Indium-mediated selective introduction of a 1,3-butadien-2-yl group at the C4-position in 2-azetidinones and application of 1,3-diene-tethered 2-azetidinones in the Diels-Alder reaction

The reaction of 4-acetoxy-2-azetidinones with organoindium reagents generated in situ from indium and 1,4-dibromo-2-butyne in the presence of LiCl in DMF selectively produced 2-azetidinones which contain a 1,3-butadienyl-2-yl group at the C4-position in good yields. The Diels-Alder reaction of 4-[(1-methylene)prop-2-enyl]-2-azetidinones with a variety of dienophiles provided 2-azetidinones with valuable functional-group-substituted six-membered rings at the C4-position in good yields.     

Synthesis of symmetrical di(pyrimidin-2-yl)-1,2,4-triazoles and di(pyrimidin-2-yl)-1,2,4,5-tetrazines

The reactions of pyrimidine-2-carbonitrile and 4,6-dimethylpyrimidine-2-carbonitrile with hydrazine hydrate were investigated. Intermediates in the route of successive transformations of pyrimidine-2-carbonitrile (pyrimidine-2-carbamidrazone and 1,2-bis[amino(pyrimidin-2-yl)methylidene]hydrazine) into trinuclear heterocyclic compounds, viz., symmetrical di(pyrimidin-2-yl)-1,4-dihydro-1,2,4,5-tetrazines and di(pyrimidin-2-yl)-4H-1,2,4-triazol-4-amines (potential polydentate ligands), were isolated. The oxidative dehydrogenation of di(pyrimidin-2-yl)-1,4-dihydro-1,2,4,5-tetrazines afforded the corresponding 3,6-di(pyrimidin-2-yl)-1,2,4,5-tetrazines.     

Nitrilimine cycloaddition onto 2-azetidinones bearing alkenyl dipolarophile(s)

Silver acetate-promoted nitrilimines cycloaddition onto 3(R*)-phenyl-4(R*)-cinnamoyl-2-azetidinone 1 were highly stereoselective giving 4-(4,5-dihydropyrazol-5-yl) carbonyl-2-azetidinones 5 as the major products and regioisomeric 4-(4,5-dihydropyrazol-4-yl) carbonyl-2-azetidinones 6 as the minor one. When the same protocol was applied to the novel 3(R*)-phenyl-4(S*)-(4-benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2 it resulted in site- and regioselective but not stereoselective cycloaddition, involving the formation of the four cycloadducts 10-13.     

An improved synthesis of 3,6-diamino-1,2,4,5-tetrazine. II. From triaminoguanidine and 2,4-pentanedione

A new synthesis for the title compound that gives an 80% overall yield was developed. Treatment of triaminoguanidine monohydrochloride ( 1 ) with 2,4-pentanedione ( 2 ) gave 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2-dihydro-1,2,4,5-tetrazine ( 3 ) in 80–85% yield. Oxidation of 3 with nitric oxide or nitrogen dioxide to 3,6-bis(3,5-dimethyylpyrazol-1-yl)-1,2,4,5-tetrazine ( 4 ) followed by ammonolysis of 4 gave 3,6-diamino-1,2,4,5-tetrazine ( 5 ) in guantitatively yields.     

Synthesis of the bi-heterocyclic parent ring system 1,2,4-triazolo[4,3-b][1,2,4,5]tetrazine and some 3,6-disubstituted derivatives

The synthesis of the previously unknown parent ring system was developed. Treatment of 3-hydrazino-1,2,4,5-tetrazine ( 4 ) with diethoxymethyl acetate gave the parent ring system. Similar treatment of 3-(3,5-dimethylpyrazol-1-yl)-6-hydrazino-1,2,4,5-tetrazine ( 2 ) with one carbon cyclizing reagents gave 3,6-di-substituted derivatives of the 1,2,4-triazolo-1,2,4,5-tetrazine ring system.     

Synthesis and Electrochemical Properties of 2-(4-R 1 -Phenyl)-6-(4-R 2 -phenyl)-4-phenyl-3,4-dihydro1,2,4,5-tetrazin-1(2 H )-yls

A new methodology for creating electroactive components for organic batteries, based on the construction of a molecular platform including stable 3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl radicals was described. A series of 2-(4-R1-phenyl)-6-(4-R2-phenyl)-4-phenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yls with substituents of various nature was obtained. It was shown that the substituents R1 in the aromatic ring at position 2 of the tetrazinyl fragment influence the value of the oxidation potential in the radical, but do not influence the value of the reduction potentials, while the substituent R2 of the aromatic ring at position 6 influence the values of the reduction potentials and practically do not influence oxidation potential values. Based on the obtained electrochemical data, a correlation structure–potential value was revealed for the cathodic and anodic process, with the help of which triarylsubstituted 3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl radicals with high values of the electrochemical gap were obtained.     

