Novel Bicyclic P,S-Heterocycles via Stereoselective hetero-Diels-Alder Reactions of Thiochalcones with 1-Phenyl-4H-phosphinin-4-one 1-Oxide.

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels-Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products.

Synthesis and crystal structures of new chiral 3-amino-2H-azirines and the Pd complex of one of them.

3-Amino-2H-azirines are potentially versatile building blocks in heterocyclic and peptide synthesis. Three new 3-amino-2H-azirines have been synthesized as racemates or mixtures of diastereoisomers in cases where another chiral residue is incorporated as the exocyclic amine. The crystal structures of two of them, an approximately 1:1 diastereoisomeric mixture of (2R)- and (2S)-2-ethyl-3-[(2S)-2-(1-methoxy-1,1-diphenylmethyl)pyrrolidin-1-yl]-2-methyl-2H-azirine, C23H28N2O, 11, and 2-benzyl-3-(N-methyl-N-phenylamino)-2-phenyl-2H-azirine, C22H20N2, 12, and the third as its diastereoisomeric trans-PdCl2 complex, trans-dichlorido[(2R)-2-ethyl-2-methyl-3-(X)-2H-azirine][(2S)-2-ethyl-2-methyl-3-(X)-2H-azirine]palladium(II), where X = N-{[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]methyl}-N-phenylamino, [PdCl2(C21H30N2)2], 14, have been determined and the geometries of the azirine rings compared with those of 11 other 3-amino-2H-azirine structures reported in the literature. Most notable is the very long formal N-C single bond, which is, with one exception, around 1.57 Å. Each compound has crystallized in a chiral space group. The Pd atom in the trans-PdCl2 complex is coordinated by one of each of the pair of diastereoisomers, while both of the diastereoisomers share the same crystallographic site in the structure of 11; this property thereby manifesting itself as disorder. The chosen crystal of 12 is either an inversion twin or composed of a pure enantiomorph, but this could not be established specifically.

Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions.

Fluorinated heterocycles constitute an important group of organic compounds with a rapidly growing number of applications in such areas as medicinal chemistry, agrochemicals production, polymer chemistry, as well as chemistry of advanced materials. In the latter case, fluorinated thiophenes are considered as a lead class of compounds with numerous spectacular applications. On the other hand, cycloaddition reactions offer a superior methodology for stereo-chemically controlled synthesis of heterocycles with a diverse ring size and a variable number of heteroatoms. A comprehensive review of methods based on cycloaddition reactions and applied for construction of fluorinated and/or fluoroalkylated S-heterocycles has not yet been published. For this reason, the main goal of the presented review was to fill the existing gap and to summarize the results published over last six decades. In this context, the [3+2]- and [4+2]-cycloadditions (Huisgen reactions, and Diels-Alder reactions, respectively) are of special importance. Some questions related to the discussed mechanisms of cycloaddition processes observed in reactions with electron deficient, fluorinated substrates (dipolarophiles and dienophiles), and electron-rich sulfur containing counter partners, are of fundamental importance for the development of interpretations of organic reaction mechanisms.

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines.

In-situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile efficiently react with polycyclic 1,4-quinones, yielding fused pyrazole derivatives as the exclusive products. The reactions proceed via the initially formed [3 + 2]-cycloadducts, which undergo spontaneous aerial oxidation to give aromatized heterocyclic products. Only for 2,3,5,6-tetramethyl-1,4-benzoquinone, the expected [3 + 2]-cycloadduct exhibited fair stability and could be isolated in moderate yield (53%). The presented method offers a straightforward access to hitherto little known trifluoromethylated polycyclic pyrazoles. All products were isolated as pale colored solids with medium-intensity absorption maxima in the range of 310-340 nm for naphthoquinone-derived products and low-intensity bands in the visible region (≈400 nm) for the anthraquinone series.

