Luminescent cyclometalated iridium(III) dipyridoquinoxaline indole complexes as biological probes

Four luminescent cyclometalated iridium(III) dipyridoquinoxaline complexes appended with an indole moiety [Ir(N∧C)₂(N∧N)] (PF₆) (HN∧C = 2-phenylpyridine, Hppy; N∧N = 2-(N-(2-(indole-3-acetamido)ethyl)aminocarbonyl)dipyrido[3,2-f:2′,3′-h]quinoxaline, dpqC2indole (1a), N∧N = 2-(N-(6-(indole-3-acetamido)hexyl)aminocarbonyl)dipyrido[3,2-f:2′,3′-h]quinoxaline, dpqC6indole (1b); HN∧C = 7,8-benzoquinoline, Hbzq, N∧N = dpqC2indole (2a), N∧N = dpqC6indole (2b)) have been synthesized and characterized. Upon irradiation, all the complexes displayed moderately intense and long-lived luminescence under ambient conditions and in 77 K glass. On the basis of the photophysical data, the emission of the complexes has been assigned to an excited state of triplet metal-to-ligand charge-transfer (³MLCT) ((dπ(Ir) → π*(N∧N)) character. Cyclic voltammetric studies revealed indole-based and iridium-based oxidations at ca. +1.10 V and +1.24 V vs. SCE, respectively, and ligand-based reductions at ca. ?1.07 to ?2.29 V vs. SCE. The interactions of the complexes with an indole-binding protein, bovine serum albumin (BSA), have been examined by emission titrations.     

Intramolecular cyclization of cycloalkene carboxylic acid chlorides

Thermal cyclization of cyclooctene-4-yl-carboxylic acid chloride (5) and cycloheptene-4-yl-carboxylic acid chloride (10) yielded mixtures of mainly endo and exo 2-chlorobicyclo[3.3.1]nonane-9-one (7 and 8), and mixtures of endo and exo 2-chlorobicyclo[3.2.1]octane-8-one (12 and 13), respectively. AlCl₃-catalyzed cyclization of 10 gave the same product composition as the uncatalyzed reaction. In the AlCl₃-catalyzed cyclization of 5 considerable amounts of bicyclo[3.3.1]non-2-en-9-one (6) and exo 3-chlorobicyclo[3.3.1]nonane-9-one (9) were obtained in addition to 7 and 8.     

Aromatization-driven Grob-fragmentation approach toward polyazaacenes. Synthesis and amination of multi-functionalized diazapentacenes

A general approach toward the synthesis of multi-functionalized diazapentacene derivatives 1, using 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene (TDCp, 2), a substituted benzene-1,2-diamine (ADA, 6), and a naphthalene-1,4-dione (BQ, 3) as the building units, is described. The synthesis basically entails three operations: (i) oxidation of the dichloroetheno-bridge in the Diels-Alder cycloadduct 4 of TDCp and 3, (ii) condensation of the 1,2-diketone 5 thus generated with an ADA to give quinoxaline-fused polycyclic compounds 7, followed by (iii) an one-pot, three-reaction process keyed upon the base- or acid-catalyzed aromatization-driven Grob-type fragmentation to produce quinoxaline ring-embedded diazapentaceneesters 1. The diazapentacene derivative 1a underwent the nucleophilic aromatic ipso-amination with primary and secondary amines to afford the amino-substituted derivatives 12, which tend to self-assemble in solid state driven by the cofacial π-stacking interactions, demonstrated by the crystal packing structures of 12a and 12f.     

Quinoxalines and related compounds—X : The formation of indolo[2,3-b]quinoxalines and 2-p-aminophenyl-3-anilinoquinoxalines from 2-anilinoquinoxalines

The reactions which occur when 2-chloroquinoxaline is heated with an excess of aromatic amine are unexpectedly complex. For example, when 2-chloroquinoxaline is heated with excess aniline a mixture of the expected anilino derivative (1), 6H-indolo[2,3-b]quinoxaline (7), 2,3-dianilinoquinoxaline (11), and 2-p-ainino-phenyl-3-anilinoquinoxaline (16) is obtained.     