X-ray studies of three 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals: an unexpected molecular conformation stabilized by hydrogen bonds

The results of the X-ray structure analysis of three novel 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals are presented. These are 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine–2,4,6-tribromophenol (1/2), C₁₂H₈N₆·2C₆H₃Br₃O, 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine–isonicotinic acid N-oxide (1/2), C₁₂H₈N₆·2C₆H₅NO₃, and 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine–4-nitrobenzenesulfonamide (1/1), C₁₂H₈N₆·C₆H₆N₂O₄S. Special attention is paid to a conformational analysis of the title tetrazine molecule in known crystal structures. Quantum chemistry methods are used to compare the energetic parameters of the investigated conformations. A structural analysis of the hydrogen and halogen bonds with acceptor aromatic tetrazine and pyrazine rings is conducted in order to elucidate factors responsible for conformational stability.     

Replacement of dimethylpyrazolyl group in 1,2,4,5-tetrazines by aliphatic alcohols and water

Reactions of 3,6-bis(4-R-3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines and 3-amino-6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines with aliphatic alcohols and water in the presence of a base involved replacement of the dimethylpyrazolyl group and resulted in the formation of mono- and dialkoxy-1,2,4,5-tetrazines and 6-substituted 3-hydroxy-1,2,4,5-tetrazines. Dissociation constants of the latter were determined by potentiometric titration.     

Synthesis and Spectral,Electrochemical, and Antioxidant Properties of 2-(5-Aryl-6-R-3-phenyl-5,6-dihydro-4H-1,2,4,5-tetrazin-1-yl)-1,3-benzothiazoles

Russian Journal of Organic Chemistry - New 2-(5-aryl-6-R-3-phenyl-5,6-dihydro-4H-1,2,4,5-tetrazin-1-yl)-1,3-benzothiazoles were synthesized from the corresponding formazans by alkylation and...     

Rearrangement of 4-(1-haloalkyl)- and 4-(2-haloalkyl)-2-azetidinones into methyl omega-alkylaminopentenoates via transient aziridines and azetidines

The synthesis of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones was investigated with use of the Staudinger reaction between in situ generated ketenes and alpha-haloimines or beta-haloimines. This new class of functionalized 2-azetidinones was further evaluated for its potential use as intermediates in the synthesis of highly functionalized compounds. The reaction of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones with sodium methoxide in methanol yielded ring-opened products, i.e., methyl 2-alkoxy-4-(alkylamino)pentenoate and methyl 5-(alkylamino)pentenoate, respectively. Further attention was paid in detail to the reaction mechanism involved in this peculiar transformation. It was proven that these reactions proceeded via intermediate aziridines or azetidines.     

Fluorinated molecules relevant to conducting polymer research

The synthesis of versatile fluorine compounds for conducting polymer research on fluorinated materials is presented. 1,2,4,5-Tetrafluorobenzene was converted to 1,2,4,5-tetrafluorobenzaldehyde (1) and protected as an acetal. This gave the acetals 1,2,4,5-tetrafluoro-3-(1,3-dioxol-2-yl)benzene (2a) and 1,2,4,5-tetrafluoro-3-(5,5-dimethyl-1,3-dioxan-2-yl)benzene (2b). Compounds 2a and 2b were converted into the semiprotected 2,3,5,6-tetrafluoroterephthaldehydes: 1,2,4,5-tetrafluoro-3-(1,3-dioxol-2-yl)-6-formylbenzene (3a) and 1,2,4,5-tetrafluoro-3-(5,5-dimethyl-1,3-dioxan-2-yl)-6-formylbenzene (3b). While 3a was easily deprotected to give 2,3,5,6-tetrafluoroterephthaldehyde (4) compound 3b proved very resilient to hydrolysis and gave a 1:1 mixture of 4 and 1,2,4,5-tetrafluoro-3,6-bis(5,5-dimethyl-1,3-dioxan-2-yl)benzene (5). Compound 4 was reduced to 1,2,4,5-tetrafluoro-3,6-dihydroxymethylbenzene (6) and converted into 1,2,4,5-tetrafluoro-3,6-dibromomethylbenzene (7). Compound 7 was finally converted into 1,2,4,5-tetrafluoro-3,6-bis(diethylphosponylmethyl)benzene (8). Compounds 4 and 8 are versatile fluorinated molecules that can be used to replace their hydrogen counterparts in many molecules and materials. To illustrate this compounds 4 and 8 were oligomerised to give partially fluorinated polyphenylenevinylene (9).     