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27-2.58 Å) and longer N..C-distances (3.02-3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

The Fluoride Anion-Catalyzed Sulfurization of Thioketones with Elemental Sulfur Leading to Sulfur-Rich Heterocycles: First Sulfurization of Thiochalcones.

Fluoride anion was demonstrated as a superior activator of elemental sulfur (S8) to perform sulfurization of thioketones leading to diverse sulfur-rich heterocycles. Due to solubility problems, reactions must be carried out either in THF using tetrabutylammonium fluoride (TBAF) or in DMF using cesium fluoride (CsF), respectively. The reactive sulfurizing reagents are in situ generated, nucleophilic fluoropolysulfide anions FS(8-x)-, which react with the C=S bond according to the carbophilic addition mode. Dithiiranes formed thereby, existing in an equilibrium with the ring-opened form (diradicals/zwitterions) are key-intermediates, which undergo either a step-wise dimerization to afford 1,2,4,5-tetrathianes or an intramolecular insertion, leading in the case of thioxo derivatives of 2,2,4,4-tetramethylcyclobutane-1,3-dione to ring enlarged products. In reactions catalyzed by TBAF, water bounded to fluoride anion via H-bridges and forming thereby its stable hydrates is involved in secondary reactions leading, e.g., in the case of 2,2,4,4-tetramethyl-3-thioxocyclobutanone to the formation of some unexpected products such as the ring enlarged dithiolactone and ring-opened dithiocarboxylate. In contrast to thioketones, the fluoride anion catalyzed sulfurization of their α,ß-unsaturated analogues, i.e., thiochalcones is slow and inefficient. However, an alternative protocol with triphenylphosphine (PPh3) applied as a catalyst, offers an attractive approach to the synthesis of 3H-1,2-dithioles via 1,5-dipolar electrocyclization of the in situ-generated α,ß-unsaturated thiocabonyl S-sulfides. All reactions occur under mild conditions and can be considered as attractive methods for the preparation of sulfur rich heterocycles with diverse ring-size.

Synthesis and Solid State Conformation of Tetrapeptide Amides Containing two Aib and two (αMe)Phe Residues - Use of Enantiomerically Pure 2-Benzyl-2-methyl-2H-azirin-3-amines as (αMe)Phe-Synthons.

A series of tetrapeptide amides containing two aminoisobutyric acids (Aib) and two α-methylphenylalanine ((αMe)Phe) units were prepared through the 'azirine/oxazolone method'. New 2-benzyl-2-methyl-2H-azirin-3-amines have been used for the selective introduction of (S)- and (R)-(αMe)Phe, respectively. The solid-state conformations of five tetrapeptide amides were determined by X-ray crystallography. In all cases, two ß-turns stabilize 310 -helical conformations and it was confirmed that, in contrast to proteinogenic amino acids, the configuration of (αMe)Phe does not determine the screw sense of the helix.

Solid-state conformations of linear depsipeptide amides with an alternating sequence of α,α-disubstituted α-amino acid and α-hydroxy acid.

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α-disubstituted α-amino acid and an α-hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)-Pms-Acp-(S)-Pms-Acp-(S)-Pms-Acp-NMe2 acetonitrile solvate, C47H58N4O9·C2H3N, (3b), as well as in the related linear tetradepsipeptide amide (S)-Pms-Aib-(S)-Pms-Aib-NMe2, C28H37N3O6, (5a), the diastereoisomeric mixture (S,R)-Pms-Acp-(R,S)-Pms-Acp-NMe2/(R,S)-Pms-Acp-(R,S)-Pms-Acp-NMe2 (1:1), C32H41N3O6, (5b), and (R,S)-Mns-Acp-(S,R)-Mns-Acp-NMe2, C30H37N3O6, (5c) (Pms is phenyllactic acid, Acp is 1-aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a ß-turn conformation in the solid state, which is stabilized by intramolecular N-H...O hydrogen bonds. Whereas ß-turns of type I (or I') are formed in the cases of (3b), (5a) and (5b), which contain phenyllactic acid, the torsion angles for (5c), which incorporates mandelic acid, indicate a ß-turn in between type I and type III. Intermolecular N-H...O and O-H...O hydrogen bonds link the molecules of (3a) and (5b) into extended chains, and those of (5a) and (5c) into two-dimensional networks.

