the same starting material into three compound classes were investigated. The possible reaction routes were studied, and N-(allenyl)indole-2-carbonitrile was identified as the key intermediate. Acyclic and cyclic products exhibit fluorescence emission in the blue to green range.

Annealing-Induced Structural Behavior of Mn Dopant Ions in Calcium Orthovanadate Ca3(VO4)2 Single Crystals.

The crystal and local structures of Czochralski-grown calcium orthovanadate (Ca3(VO4)2) single crystals doped with over-stoichiometric 0.05 wt % Mn2O3 (CVO:0.05Mn) and annealed under different conditions are studied by single-crystal conventional and synchrotron X-ray diffraction, X-ray absorption spectroscopy, and electron paramagnetic resonance for the first time. Bottom (annealing in air) and top (annealing in air and in vacuum) parts of the CVO:0.05Mn crystal differ in the manganese content (higher in the bottom part), formal charge (Mn4+ and Mn(3+δ)+, respectively), and color (orange bottom part; light orange and yellow top parts annealed in air and vacuum, respectively). Manganese ions are located in one (Ca3, distorted two-capped trigonal prism) of five crystallographic Ca sites and have octahedral coordination, which is consistent with crystal-chemical properties of transition-metal ions. The presence of vacancies in one of three V sites is revealed. Formal charge 5+ for vanadium ions is confirmed by X-ray photoelectron spectroscopy. Different colors of CVO:Mn crystals and different formal charges of manganese are explained depending on the growth and post-growth treatment conditions.

Revealing the peculiar local behavior of manganese and cobalt in diffusion-doped calcium orthovanadate Ca3(VO4)2.

Laser Ca3(VO4)2 single crystals (СVO; space group R3c, Z = 21) with crystallochemical formula Ca118Ca218Ca318Ca46(Ca5 + Са5А)3(V118V218V36)O168 grown by the Czochralski method were doped with Мn2O3 (CVO:Мn2O3) and Сo3O4 (CVO:Co3O4) by high-temperature diffusion annealing. Statistical and local structures were comprehensively studied by single-crystal and powder synchrotron X-ray diffraction and conventional single-crystal X-ray diffraction as well as by X-ray absorption spectroscopy for the first time. The presence of Mn(2+δ)+ ions with a mixed formal charge and Co2+ ions in the Ca2 (monocapped trigonal prism), Ca3 (two-capped trigonal prism), and Ca4 (octahedron) sites was revealed by diffraction methods. The tetrahedral coordination and the coordination intermediate between tetrahedral and octahedral were established for Mn(2+δ)+ and Co2+ ions, respectively. A fundamentally different structural behavior of dopant ions (concentration, formal charge, and coordination environment) in the CVO crystals doped with manganese in the form of Mn2O3 during the crystal growth or by high-temperature diffusion annealing was observed. The relationship between characteristic bands in the absorption, fluorescence, and excitation spectra of CVO:Мn2O3 and CVO:Co3O4 samples and transition metals with specific formal charges is discussed.

A Facile Approach to Bis(isoxazoles), Promising Ligands of the AMPA Receptor.

A convenient synthetic approach to novel functionalized bis(isoxazoles), the promising bivalent ligands of the AMPA receptor, was elaborated. It was based on the heterocyclization reactions of readily available electrophilic alkenes with the tetranitromethane-triethylamine complex. The structural diversity of the synthesized compounds was demonstrated. In the electrophysiological experiments using the patch clamp technique on Purkinje neurons, the compound 1,4-phenylenedi(methylene)bis(5-aminoisoxazole-3-carboxylate) was shown to be highly potent positive modulator of the AMPA receptor, potentiating kainate-induced currents up to 70% at 10-11 M.

Expanding Stereoelectronic Limits of endo-tet Cyclizations: Synthesis of Benz[b]azepines from Donor-Acceptor Cyclopropanes.

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.

Donor-Acceptor Cyclopropane Ring Opening with 6-Amino-1,3-dimethyluracil and Its Use in Pyrimido[4,5-b]azepines Synthesis.

A scandium trifluoromethanesulfonate-catalyzed reaction of donor-acceptor cyclopropanes with 6-amino-1,3-dimethyluracil was found to proceed as three-membered ring opening via nucleophilic attack of the C(5) atom of an ambident nucleophile serving as an enamine equivalent. It was shown that, under basic conditions, the obtained products underwent cyclization to 6,7-dihydro-1H-pyrimido[4,5-b]azepine-2,4,8-triones, an interesting subclass of nucleobase analogues.

