Benzo[c]isothiazole 2‐Oxides: Three‐Dimensional Heterocycles with Cross‐Coupling and Functionalization Potential

A robust method for the synthesis of benzo[c]isothiazole 2‐oxides has been developed providing a range of functionalized derivatives starting from anilines and DMSO. The reaction sequence can be performed on a gram scale and leads to products that can easily be modified by standard cross‐coupling reactions.

     

Diversified Construction of Chromeno[3,4‐c]pyridin‐5‐one and Benzo[c]chromen‐6‐one Derivatives by Domino Reaction of 4‐Alkynyl‐2‐oxo‐2H‐chromene‐3‐carbaldehydes

Silver‐catalyzed three‐component, tandem reactions of 4‐alkynyl‐2‐oxo‐2H‐chromene‐3‐carbaldehydes, amines and various nucleophiles result in the formation of highly functionalized chromeno[3,4‐c]pyridin‐5‐ones in high yields. Gold‐catalyzed [4+2] cycloadditions of 4‐alkynyl‐2‐oxo‐2H‐chromene‐3‐carbaldehydes with alkynes or alkenes have also been achieved to afford benzo[c]chromen‐6‐ones efficiently.

     

苯并呋喃类化合物的合成研究新进展

文章介绍了苯并呋喃的生物活性研究及最新应用,并综述了近几年来苯并呋喃类化合物结构骨架的构建与合成方法。     

Iron(III) Chloride‐Catalyzed Tandem Aza‐Prins/Friedel–Crafts Cyclization of 2‐Arylethyl‐2,3‐butadienyl Tosylamides and Aldehydes‐An Efficient Synthesis of Benzo[f]isoquinolines

An efficient approach for the synthesis of 1,2,3,4,5,6‐hexahydrobenzo[f]isoquinolines via a tandem aza‐Prins/Friedel–Crafts cyclization from 2‐arylethyl‐2,3‐butadienyl tosylamides and aldehydes has been developed. This iron(III) chloride‐catalyzed cascade cyclization at the room temperature with different types of aldehydes, such as aromatic and heteroaromatic aldehydes, alkyl aldehydes, and α,β‐unsaturated aldehydes, affords the products in moderate to excellent yields (up to 97 %). In this reaction, chlorotrimethylsilane was applied to activate the aldehydes. The cheap catalyst, the mild reaction conditions, and the broad scope of the substrates make this method highly useful.

     

Phosphine‐Catalyzed Cascade Reaction of Unsaturated Pyrazolones with Alkyne Derivatives: Efficient Synthesis of Pyrano[2,3‐c]pyrazoles and Spiro‐cyclopentanone‐pyrazolones

A triphenylphosphine‐catalyzed cascade reaction of unsaturated pyrazolones with dialkyl acetylenedicarboxylates or but‐3‐yn‐2‐one to synthesize the bioactive pyrano[2,3‐c]pyrazoles in moderate to excellent yields has been developed. Meanwhile, spiro‐cyclopentanone‐pyrazolones were also first constructed by the triphenylphosphine‐catalyzed cascade reaction of unsaturated pyrazolones with 4‐phenylbut‐3‐yn‐2‐one in moderate to good yields.

     

Gold(I)‐Catalyzed Cascade for Synthesis of Pyrrolo[1,2‐a:2′,1′‐c]‐/Pyrido[2,1‐c]pyrrolo[1,2‐a]quinoxalinones

An efficient and convenient method was developed for the one‐pot construction of the complex polycyclic heterocycles pyrrolo[1,2‐a:2′,1′‐c]‐/pyrido[2,1‐c]pyrrolo[1,2‐a]quinoxalinones from two simple starting materials via a gold(I)‐catalyzed domino reaction. This strategy presents an atom economical and environmentally friendly transformation, in which two new C N bonds and one new C C bond are formed in a one‐pot reaction process.     

