Ring expansion of trans-divinyl ethylene oxide by oxonium ylide [2,3] sigmatropic rearrangement

Oxonium ylide [2,3] sigmatropic rearrangement of trans-divinyl ethylene oxide is observed upon its exposure to ethyl or t-butyl diazoacetate in the presence of either Rh(II) or Cu(II) catalysts to produce cis-6-vinyl-3,6-dihydropyran-2-carboxylates.     

Synthesis of Novel Methyl 7-[(Hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates and Antitumor Activity Evaluation: Effects in Human Tumor Cells Growth,Cell Cycle Analysis,Apoptosis and Toxicity in Non-Tumor Cells

Several novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI₅₀ ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI₅₀ values. The effects of the methoxylated compounds 2b (2-OMeC₆H₄), 2f and 2g (3,4- or 3,5-diOMeC₆H₃, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI₅₀ = 7.8 µM) and selective compound (2g) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition.     

Challenges in the Highly Selective [3 + 1]-Cycloaddition of an Enoldiazoacetamide to Form a Donor–Acceptor Cis-Cyclobutenecarboxamide

A substituted donor–acceptor cyclobutenecarboxamide is synthesized with modest enantiocontrol through a chiral copper(I) complex catalyzed [3 + 1]-cycloaddition reaction of α-acyl diphenylsulfur ylides with 3-siloxy-2-diazo-3-butenamides. With a methyl substituent on the 4-position of the 3-butenamide, the cis-vicinal-3,4-disubstituted cyclobutenecarboxamide is formed with >20:1 diastereocontrol. Donor-acceptor 3-methyl-2-siloxycyclopropenecarboxamide is rapidly formed from the reactant enoldiazoamide and undergoes catalytic ring opening to give only the Z-γ-substituted metallo-enolcarbene. Elimination from 3-siloxy-2-diazo-3-pentenamide to form the conjugated 3-siloxy-2,4-pentadienamide is competitive but minimized at low temperature.     

Molecular iodine: An efficient and environment-friendly catalyst for the synthesis of calix[4]resorcinarenes

Iodine catalyzes the cyclocondensation of various aldehydes with resorcinol to give tetrameric cyclic products, resorcinarenes. Through the reaction of resorcinol with aromatic aldehydes, the product is obtained as a mixture of two isomers, the all-cis isomer (rccc) and the cis-trans-trans isomer (rctt), whereas a single diastereomer, the all-cis, is formed with aliphatic aldehydes. Besides excellent isolated yields, the use of iodine makes this procedure simple, convenient, cost-effective and practical.     

Reactivity of allenoates toward aziridines: [3+2] and formal [3+2] cycloadditions

The reactivity of buta-2,3-dienoates toward aziridines is reported. Allenoates react as 2π-component in the [3+2] cycloaddition with the azomethine ylide generated from cis-1-benzyl-2-benzoyl-3-phenylaziridine affording 4-methylenepyrrolidines in a site-, regio-, and stereoselective fashion. Under conventional thermolysis, cis- and trans-2-benzoyl-1-cyclohexyl-3-phenylaziridines showed a different reactivity. These aziridines participate in formal [3+2] cycloadditions with allenes via C-N bond cleavage of the three-membered ring leading to functionalized pyrroles.     

Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions

The Diels–Alder cycloaddition between bisdienes and bisdienophile incorporating the 7-oxa-bicyclo[2.2.1]heptane unit are well known to show high diastereoselectivity that can be exploited for the synthesis of molecular belts. The related bisdiene 5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octene is a valuable building block for the synthesis of photoprecursors for acenes, but it has not been employed for the synthesis of molecular belts. The present work investigates by computational means the Diels–Alder reaction between these bisdiene building blocks with syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene, which shows that the diastereoselectivity of the Diels–Alder reaction of the etheno-bridged bisdiene is lower than that of the epoxy-bridged bisdiene. The reaction of the etheno-bridged bisdiene and syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene in 2:1 ratio yields two diastereomers that differ in the orientation of the oxa and etheno bridges based on NMR and X-ray crystallography. The all-syn diastereomer can be transformed into a molecular belt by inter- and intramolecular Diels–Alder reactions with a bifunctional building block. The molecular belt could function as a synthetic intermediate en route to a [11]cyclacene photoprecursor.     