The [4+2]-Cycloaddition of α-Nitrosoalkenes with Thiochalcones as a Prototype of Periselective Hetero-Diels-Alder Reactions-Experimental and Computational Studies.

The [4+2]-cycloadditions of α-nitrosoalkenes with thiochalcones occur with high selectivity at the thioketone moiety of the dienophile providing styryl-substituted 4H-1,5,2-oxathiazines in moderate to good yields. Of the eight conceivable hetero-Diels-Alder adducts only this isomer was observed, thus a prototype of a highly periselective and regioselective cycloaddition has been identified. Analysis of crude product mixtures revealed that the α-nitrosoalkene also adds competitively to the thioketone moiety of the thiochalcone dimer affording bis-heterocyclic [4+2]-cycloadducts. The experiments are supported by high-level DFT calculations that were also extended to related hetero-Diels-Alder reactions of other nitroso compounds and thioketones. These calculations reveal that the title cycloadditions are kinetically controlled processes confirming the role of thioketones as superdienophiles. The computational study was also applied to the experimentally studied thiochalcone dimerization, and showed that the 1,2-dithiin and 2H-thiopyran isomers are in equilibrium with the monomer. Again, the DFT calculations indicate kinetic control of this process.

2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds.

'Desymmetrization' of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH2 derivatives ('primary-tertiary diamines'). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained, which were deprotonated by treatment with triethylamine in the presence of elemental sulfur. Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur, yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines, amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were also studied.

Synthesis and selected transformations of 2-unsubstituted 1-(adamantyloxy)imidazole 3-oxides: straightforward access to non-symmetric 1,3-dialkoxyimidazolium salts.

Adamantyloxyamine reacts with formaldehyde to give N-(adamantyloxy)formaldimine as a room-temperature-stable compound that exists in solution in monomeric form. This product was used for reactions with α-hydroxyiminoketones leading to a new class of 2-unsubstituted imidazole 3-oxides bearing the adamantyloxy substituent at N(1). Their reactions with 2,2,4,4-tetramethylcyclobutane-1,3-dithione or with acetic acid anhydride occurred analogously to those of 1-alkylimidazole 3-oxides to give imidazol-2-thiones and imidazol-2-ones, respectively. Treatment of 1-(adamantyloxy)imidazole 3-oxides with Raney-Ni afforded the corresponding imidazole derivatives without cleavage of the N(1)-O bond. Finally, the O-alkylation reactions of the new imidazole N-oxides with 1-bromopentane or 1-bromododecane open access to diversely substituted, non-symmetric 1,3-dialkoxyimidazolium salts. Adamantyloxyamine reacts with glyoxal and formaldehyde in the presence of hydrobromic acid yielding symmetric 1,3-di(adamantyloxy)-1H-imidazolium bromide in good yield. Deprotonation of the latter with triethylamine in the presence of elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-dihydro-2H-imidazole-2-thione as the final product.

Chemo- and regioselective [3 + 2]-cyclo-additions of thio-carbonyl ylides: crystal structures of trans-8-benzoyl-1,1,3,3-tetra-methyl-7-tri-fluoro-methyl-5-thia-spiro-[3.4]octan-2-one and trans-3-benzoyl-2,2-diphenyl-4-(tri-fluoro-meth-yl)tetra-hydro-thio-phene.