5-Nitroisoxazoles in SNAr reactions: access to polysubstituted isoxazole derivatives.

An efficient protocol for the straightforward functionalization of the isoxazole ring via the reactions of aromatic nucleophilic substitution of the nitro group with various nucleophiles has been elaborated. The method features excellent chemical yields, easy operability of the reaction, mild reaction conditions and a broad scope of both 5-nitroisoxazoles and nucleophiles. A synthetic approach to 3,5- and 3,4,5-substituted isoxazoles via the sequential functionalization of the isoxazole ring has been developed based on the excellent regioselectivity of the reaction of 3,5-dinitroisoxazoles with nucleophiles.

Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines.

A multicomponent reaction of isocyanides with aryl(indol-3-yl)methylium salts and amines has been found. A series of aryl(indol-3-yl)acetimidamides was obtained in up to 96% yields. In the case of ethyl isocyanoacetate, the reaction is followed by cyclization to form 3,5-dihydro-4H-imidazol-4-one derivatives.

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction.

A new synthetic strategy toward nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes with three and five contiguous stereocenters is presented. Readily available ß-keto phosphonates react with conjugated nitroolefins in the presence of a chiral Ni(II) complex to give nitro keto phosphonates with two stereocenters with excellent enantioselectivity and moderate to high diastereoselectivity. These products were used for a reductive cyclization leading to pyrrolidin-3-ylphosphonic acid and for reactions with aldehydes yielding tetrahydropyranylphosphonates as individual stereoisomers. These nonracemic heterocycles containing phosphoryl moieties are useful for designing new pharmacologically active compounds.

Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones.

Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines were studied, showing green light emission with high fluorescence quantum yields.

Aza-Henry and aza-Knoevenagel reactions of nitriles for the synthesis of pyrido[1,2-a]indoles.

N-(Propargyl)indole-2-carbonitriles undergo DBU-catalyzed addition of CH-acids to nitriles, followed by cyclization to give 9-aminopyrido[1,2-a]indoles. The reaction proceeds through the initial formation of a push-pull enamine, alkyne-allene rearrangement and intramolecular nucleophilic cyclization. Nitromethane and malonate esters can be employed as the CH-acids. The resulting compounds were found to exhibit fluorescence properties.

Phenacylation of 6-Methyl-Beta-Nitropyridin-2-Ones and Further Heterocyclization of Products.

Reaction between the derivatives of 6-methyl-beta-nitropyridin-2-one and phenacyl bromides was studied, and the yields observed were extremely low. The pyridones were converted via chloropyridines to methoxyderivatives, which were N-phenacylated. N-Phenacyl derivatives of 4,6-dimethyl-5-nitropyridin-2-one under the action of base gave 5-hydroxy-8-nitroindolizine and under acidic conditions gave 5-methyl-6-nitrooxazole[3,2-a]pyridinium salt, which underwent recycization with MeONa to 5-methoxy-8-nitroindolizine.

Wagner-Meerwein type rearrangement in 5-oxohomoadamantane series.

Efficient methods for introducing various substituents into the α-position of ethyl 5-oxohomoadamantyl-4-carboxylate are reported. An unexpected acid-catalysed 1,2-alkyl shift in the series of synthesized α,α-bis-substituted 5-oxohomoadamantanes, and also in the hydroxy derivatives of homoadamantane was found. Such a retropinacol-like rearrangement leads to tetra- or pentacyclic mono- or bis-lactones containing a homoadamantane moiety. This new transformation opens access to the synthesis of previously unknown 2,4-di and 2,3,4-trisubstituted derivatives of homoadamantane. The resulting caged γ-butyro- and δ-valerolactones could be considered as potential synthetic or metabolic precursors of conformationally restricted GABA and δ-aminovaleric acid analogues.

Photoredox-Catalyzed Hydrosulfonylation of Arylallenes.

(Het)Arylallenes undergo hydrosulfonylation under photoredox-catalyzed conditions. The reaction gives vinyl sulfones in a regio- and diastereoselective manner, employing sodium sulfinates as the sulfonyl source and eosin Y as the photocatalyst. Indol-1-yl, pyrrol-1-yl, phenyl, and naphtylallenes might be used. Aliphatic allenes are incompatible with the reaction conditions.