Thermal isomerizations of cis,anti,cis-tricyclo[6.4.0.0]dodec-3-ene to trans- and cis,endo-tricyclo[6.2.2.0]dodec-9-ene: diradical conformations and stereochemical outcomes in [1,3] carbon shifts

The gas-phase thermal isomerizations at 315 °C of cis,anti,cis-tricyclo[6.4.0.0^2,7]dodec-3-ene to trans-tricyclo[6.2.2.0^2,7]dodec-9-ene and to cis,endo-tricyclo[6.2.2.0^2,7]dodec-9-ene favor the former, the more geometrically strained product, by a ratio of 2.4:1. These products correspond to suprafacial inversion (si) and suprafacial retention (sr) stereochemical outcomes. The reaction stereochemistry shown by the 11-carbon homolog, cis,anti,cis-tricyclo[6.3.0.0^2,7]undec-3-ene, is strikingly different: the [1,3] carbon shift takes place to give only the ‘forbidden’ sr product. Two related bicyclic vinylcyclobutanes, 8-deuterio- and 8-exo-methylbicyclo[4.2.0]oct-2-enes, evidence contrasting reaction stereochemical predilections in [1,3] shifts, but the 12-carbon tricyclic system and the 8-exo-methyl bicyclic analog isomerize with the same si:sr ratio! These observations prompt fresh considerations of structural influences on conformational preferences available to the alkyl, allyl diradical reactive intermediates involved.     

Cyclization of 1,3-diaryl-3-phenylsulfanyl-1-propanols to thiochromans with the participation of [1,3]-PhS shift

Optically active (3R,1RS)-3-aryl-1-phenyl-3-phenylsulfanyl-1-propanols were easily dehydrated forming mainly rac-cis-2-aryl-4-phenylthiochroman, and rac-cis-4-aryl-2-phenylthiochroman along with the corresponding trans-isomers. The observed reaction outcome (rearrangement and racemisation) apparently results from the S_EAr reaction involving the unusual 1,3-phenylsulfanyl group migration. This interpretation is supported by the results of theoretical studies (DFT) on the supposed intermediates.     

Synthesis and Reactions of 4-Oxiranylmethylfuro[3,2-b]pyrroles and Their Benzo Derivatives

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1-c][1,4]oxazin-8-ones 4a-e.     

The Structural and Optical Properties of 1,2,4-Triazolo[4,3-a]pyridine-3-amine

The structural and spectroscopic properties of a new triazolopyridine derivative (1,2,4-triazolo[4,3-a]pyridin-3-amine) are described in this paper. Its FTIR spectrum was recorded in the 100–4000 cm⁻¹ range and its FT-Raman spectrum in the range 80–4000 cm⁻¹. The molecular structure and vibrational spectra were analyzed using the B3LYP/6-311G(2d,2p) approach and the GAUSSIAN 16W program. The assignment of the observed bands to the respective normal modes was proposed on the basis of PED calculations. XRD studies revealed that the studied compound crystallizes in the centrosymmetric monoclinic space group P2₁/n with eight molecules per unit cell. However, the asymmetric unit contains two 1,2,4-triazolo[4,3-a]pyridin-3-amine molecules linked via N–H⋯N hydrogen bonds with a R₂²(8) graph. The stability of the studied molecule was considered using NBO analysis. Electron absorption and the luminescence spectra were measured and discussed in terms of the calculated singlet, triplet, HOMO and LUMO electron energies. The Stokes shifts derived from the optical spectra were equal to 9410 cm⁻¹ for the triazole ring and 7625 cm⁻¹ for the pyridine ring.     

Die thermische Umlagerung von 2-(Buta-1′,3′-dienyl)-phenolen in 2-Alkyl-2H-chromene; Beispiele für aromatische [1,7a]- und [1,5s]sigmatropische Wasserstoffverschiebungen