Palladium(0)/Copper(I)‐Catalyzed Tandem Cyclization of Aryl 1‐Cyanoalk‐5‐ynyl Ketone System: Rapid Assembly of Cyclopenta[b]naphthalene and Benzo[b]fluorene Derivatives

We have developed a new and general approach to construct a variety of benzo[b]fluorene and cyclopenta‐[b]naphthalene derivatives via the palladium(0)/copper(I)‐catalyzed tandem cyclization of aryl 1‐cyanoalk‐5‐ynyl ketone systems in an extremely efficient manner. The key operation lies in the copper(I)‐catalyzed aerobic oxidation, which allows for activation of two successive intramolecular cycloadditions immediately after the Sonogashira coupling reaction has occurred.     

Proton‐Promoted Hydroamination of 3‐Dialkylthiomethylene‐1,4‐pentadiynes with o‐Phenylenediamines: A Facile Route to Benzo[b][1,4]diazepines

The first proton‐promoted intermolecular hydroamination reaction of the enynes, α,α‐dialkynylketene S,S‐acetals 2 , is described. A series of benzo[b][1,4]diazepines, with the structures of 3 and 5 , were prepared chemo‐ and regioselectively in good to high yields by reacting the readily available 1,4‐diynes 2 with both terminal and internal alkyne functions with o‐phenylenediamines under very mild conditions.     

Copper‐Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2‐a]pyrimidin‐4(10H)‐ones using Cyanamide as a Building Block

An efficient and practical copper‐catalyzed domino synthesis of benzo[4,5]imidazo[1,2‐a]pyrimidin‐4(10H)‐ones has been developed. The protocol uses N‐(2‐halophenyl)‐3‐alkylpropiolamides and cyanamide as the starting materials, inexpensive copper(I) iodide and pipecolinic acid as the catalyst and ligand, and the corresponding products were obtained in moderate to good yields.

     

An Abbreviated Synthesis of 7,12-Dimethylbenz[ a ]anthracene and Benzo[ c ]chrysene Metabolites Using the Suzuki Reaction

Efficient syntheses of important metabolites of 7,12-dimethylbenz[ a ]anthracene (DMBA) and benzo[ c ]chrysene (B[ c ]C), via Suzuki coupling reaction are described. This approach provides an excellent method for the preparation of 3-methoxy-DMBA 5 , 10-methoxy-B[ c ]C 14 and 2-methoxy B[ c ]C 20 , and hence for the corresponding dihydrodiols 6 , 15 , and 21 . Following a similar Suzuki reaction, DMBA-6(5 H )-one 8 was also synthesized in high yield.     

Evaluation of Benzo[c]Chrysene Dihydrodiols in the Morphological Cell Transformation of Mouse Embryo Fibroblast C3H10T1/2CL8 Cells

The morphological cell transforming activities of three dihydrodiols of benzo[c]chrysene (B[c]C), trans?B[c]C-7,8-diol, trans?B[c]C-9,10-diol, and trans?B[c]C-1,2-diol were compared to those of B[c]C in order to study the possible routes of metabolic activation in transformable C3H10T1/2 mouse embryo fibroblasts. B[c]C-treated C3H10T1/2 cells exhibited a concentration-related increase in morphologically transformed foci over a concentration range of 0–3 μg/ml. At 3 μg/ml, B[c]C induced 1.23 Type II & III foci/dish, with 73% of the dishes exhibiting Type II or Type III foci, and a survival of 87%. trans?B[c]C-7,8-diol produced concentration-related responses over a range of 0–5 μg/ml. At 3 μg/ml, trans?B[c]C-7,8-diol produced 1.13 Type II & III foci/dish with 72% of the dishes exhibiting foci, and a survival of 76%. trans?B[c]C-9,10-diol was inactive as a morphological cell transforming agent over a concentration range of 0–3 μg/ml. trans?B[c]C-1,2-diol was also inactive as a morphological cell transforming agent over a concentration range of 0–3 μg/ml. These results suggest that a K-region dihydrodiol of B[c]C, trans?B[cC-7,8-diol, may play a role in the ability of B[c]C to morphologically transform C3H10T1/2 cells.     