The unexpected conversion of a thiophene ring into a pyrrole ring via a putative nitrene intermediate

Triethylphosphite induced reductive cyclisation of 1-(2-nitrophenyl)-3,5-di(2-thienyl)pyrazole 6 afforded the expected 1,3-di(2-thienyl)pyrazolo[1,2-a]benzotriazole 7 (14%) together with an unexpected product which was shown to be a 2-(2-thienyl)pyrazolo[1,5-a]pyrrolo[2,1-c]quinoxaline 8 derivative (27%). A mechanism for the extrusion of sulfur during the transformation of heterocycle 6 into product 8 is proposed.     

Substituent effects of pyrazine on construction of crystal structures of Zn(II)-benzoate complexes and their catalytic activities (dinuclear,trinuclear, and pentanuclear to 1-D and 2-D)

Several substituted pyrazine ligands (2,3-dimethylpyrazine, 2,6-dimethylpyrazine, 2,5-dimethylpyrazine, quinoxaline) as well as simple pyrazine have been employed to investigate how the bridging pyrazine ligand influences on construction of Zn-benzoate complexes. Simple pyrazine and 2,5-dimethlpyrazine are used as bridging ligands to form two-dimensional and one-dimensional polymeric compounds, respectively. The other quinoxaline and two dimethyl-substituted pyrazine ligands are used only as terminal ligands to form dinuclear, trinuclear, and pentanuclear complexes. This result indicates that the substituents of pyrazine are very important roles for construction of Zn-benzoate complexes. Interestingly, the compounds 1–5 catalyzed efficiently the transesterification of a variety of esters, and among them, the pentanuclear complex 3 showed the most efficient reactivity. The substrates with the electron-withdrawing substituents have undergone faster transesterification, while those with the electron-donating ones have shown slow reaction. In addition, p-nitrophenyl acetate and p-nitrophenyl benzoate, known to be problematic substrates for the transesterification reaction, were also converted quantitatively to the corresponding products. Selectivity test of primary over secondary alcohol protection in the presence of 3 has provided, exclusively, the primary acetate, propyl acetate, suggesting that this catalytic system can be potentially useful in selecting for primary alcohols.     

Design,synthesis of new novel quinoxalin-2(1H)-one derivatives incorporating hydrazone,hydrazine, and pyrazole moieties as antimicrobial potential with in-silico ADME and molecular docking simulation

A series of 6-(morpholinosulfonyl)quinoxalin-2(1H)-one based hydrazone, hydrazine, and pyrazole moieties were designed, synthesized, and evaluated for their in vitro antimicrobial activity. All the synthesized quinoxaline derivatives were characterized by IR, NMR (¹H /¹³C), and EI MS. The results displayed good to moderate antimicrobial potential against six bacterial, and two fungal standard strains. Among the tested derivatives, six quinoxalin-2(1H)-one derivatives 4a, 7, 8a, 11b, 13, and 16 exhibited a significant antibacterial activity with MIC values (0.97–62.5 µg/mL), and MBC values (1.94–88.8 µg/mL) compared with Tetracycline (MICs = 15.62–62.5 µg/mL, and MBCs = 18.74–93.75 µg/mL), and Amphotericin B (MICs = 12.49–88.8 µg/mL, and MFC = 34.62–65.62 µg/mL). In addition, according to CLSI standards, the most active quinoxalin-2(1H)-one derivatives demonstrated bactericidal and fungicidal behavior. Moreover, the most active quinoxaline derivatives showed a considerable antibacterial activity with bactericidal potential against multi-drug resistance bacteria (MDRB) strains with MIC values ranged between (1.95–15.62 µg/mL), and MBC values (3.31–31.25 µg/mL) near to standard Norfloxacin (MIC = 0.78–3.13 µg/mL, and MBC = 1.4–5.32 µg/mL. Further, in vitro S. aureus DNA gyrase inhibition activity were evaluated for the promising derivatives and displayed potency with IC₅₀ values (10.93 ± 1.81–26.18 ± 1.22 µM) compared with Ciprofloxacin (26.31 ± 1.64 µM). Interestingly, these derivatives revealed as good immunomodulatory agents by a percentage ranging between 82.8 ± 0.37 and 142.4 ± 0.98 %. Finally, some in silico ADME, toxicity prediction, and molecular docking simulation were performed and showed a promising safety profile with good binding mode.     