2-(1′-cis,3′-cis-)- and 2-(1′-cis,3′-trans-Penta-1′,3′-dienyl)-phenol (cis, cis- 4 and cis, trans- 4 , cf. scheme 1) rearrange thermally at 85–110° via [1,7 a] hydrogen shifts to yield the o-quinomethide 2 (R ? CH₃) which rapidly cyclises to give 2-ethyl-2H-chromene ( 7 ). The trans formation of cis, cis- and cis, trans- 4 into 7 is accompanied by a thermal cis, trans isomerisation of the 3′ double bond in 4. The isomerisation indicates that [1,7 a] hydrogen shifts in 2 compete with the electrocyclic ring closure of 2 . The isomeric phenols, trans, trans- and trans, cis- 4 , are stable at 85–110° but at 190° rearrange also to form 7 . This rearrangement is induced by a thermal cis, trans isomerisation of the 1′ double bond which occurs via [1, 5s] hydrogen shifts. Deuterium labelling experiments show that the chromene 7 is in equilibrium with the o-quinomethide 2 (R ? CH₃), at 210°. Thus, when 2-benzyl-2H-chromene ( 9 ) or 2-(1′-trans,3′-trans,-4′-phenyl-buta1′,3′-dienyl)-phenol (trans, trans- 6 ) is heated in diglyme solution at >200°, an equilibrium mixture of both compounds (～ 55% 9 and 45% 6 ) is obtained.     

[4+3] Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects

Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.     

Angular Regioselectivity in the Reactions of 2-Thioxopyrimidin-4-ones and Hydrazonoyl Chlorides: Synthesis of Novel Stereoisomeric Octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones

The regioselective synthesis of cis and trans stereoisomers of variously functionalized octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones was performed. The 2-thioxopyrimidin-4-ones used in the synthesis reacted with hydrazonoyl chlorides in a regioselective manner to produce the angular regioisomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones rather than the linear isomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones. The synthesis process took place with electronic control. The angular regiochemistry of the products was confirmed by X-ray experiments and two-dimensional NMR studies.     

Determination of 13-cis-Retinoic Acid and Its Metabolites in Plasma by Micellar Electrokinetic Chromatography Using Cyclodextrin-Assisted Sweeping for Sample Preconcentration

The online preconcentration technique, cyclodextrin-assisted sweeping (CD-sweeping), coupled with micellar electrokinetic chromatography (MEKC) was established to determine 13-cis-retinoic acid (13-cis-RA), all-trans-retinoic acid (all-trans-RA) and 4-oxo-13-cis-retinoic acid (4-oxo-13-cis-RA) in human plasma. A CD-sweeping buffer (45 mM borate (pH 9.2), containing 80 mM sodium dodecyl sulfate (SDS) and 22 mM hydroxypropyl β-CD (HP-β-CD) was introduced into the capillary and, then, the sample dissolved in 70 mM borate (pH 9.2): methanol = 9:1 (v/v) was injected into capillary by pressure. The separation voltage was 23 kV. Compared to the conventional cyclodextrin-micellar electrokinetic chromatography (CD-MEKC) method, the new technique achieved 224–257-fold sensitivity enrichment of analytes. The limits of detection of 13-cis-RA, all-trans-RA were 1 ng/mL, whereas that of 4-oxo-13-cis-RA was 25 ng/mL in plasma. The linear ranges of 13-cis-RA, all-trans-RA were between 15 and 1000 ng/mL, whereas that of 4-oxo-13-cis-RA was between 75 and 1500 ng/mL. The coefficient of correlation between the concentration of analytes and peak area ratio of analytes and internal standard (2, 4-dihydroxy-benzophenone) for intra-day (n = 3) and inter-day (n = 5) analyses were both greater than 0.999. The optimized experimental conditions were successfully applied to determine 13-cis-retinoic acid and its metabolites in plasma samples from a patient during the administration of 13-cis-RA for treating acne.     

Study of the rearrangement of cyclononatetraenyl(dipropyl)borane to 7,8-dipropyl-7-borabicyclo[4.2.2]deca-2,4,9-triene by NMR spectroscopy

Using NMR spectroscopy it was found that at ambient temperature 9-cyclononatetraenyl(dipropyl)borane (1) rapidly rearranges to give 7,8-dipropyl-7-borabicyclo[4.2.2]deca-2,4,9-triene (2),cis-endo-9-dipropylborylbicyclo[6.1.0]nona-2,4,6-triene (3a), and two isomeric boranes with dihydroindene skeletons (4a,b) (the ratio2 :3a :4a,b is 10 : 1 : 2).cis-exo-9-Dipropylborylbicyclo[6.1.01nona-2,4,6-triene (3b) is an intermediate product of the rearrangement; it is formed as a result of 8-electrocyclization inE,Z,Z,Z-cyclononatetraenyl(dipropyl)boranela. The transformation of bicycle3b to final product 2 occurs apparently via a synchronous exchange of the groups at the B atom (the transformation of the cyclopropane ring to the boracyclobutane ring accompanied by simultaneous migration of the propyl group from the B atom to thea-C atom). Borane6 formed in this rearrangement rapidly isomerizes to2 via a [1,3]-B shift.For preliminary report see Ref. 1Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. I, pp. 117–124, January, 1996.     