Impact of alkyl side chain on the photostability and optoelectronic properties of indacenodithieno[3,2‐b]thiophene‐alt‐naphtho[1,2‐c:5,6‐ c′]bis[1,2,5]thiadiazole medium bandgap copolymers

Three donor‐π‐acceptor (D‐π‐A) type alternating conjugated polymers, namely PIDTT‐DTNT‐C16, PIDTT‐DTNT‐HD and PIDTT‐DTNT‐OD bearing the same backbone of indacenodithieno[3,2‐b]thiophene (IDTT) as the D unit and naphtho[1,2‐c:5,6‐c′]bis[1,2,5]thiadiazole (NT) as the A moiety but with different flexible side chain (n‐hexadecyl (C16), 2‐hexyldecyl (HD) and 2‐octyldodecyl (OD)) substituted thiophene employed as π‐bridges, were synthesized and characterized. The effects of the side chain on absorption, photostability, energy levels, aggregation, backbone conformation, morphology and photovoltaic properties were systematically investigated. Because moderate D and strong A units were selected to construct the polymer backbone, a medium optical bandgap (ca. 1.66 eV) and low‐lying highest occupied molecular orbital energy level (E_HOMO ≈ ?5.36 V), thus resulting in a relatively higher open‐circuit voltage (V_OC) of 0.80–0.83 V, were achieved. It was found that the side chain gave rise to an insignificant impact on absorption, aggregation and photostability in chlorobenzene solution and energy levels but a non‐negligible influence on absorption, photostability and aggregation behavior in the film state. It was found that PIDTT‐DTNT‐C16 with the densest and most ordered packing structure exhibited the best photostability. Inverted bulk heterojunction polymer solar cells based on PIDTT‐DTNT‐HD:PC₆₁BM ([6,6]‐phenyl‐C₆₁‐butyric acid methyl ester) showed at least a 1.5‐fold increase in power conversion efficiency, chiefly originating from its slightly improved absorption, more balanced μ_h/μ_e ratio and favorable morphology of the active layer as a result of incorporating branched HD side chains into the IDTT‐alt‐DTNT backbone. © 2019 Society of Chemical Industry     

New Rapid HPLC Method for Separation and Determination of Benzo[A]Pyrene Hydroxyderivatives

A new rapid, one-step semi-quantitative HPLC-MS method applicable for the separation and characterization of the group of total 10 BaP hydroxyderivatives (1-hydroxy benzo[a]pyrene, 2-hydroxybenzo[a]pyrene, 3-hydroxybenzo[a]pyrene, 4-hydroxybenzo [a]pyrene, 7-hydroxybenzo[a]pyrene, 8-hydroxybenzo[a]pyrene, 9-hydroxybenzo[a]py rene, 10-hydroxybenzo[a]pyrene, 12-hydroxybenzo[a]pyrene and benzo[a]pyrene-9,10-dihydrodiol) was developed, involving electrospray ionization technique (ESI) in positive mode. Its qualitative and quantitative characteristics were selected by the analysis of the model OH-BaP mixture consisted of compounds mentioned above. The model system offered the linear response in the whole concentration range used (50–1000 ng.mL^?1) as well as the resolution sufficient for semi-quantitative purposes (R_S > 0.5). Subsequently, the suitability of the developed method was tested on BaP decomposition products to be formed during photooxidation at λ = 365 nm. These analyses confirmed the applicability of the proposed method, succeeding in the identification of 5 BaP hydroxyderivatives formed upon the BaP photooxidation experiment.     

Species-Dependent Metabolism of Benzo[c]Chrysene Mediated by c-DNA-Expressed Human,Rodent and Fish Cytochrome P450 Enzymes

The metabolism of benzo[c]chrysene (B[c]Ch) with various cytochrome P450 (CYP) enzymes including rat 1A1, 1A2, 2B1 and 2E1, human 1A1, 1A2, 2A6, 1B1, 3A4 and 2E1, mouse 1B1, and scup fish 1A1 expressed in Chinese hamster V79 cells has been investigated to clarify the role of individual enzymes in the regioselective oxidation of B[c]Ch and the species dependency. In six cell lines expressing individual CYP enzymes from four different species B[c]Ch was metabolized to several isomeric phenols and trans?dihydrodiols. However, cell lines expressing human 3A4, 2A6 and 2E1 or rat 1A2, 2B1 and 2E1 were metabolically in-competent towards B[c]Ch. Among the trans?dihydrodiols the 9,10-isomer could be detected in cells expressing human, rat and fish CYP 1A1 and to a minor extent in cells with human 1A2, but not in cells expressing human and mouse CYP 1B1. The latter two cell lines produced high amounts of the bay region 3,4-dihydrodiol, whereas the K-region 7,8-dihydrodiol was a minor metabolite. Oxidation of B[c]Ch to the 1,2-dihydrodiol could not be catalyzed by any of the CYP enzymes investigated except fish 1A1. Our results suggest that metabolic activation of B[c]Ch is initiated predominantly by CYP 1A1 to result selectively in the formation of fjord region 9,10-dihydrodiol 11,12-epoxides regardless of the species involved. The activation of B[c]Ch appears to be limited by a low regioselectivity for the 9,10-oxidation.     