Synthesis of Cytotoxic 1,3,4-trisubstituted 2-azetidinones

A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones were synthesized in order to study the relation between their structure and biological characteristics. Study of the cytotoxic activity of these compounds revealed an anticancer effect in (3S,4S)-1-(4-methoxyphenyl)-3-methyl-2-azetidinones containing 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl substituents at position 4 in vitro with respect to a wide range of monolayer cultures of cancer cells.     

Cyclization of (1,2,4,5-tetrazin-3-yl)hydrazones to 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines

The intramolecular cyclization of (6-R-1,2,4,5-tetrazin-3-yl)hydrazones of ketones (R is 3,5-dimethylpyrazol-1-yl, 4-methylimidazol-1-yl, or 2-alkylidenehydrazino) giving rise to the previously unknown 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines, including spiro compounds, was studied. The reactivity and the yields of the reaction products depend on the structure of the alkylidene fragment and the nature of the substituent in the tetrazine ring.

     

Microwave-assisted synthesis of 3,6-di(pyridin-2-yl)pyridazines: unexpected ketone and aldehyde cycloadditions

3,6-Di(pyridin-2-yl)pyridazines are an interesting class of compounds because of their metal-coordinating ability resulting in the self-assembly into [2x2] gridlike metal complexes with copper(I) or silver(I) ions. These and other substituted pyridazines can be prepared by the inverse-electron-demand Diels-Alder reactions between acetylenes and 1,2,4,5-tetrazines. In this contribution, the effect of (superheated) microwave conditions on these generally slow cycloadditions is described. The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine could be accelerated from several days reflux in toluene or N,N-dimethylformamide to several hours in dichloromethane at 150 degrees C. In addition, the unexpected cycloaddition of the enol tautomers of various ketones and aldehydes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine is described in detail providing an alternative route for the synthesis of (substituted) pyridazines.     

1,4-Disubstituted and 1,4,5-Trisubstituted 2-[(Benzotriazol-1-yl)methyl]pyrroles as Versatile Synthetic Intermediates

The CH(2)Bt substituent, unlike previously used CH(2)X substituents, enables (i) the synthetic elaboration of pyrroles with unsubstituted ring positions and (ii) electrophilic as well as nucleophilic substitutions to give pyrroles of type pyrrolyl-2-CHENu. Thus, 1,4-disubstituted (7) and 1,4,5-trisubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles (15) were easily prepared from the reaction of 5-(benzotriazol-1-yl)-1,2-epoxy-3-pentynes 4 or 14 with primary amines in i-PrOH. The 2-(benzotriazol-1-yl)methyl side chains of compounds 7 and 15 were elaborated by nucleophilic substitution and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety to afford a variety of 1,2,4-trisubstituted (6, 8-9, 11-13) and 1,2,4,5-tetrasubstituted pyrroles (18, 20-22).     

Structural Study on Four co-Crystals of N-Containing Heteroaromatics with Iodofluorobenzene

N-Containing heteroaromatics 1,2,4,5-tetra(pyridin-3-yl)benzene[1,2,4,5-T(3-PY)B] and 1,2,4,5-tetra-(pyridin-4-yl)benzene[1,2,4,5-T(4-PY)B] were each co-crystallized with 1,2-diiodo-tetrafluoro-benzene(1,2-DITFB), or 1,4-diiodo-tetrafluoro-benzene(1,4-DITFB), respectively, generating four co-crystals, namely, (1,2-DITFB)₄·[1,2,4,5-T(3-PY)B](1), (1,2-DITFB)₄·[1,2,4,5-T(4-PY)B](2), (1,4-DITFB)₂·[1,2,4,5-T(3-PY)B]·CHCl₃(3), and (1,4-DITFB)·[1,2,4,5-T(4-PY)B]·2CHCl₃(4). This study takes aim at providing an insight into the relative importance of fundamental solid state halogen bonding interactions(i.e., halogen…N, halogen…halogen, and halogen…π) in systems. The effects of the donor and acceptor on supramolecular assembly and the crystal structure determined interactions were discussed. The N…I halogen bonds are the main directing interactions responsible for the observed structures. In compounds 1 and 2, the donors exhibited lower-than-expected supramolecular connectivity. In spite of this, co-crystal 2 exhibits polymeric structures consisting of infinite one-dimensional(1D) double-zigzag chains of alternating electron donor and acceptor. The basic structure of co-crystals 3 and 4 is also infinite 1D chain. Therefore, the 1D halogen bonded supramolecular assemblies can be obtained by matching the appropriate donor and acceptor.     