The title compounds, C19H21F3O2S and C24H19F3OS, were prepared via chemo- and regioselective [3 + 2]-cyclo-additions of the respective thio-carbonyl ylides (thio-carbonyl S-methanides), generated in situ, with (E)-4,4,4-tri-fluoro-1-phenyl-but-2-en-1-one. The thio-phene ring in the crystal structure of each compound has an envelope conformation. The largest differences between the two mol-ecular structures is in the bond lengths about the quaternary C atom of the thio-phene ring; in the spiro-cyclic structure, the C-C bonds to the spiro C atom in the cyclo-butane ring are around 1.60 Å, although this is also observed in related structures. In the same structure, weak inter-molecular C-H⋯X (X = S, O) inter-actions link the mol-ecules into extended ribbons running parallel to the [001] direction. In the other structure, weak C-H⋯π inter-actions link the mol-ecules into sheets parallel to the (010) plane.

First thia-Diels-Alder reactions of thiochalcones with 1,4-quinones.

Aryl and hetaryl thiochalcones react smoothly with 1,4-quinones in THF solution at 60 °C yielding the corresponding fused 4H-thiopyrans after spontaneous dehydrogenation of the initially formed [4 + 2] cycloadducts. In general, the yields of the isolated products were high. With 5-chloro-10-hydroxy-1,4-anthraquinone, the thia-Diels-Alder reaction occurred with complete regioselectivity. In the case of the reaction of vitamin K3 (menadione) with diphenylthiochalcone, the initial cycloadduct was isolated in 37% yield.

Efficient synthesis of ferrocifens and other ferrocenyl-substituted ethylenes via a 'sulfur approach'.

Stable and non-odorous alkyl ferrocenyl thioketones react with bis(4-methoxyphenyl)diazomethane according to the 'two-fold extrusion' reaction principles, and tetrasubstituted ethylenes obtained thereby can be demethylated to give (Fc,2OH)-ferrocifens in good yields. The method offers an alternative approach to this class of medically relevant compounds. A similar protocol with alkyl ferrocenyl thioketones and selected diaryldiazomethanes leads to ferrocenyl-substituted ethylenes including dibenzofulvenes. These products are of potential interest for electrochemical and photophysical studies.

Crystal structure of (E)-1,2-diferrocenyl-1,2-bis(furan-2-yl)ethene.

The title compound, [Fe2(C5H5)2(C20H14O2)], is the product of a new synthetic route towards tetra-aryl/hetaryl-substituted ethenes that reduces the occurrence of side-products. In the crystal, the mol-ecule is centrosymmetric and the cyclo-penta-dienyl (Cp) rings are nearly coplanar and aligned slightly closer to a staggered conformation than to an eclipsed one. The ethene plane is tilted by 32.40 (18)° with respect to that of the substituted Cp ring and by 63.19 (19)° with respect to that of the furan ring. C-H⋯π inter-actions link the mol-ecules into a three-dimensional supramolecular framework.

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies.

The scope of applications of dialkyl dicyanofumarates and maleates as highly functionalized electron-deficient dipolarophiles, dienophiles and Michael acceptors is summarized. The importance for the studies on reaction mechanisms of cycloadditions is demonstrated. Multistep reactions with 1,2-diamines and ß-aminoalcohols leading to diverse five- and six-membered heterocycles are discussed. Applications of dialkyl dicyanofumarates as oxidizing agents in the syntheses of disulfides and diselenides are described. The reactions with metallocenes leading to charge-transfer complexes with magnetic properties are also presented.

A novel application of 2-silylated 1,3-dithiolanes for the synthesis of aryl/hetaryl-substituted ethenes and dibenzofulvenes.