Addition reactions of nucleophiles to dibenzoylacetylene

Several enamine diones have been prepared through the nucleophilic addition of different amines to dibenzoylacetylene (DBA). Thus, the reaction of aniline, piperidine, o-aminophenol and N-phenylbenzylamine with DBA gave the corresponding 1:1 adducts namely, 1,4 - diphenyl - 2 - (N - phenylamino)but - 2 - ene -1,4 - dione (1), 1,4 - diphenyl - 2 - piperidinobut - 2 - ene - 1,4 - dione (2), 2 - (N - 2 - hydroxyphenylamino)1,4 - diphenylbut - 2 -ene - 1,4 - dione (3) and 1,4 - diphenyl - 2 - (N - phenylbenzylamino)but - 2 - ene - 1,4 - dione (4). UV absorption data reveal that the adducts 1 and 3, formed from aniline and o-aminophenol, respectively, are the E-isomers, arising through a trans-mode of addition whereas the adducts 2 and 4, formed from piperidine and N-phenyl-benzylamine are the Z-isomers, formed through a cis-mode of addition.The reaction of N-phenaeylaniline with DBA gave 2,3 - dibenzoyl - 1,4 - diphenylpyrrole (5), whereas the reaction of 1,8 - diaminonaphthalene with DBA gave a mixture of products consisting of 2 - benzoyl - 2 - phenacyl -2,3 - dihydroperimidine (11) and 2 - benzoylperimidine (12). The reaction of 2-aminopyridine with DBA gave a mixture of two 1:1-adducts, 2 - (2 - imino - 1(2H) - pyridyl) - 1,4 - diphenylbut - 2 - ene - 1,4 - dione (14) and 1,4 -diphenyl - 2 - (N - 2 - pyridylamino)but - 2 - ene - 1,4 - dione (15).     

Quinoxaline-benzimidazole rearrangement in the synthesis of benzimidazole-based podands

Alkylation of 3-benzoylquinoxalin-2(1H)-one with 1,5-dibromo-3-oxapentane, 1,8-dibromo-3,6-dioxaoctane, and α,ω-dihaloalkanes with different lengths of the polymethylene chain gave the corresponding quinoxaline podands. In the reaction with 1,2-dibromoethane, the N,O-rather than N,N′-alkylation product was obtained. The reaction of the obtained quinoxaline-based podands with benzene-1,2-diamine followed the quinoxaline-benzimidazole rearrangement pattern with formation of 2-(3-phenylquinoxalin-2-yl)benzimidazole-based podands.     

Development of an unexpected reaction pathway for the synthesis of 1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-catalyzed cascade reactions

1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines are synthesized through the multi-component reaction of 3-substituted 2-chloroquinoxalines, propargyl bromide, and excess secondary amines in the presence of a palladium copper catalytic system. This one-pot process provides an unexpected synthesis of new trisubstituted pyrrolo[1,2-a]quinoxalines by the introduction of two amine substituents onto the fused pyrrole rings in a single reaction procedure. The compounds formed are fully characterized by the analytical spectral data and X-ray analysis. A number of synthesized pyrrolo[1,2-a]quinoxaline derivatives are also screened against the three bacterial strains Micrococcus luteus, Pseudomonas aeruginos, and Bacillus subtilis. According to the results obtained, compounds 3b, 3c, and 3e are active against M. luteus, compounds 3b and 3e are active against Ps. Aeruginos, and only compound 3f is active against all the three bacterial strains.     

Isolation, X-ray structure and properties of an unusual pentacarbonyl(2,2′-pyridyl-quinoxaline) tungsten complex

The first example of a monodentate complexation of 2-(2′-pyridyl)quinoxaline (pq) to a metal centre through N₄ is reported. Photochemical exchange of the THF ligand in W(CO)₅THF by pq yields W(CO)₅(N₄-pq) (1), where the potentially bidentate pq ligand coordinates in an unusual monodentate fashion. Complex 1 is isolated as orange crystals and fully characterized on the basis of NMR, IR, UV-Vis and emission spectroscopy. The structure of 1 was determined by X-ray analysis. W(CO)₅(N₄-pq) (1) crystallizes in space group P2_1/n, monoclinic crystal system with α = 7.0237(5) Å, b = 10.4618(8) Å, c = 23.7768(18) Å, Z = 4 and V = 1731.9(2) Å³. Complex 1 exhibits intramolecular CH?N and intermolecular CH?O hydrogen bonds between the CH groups and nitrogen atoms of quinoxaline and CH groups and oxygen atoms of carbonyls, respectively, resulting in a supramolecular architecture in solid state. The preference to N₄ as coordination site is discussed in terms of electronic interactions. Solutions of 1 emits dually at 77 K while they are moderately instable at room temperature, as 1 undergoes chelation via a first-order kinetic process to form W(CO)₄pq (2). The determined reaction rate of 1 in toluene is 2.3 × 10⁻⁵ s⁻¹ (at 298 K) and is compared with literature values for other W(CO)₅L (L:diimine) complexes.     