Synthesis,Antibacterial and Antifungal Activity of New 3-Aryl-5H-pyrrolo[1,2-a]imidazole and 5H-Imidazo[1,2-a]azepine Quaternary Salts

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD₅₀ > 2000 mg/kg).     

Synthesis,Structure and Cytotoxicity Testing of Novel 7-(4,5-Dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives

The appropriate 1-arylhydrazinecarbonitriles 1a–c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a–c, which are subsequently converted into the corresponding amides 4a–e, 8a–c, sulfonamides 5a–n, 9, ureas 6a–I, and thioureas 7a–d. The structures of the newly prepared derivatives 3a–c, 4a–e, 5a–n, 6a–i, 7a–d, 8a–c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1′-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC₅₀ values in the range of 2.38–3.77 μM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

A Mononuclear Iron(II) Spin-Crossover Molecule Decorated by Photochromic Azobenzene Group

Aiming at constructing photoresponsive spin crossover (SCO) behavior, herein we designed a new ligand Abtz (Abtz = (E)-N-(4-((E)-phenyldiazenyl)phenyl)-1-(thiazol-4-yl)methanimine) which was decorated by a photochromic azobenzene group. Based on this photochromic ligand, a mononuclear Fe(II) SCO molecule [Fe(Abtz)₃](BF₄)₂·(EAC)₂ (1, EAC = ethyl acetate) was successfully synthesized and showed a complete one-step SCO behavior. Under continuous UV light and blue-light exposure, the cis–trans photoisomerization of both ligand Abtz and compound 1 in the liquid phase was confirmed through UV–Vis spectra. Moreover, the ¹H-NMR spectra of Abtz reveal a trans–cis conversion ratio of 37%. Although the UV–Vis spectra reveal the photochromic behavior for 1 in the solution phase, the SCO behavior in the liquid state is absent according to the variable-temperature Evans method, suggesting the possible decomposition. Moreover, in the solid state, the cis–trans photoisomerization of both Abtz and 1 was not observed, due to the steric hindrance.     

New approaches to synthesis of tris[1,2,4]triazolo[1,3,5]triazines

Thermal cyclization of 3-R-5-chloro-1,2,4-triazoles (R = Cl, Ph) afforded 2,6,10-tri-R- tris[1,2,4]triazolo[1,5-a:1′,5′c:1″,5″-e][1,3,5]triazines 5 (R = Ph) and 7 (R = Cl). These compounds are first representatives of this class of heterocycles, whose structures were unambiguously established. Treatment of these compounds with nucleophiles (H₂O/NaOH, NH₃) results in the triazine ring opening to give compounds consisting of three 1,2,4-triazole rings linked in a chain. For example, treatment of cyclic compound 5 with aqueous alkali affords 3-phenyl-1-3-phenyl-1-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,2,4-triazol-5-yl-1H-1,2,4-triazol-5-one. Treatment of 3,7,11-triphenyltris[1,2,4]triazolo[4,3-a:4′,3′c:4″,3″-e][1,3,5]triazine (2) with HCl/SbCl₅ leads to the triazine ring opening giving rise to 5-(3-chloro-5-phenyl-1,2,4-triazol-4-yl)-3-phenyl-4-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,4-triazole. Thermal cyclization of the latter produces 3,7,10-triphenyltris[1,2,4]triazolo[1,5-a:4′,3′c:4″,3″-e][1,3,5]triazine (13). Thermolysis of both cyclic compound 2 and cyclic compound 13 is accompanied by the Dimroth rearrangement to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:1′, 5′-c:4″,3″-e][1,3,5]triazine (14). Compounds 13 and 14 are the first representatives of cyclic compounds with this skeleton. ¹³C NMR spectroscopy allows the determination of the isomer type in a series of tris[1,2,4]triazolo[1,3,5]triazines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 706–712, March, 2005.