[4+2]-Cycloaddition of 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines with alkenes

A number of 1,4-dihydropyridazines and pyridazines were prepared by the Diels-Alder reaction with an inverse electron demand from cyclic heterodiene systems, 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines, and some enamines as well as from 4-vinylpyridine, butyl vinyl ether, phenylacetylene, and acrylamide. The reaction of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with styrene afforded 4,5-dihydropyridazine, which was readily oxidized by atmospheric oxygen to form the corresponding pyridazine. Electron-withdrawing substituents (Br or Cl) in the pyrazole rings accelerate [4+2]-cycloaddition. When heated, 1,4-dihydropyridazines, which were synthesized from tetrazines and enamines, eliminated amine to give pyridazines. The reactivities of tetrazines were evaluated by quantum-chemical methods. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 354–360, February, 2000.     

New general synthesis of tetrahydro-1,2,4,5-tetrazin-3(2H)-one derivatives and stable 3,4-dihydro-3-oxo-1,2,4,5-tetrazin-1(2H)-yl radical derivatives

Reactions of 2-chloroformylhydrazones of aromatic aldehydes or ketones 2 with various hydrazines were converted to monocarbonohydrazone derivatives 3 or 5 and/or tetrahydro-1,2,4,5-tetrazin-3(2H)-one derivatives 6 , 7 . By oxidation with lead dioxide, compounds 6 were transformed into stable 3,4-dihydro-3-oxo-1,2,4,5-tetrazin-1(2H)-yl radical derivatives 8 .     

Stereoselective Synthesis of 3-Substituted 4-(Formyloxy)-2-azetidinones by the Unusual Baeyer-Villiger Reaction of beta-Lactam Aldehydes. Scope and Synthetic Applications

The Baeyer-Villiger oxidation of 4-formyl-beta-lactams 1with m-CPBA gave 4-(formyloxy) beta-lactams 2 in a simple, efficient, and totally stereoselective process. This reaction is one of the scarce examples of the preferred migration of a carbon moiety in an aliphatic aldehyde. The influence of the substituents at N1 and C3 of the four-membered ring in the Baeyer-Villiger rearrangement has been studied. Thus, alkyl, alkenyl, aryl, and alkyloxy 3-substituted-1-(p-anisyl)-2-azetidinones 1 form exclusively 4-(formyloxy) beta-lactams 2. Amide or acetoxy substituents at C3 of the four-membered ring produce mixtures of 4-(formyloxy) beta-lactams 2and 4-carboxy beta-lactams 5. The exclusive formation of carboxy derivatives is observed sometimes for 1-alkyl-substituted-2-azetidinones 1. 4-(Formyloxy) beta-lactams 2 are suitable starting materials to prepare different 4-unsubstituted beta-lactams 9 using beta-hydroxy amides 8 as isolable intermediates. The overall transformation 4-formyl-2-azetidinone to 4-unsubstituted beta-lactam is an easy and convenient stereoselective route to these interesting types of compounds.     

Locoselective [4 + 2] Cycloadditions of Vinylindoles with Inverse Electron Demand: A new access of indolyl-substituted and annellated pyridazines

2-Vinylindole ( 1a ) and its donor- and acceptor-substituted (E)-derivatives 1b – e react highly locoselectively with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate ( 3 ) to form the novel (indol-2-yl)-1,4-dihydropyridazines 4a and 7 as well as the heterocyclic annellated pyridazines 4b , 5 , and 6 . The reactions of the structurally related 3-vinylindoles 2a – e with 3 also gave rise to new indol-3-ylpyridazines 8 , 9 , and 10 . The locoselectivities of these Diels-Alder reactions were controlled mainly by steric effects.