Synthesis and properties of 1H-1,2,4-benzotriazepines

The synthesis of some N,N-disubstituted benzhydrazidoyl chlorides and their reaction with cyano compounds in the presence of a Lewis acid are described. Whereas N-methyl-N-phenylbenzhydrazidoyl chloride (1a) gave 1H-1,2,4-triazoles, N,N-diphenylbenzhydrazidoyl chloride (1b) afforded 1H-1,2,4-benzotriazepines (3b) and N,N-(2,2′-biphenylen)benzhydrazidoyl chloride (10) yielded the corresponding 1H-1,2,4-benzotriazepine (12) or a hydrolysis product (13). Properties of compounds 3b, specially their near-quantative acid hydrolysis to 1-phenylindazoles, are reported.     

The coordination chemistry of enantiopure diimines derived from 1-phosphanorbornadiene-2-carboxaldehydes

The reaction of trans-1,2-diaminocyclohexane with enantiopure (R)-2-formyl-1-phosphanorbornadiene (1) takes place with efficient kinetic resolution and gives an easily separable mixture of the corresponding (S,S)-bis-imine (3) and (R)-mono-imine (4). The absolute configuration of 3 has been established by X-ray crystal structure analysis. The coordination chemistry of enantiopure 3 with Pd(II), Rh(I), and Ru(II) has been investigated. The reaction of [PdCl₂(cod)] mainly affords a binuclear complex 6 whose structure has been established by X-ray analysis. One unit is coordinated to one P and one PdCl⁺ unit is tricoordinated to the other P and the two N. The two square planar units are parallel and the Pd?Pd distance is 3.1787(5) Å. The reaction of [RhCl(cod)]₂ gives the very reactive tetracoordinate cationic [Rh(P₂N₂)]⁺ species 7 which is able to activate one C-Cl bond of chloroform to give the dichloromethyl-Rh complex (8) whose octahedral structure has been ascertained by X-ray analysis.     

Substrate engineering: Effects of different N-protecting groups in the CAL-B-catalysed asymmetric O-acylation of 1-hydroxymethyl-tetrahydro-β-carbolines

In the frame of substrate engineering, the steric effect of different N-protecting groups on the enantioselectivity and reaction rate of CAL-B-catalysed (S)-selective O-acylation of N-protected 1-hydroxymethyl-tetrahydro-β-carbolines was investigated. Excellent enantioselectivities (E?>?200) were observed when the acylation of N-Boc [(±)-1], N-Cbz [(±)-3], and N-Fmoc-protected [(±)-4] substrates was performed with the use of CAL-B and acetic anhydride in toluene at 60?°C. The resolution of N-acetyl-protected substrate (±)-2 showed excellent E (>200) after 30?min, but as the reaction progressed, E started decreasing after 2 days, because of N→O and O→N acyl migrations. Preparative resolutions of (±)-3 and (±)-4 resulted in unreacted amino alcohols (R)-3 and (R)-4 and esters (S)-7a and (S)-8a with good enantiomeric excesses (≥88%) and high yields (≥44%).     

Formation and amination of dibenz[b,f,-1]azapen-talene dianion: Attempted synthesis of dibenz[b,f,-1]azapentalene

Dibenz[b, f,-1]azapentalene dianion (3) was allowed to react with N,N diethyl - O - mesitylenesulfonylhydroxylamine (4) in order to obtain N,N - diethyl - 5,10 - dihydroindeno[1,2 - b] - indol - 10 - amine (11). The available data indicated that electron transfer processes were involved in the formation of 11. Attempts to obtain dibenz[b, f,-1]azapentalene (1) and 11 by Hofman elimination or by the reaction of 11 with trifluoroacetic acid were unsuccessful.     

Thermochromism and photochromism of aryl substituted acyclic azines: Uncatalised and acid-catalised thermal isomerisation

The photochemical E-Z isomerisation of the benzophenone-9-anthraldehyde azine (1), benzophenone-9-acridine aldehyde azine (2) and 9-anthraldehyde azine (3) is thermally reversible. The thermal reaction gives the same isomers as the photochemical reaction. We have studied the mechanism of the thermal isomerisation of these azines. Our results are in accordance with an inversion of the N atom which is connected with a rotation movement about the N-N single or the CN double bond.     