Trimethylsilyldiazomethane (TMS-CHN2) reacts readily with hetaryl thioketones to give sterically crowded 2-trimethylsilyl-4,4,5,5-tetrahetaryl-1,3-dithiolanes with complete regioselectivity at -75 °C as well as at rt. Thiofluorenone, a relatively stable and highly reactive aryl thioketone, yields upon treatment with TMS-CHN2 at -60 °C the corresponding 1,3,4-thiadiazoline. This unstable cycloadduct undergoes decomposition at ca. -45 °C and the silylated thiocarbonyl S-methanide generated thereby is trapped with complete regioselectivity by aryl or hetaryl thioketones forming also sterically crowded 2-trimethylsilyl-1,3-dithiolanes. The obtained 1,3-dithiolanes, by treatment with an equimolar amount of TBAF in a one-pot procedure, are converted in high yields into hetaryl/aryl-substituted ethenes or dibenzofulvenes, respectively, via a cycloreversion reaction of the intermediate 1,3-dithiolane carbanion. The presented protocol offers a new, highly efficient approach to tetrasubstituted ethenes and dibenzofulvenes bearing aryl and/or hetaryl substituents.

Dimerization reactions of aryl selenophen-2-yl-substituted thiocarbonyl S-methanides as diradical processes: a computational study.

An intriguing stepwise diradical mechanism of the dimerization of the reactive intermediate (thiocarbonyl S-methanide) appearing in the reaction of phenyl selenophen-2-yl thioketone with diazomethane was studied by means of computational methods. The preferred formation of the unusual macroheterocycle, competitive with the 1,3-ring closure leading to a thiirane and the head-to-head dimerization yielding a 1,4-dithiane derivative, respectively, was explained based on the analysis of the structure of the favored conformer of the intermediate, delocalized diradical species. The influence of selenium as a 'heavy atom' for stabilization of this intermediate has been emphasized.

Synthesis of ferrocenyl-substituted 1,3-dithiolanes via [3 + 2]-cycloadditions of ferrocenyl hetaryl thioketones with thiocarbonyl S-methanides.

Ferrocenyl hetaryl thioketones react smoothly with in situ generated thiocarbonyl S-methanides to give 1,3-dithiolanes. In the case of aromatic S-methanides, the sterically more crowded 4,4,5,5-tetrasubstituted 1,3-dithiolanes (2-CH2 isomers) were formed as sole products. The reactions with cycloaliphatic S-methanides led to mixtures of 2-CH2 and 5-CH2 isomers with the major component being the sterically more crowded 2-CH2 isomers. The preferred formation of the latter products is explained by the assumption that the formal [3 + 2]-cycloadducts were formed via a stepwise reaction mechanism with a stabilized 1,5-diradical as a key intermediate. The complete change of the reaction mechanism toward the concerted [3 + 2]-cycloaddition was observed in the reaction of a sterically crowded cycloaliphatic thiocarbonyl ylide with ferrocenyl methyl thioketone.

Diradical reaction mechanisms in [3 + 2]-cycloadditions of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes.

Reactions of dihetaryl and aryl/hetaryl thioketones with 2-diazopropane, diazoethane, and (trimethylsilyl)diazomethane were studied at variable temperature. The experiments showed that reactions with 2-diazopropane carried out at -75 °C occur mainly via the initially formed, relatively stable 1,3,4-thiadiazolines as products of the [3 + 2]-cycloaddition of the diazo dipole onto the C=S bond. The latter decompose only at higher temperature (ca. -40 °C) to generate thiocarbonyl S-isopropanide. In the absence of the starting thioketone, the corresponding thiiranes and/or ethene derivatives, formed from them via spontaneous desulfurization, are the main products. In contrast, reactions with diazoethane occurred predominantly via initially formed diradicals, which in cascade processes gave sterically crowded 4,4,5,5-tetrahetaryl-1,3-dithiolanes as major products. Finally, the reaction of dihetaryl thioketones with (trimethylsilyl)diazomethane occur smoothly at -75 °C leading to the corresponding 4,4,5,5-tetrahetaryl-1,3-dithiolanes as the exclusive [3 + 2]-cycloadducts formed via a cascade of postulated diradicals. The presence of S or Se atoms in the hetaryl rings is of importance for stabilizing diradical intermediates. Remarkably, in no single case, the 'head-to-head dimerization' of aryl/hetaryl and dihetaryl substituted thiocarbonyl ylides was observed.