Activation and transfer of oxygen—XII : Alkoxy adducts derived from 1,3,10-trimethylalloxazinium (1,3-dimethylflavinium) cations

Monoalkoxy adducts, derived from an alloxazinium cation and an alcohol in the presence of a base, are readily converted into dialkoxy adducts. Two types of dialkoxy adducts are formed. In the reaction with a monohydric alcohol C₄ is preferred for the second intermolecular nucleophilic attack to give the 4,10a-dialkoxy adduct, which rearranges into a hexahydroimidazo[4,5-b]quinoxalme derivative 5c. In the reaction with a dihydric alcohol C_4a, is the second reaction site in an intramolecular nucleophilic ringclosure to give a 4a,10a-dialkoxy adduct 6c which can be isolated as such. Both types of dialkoxy adducts can be reconverted into the alloxazinium cation.The structures of the dialkoxy adducts give every reason to reject the conclusion in the literature that C_9a is the primary addition site.Starting from 5c several reactions have been effected: (a) conversions into tetra- and di-hydroimidazo[4,5-b]quinoxalinium cations 7 and 9 and ring opening of 9 into a ureido-dihydroquinoxaline 10 (Scheme 4); (b) a rearrangement of a transient hexahydroimidazo[4,5-b]quinoxaline 5d into spirohydantoin 4 and a rearrangement of cation 7 into the alloxazinium cation 1 (Scheme 5); (c) preparation of acetylated tetra- and hexa-hydroimidazo[4,5-b]quinoxalines 11 and 12. Conversions of cation 11 into 9 and 1 and conversions of 12 into a benzimidazolinium cation 14 (Schemes 6 and 7). Degradation of 14 affords 1,2-dimethylbenzimidazole (15, Scheme 6).     

Deoxygenation of quinoxaline N-oxides and related compounds

The alkali induced deoxygenation of 3-(α-hydroxyalkyl)-quinoxaline-1-oxides is shown to be first order in substrate and in hydroxide ion. Examples are given to illustrate the synthetic utility of this reaction for the synthesis of quinoxaline and quinoline derivatives of type 4, 5, 8, and 11. The mechanism of the reaction is related to the mechanism of deoxygenation of heteroaromatic N-oxides by sodium dithionite.     

A three-dimensional copper(II) coordination polymer featuring the 2,3-dioxyquinoxalinate(-2) ligand: Preparation,structural characterization and magnetic study

The synthesis, single-crystal X-ray structure and magnetic properties of [Cu₃L₂Cl₂(DMF)₄]_n (1), where L^2? is the 2,3-dioxyquinoxalinate(-2) ligand, are reported. The complex was prepared by the reaction of CuCl₂ and 1,4-dihydro-2,3-quinoxalinedione (H₂L′) under basic conditions using either solvothermal or normal laboratory techniques. Compound 1 is a 3D coordination polymer with an (8².10)-a, lig (LiGe) topology, containing the ligand in a novel 3.1111 (Harris notation) coordination mode. Variable-temperature and variable-field magnetic studies reveal that the ligand L^2? propagates weak antiferromagnetic exchange interactions through its “quinoxaline” part. IR data are discussed in terms of the structural features of 1 and the coordination mode of L^2?.     

Asymmetric halolactonisation reaction—1 : Asymmetric synthesis of optically active α,α-disubstituted-α-hydroxy acids from α,β-unsaturated acids by the novel use of halolactonisation r

Considering the usefulness of optically active α,α-disubstituted -α -hydroxy acids (1) andα,α- disubstituted-α-hydroxy ketones (2) readily accessible from 1 exploitation of a new asymmetric synthesis of 1 from α,β-unsaturated acids (3) which utilised halolactonisation reaction as its key step, was studied.The asymmetric bromolactonisation of (S) N-(α, β-unsaturated)acylproline((S) 5) derivable from 3 such as tiglic acid (3a) and trans-α methylcinnamic acid (3b), with N-bromosuccinimide in N,N dimethylformamide was found to proceed in a highly stereoselective and regiospecific manner giving a mixture of the two diastereomeric bromolactones (8) in which one diastereomer (8A) was highly predominant. Debromination of 8 followed by acidic hydrolysis readily afforded (R)-1 being 89-98% optically pure.