Design and synthesis of thieno[3,4‐c]pyrrole‐4,6‐dione based conjugated copolymers for organic solar cells

A new series of conjugated copolymers (PBDT‐TPD , PBDT ‐Th‐TPD , PBDT‐TT‐TPD ) containing donor–acceptor (D ? A) structure electron‐rich benzo[1,2‐b :4,5‐b ′]dithiophene (BDT ) units with branched alkyl thiophene side chains and electron‐deficient 5‐(2‐octyl)‐4H ‐thieno[3,4‐c ]pyrrole‐4,6(5H )‐dione (TPD) units was designed and synthesized. To tune the optical and electrochemical properties of the copolymers, the conjugation length of the copolymers was extended by introducing π‐conjugated spacers such as thiophene and thieno[3,2‐b ]thiophene units. It was observed that PBDT‐TPD showed broader absorption spectra in the longer wavelength region and the absorption maximum was red‐shifted compared to that of PBDT‐Th‐TPD, PBDT‐TT‐TPD. Stokes shifts were calculated to be 52 nm for PBDT‐TPD, 153 nm for PBDT‐Th‐TPD and 146 nm for PBDT‐TT‐TPD. Further, PBDT‐TPD exhibited a deeper highest occupied molecular orbital energy level of ?5.53 eV as calculated by cyclic voltammetry. Bulk heterojunction solar cells fabricated using PBDT‐TPD as donor material exhibited a power conversion efficiency of 1.92%. © 2017 Society of Chemical Industry     

GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines

Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo[7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 20 a , K_i=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 23 a , K_i=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ₁ and σ₂ receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands.     

2,3‐Disubstituted Benzo[b]thiophenes from Diarylalkynes via Electrophilic Addition‐Cyclization and Palladium‐Catalyzed Cross‐Coupling

Diarylalkynes are readily transformed in 3‐chlorobenzo[b]thiophenes in a two‐step electrophilic addition‐cyclization procedure that runs highly efficiently in solution or in the solid phase. The heteroaromatic carbon‐chlorine bond participates in palladium‐catalyzed Suzuki–Miyaura or Buchwald–Hartwig cross‐couplings to give, in a single step, 2,3‐disubstituted derivatives of pharmacological relevance .     

New Benzo[c]phenanthridine and Benzenoid Derivatives,and Other Constituents from Zanthoxylum ailanthoides: Effects on Neutrophil Pro-Inflammatory Responses

A new benzo[c]phenanthridine, oxynorchelerythrine (1), and two new benzenoid derivatives, methyl 4-(2-hydroxy-4-methoxy-3-methyl-4-oxobutoxy)benzoate (2) and (E)-methyl 4-(4-((Z)-3-methoxy-3-oxoprop-1-enyl)phenoxy)-2-methylbut-2-enoate (3), have been isolated from the twigs of Zanthoxylum ailanthoides, together with 11 known compounds (4–14). The structures of these new compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, decarine (4), (−)-syringaresinol (6), (+)-episesamin (8), glaberide I (9), (−)-dihydrocubebin (10), and xanthyletin (11) exhibited potent inhibition (IC₅₀ values ≤ 4.79 μg/mL) of superoxide anion generation by human nutrophils in response to N-formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (fMLP/CB). Compounds 4, 8, and 11 also inhibited fMLP/CB-induced elastase release with IC₅₀ values ≤ 5.48 μg/mL.     

Syntheses and Identification of Benzo[C]Chrysene Metabolites

Like other PAHs, chrysenes are thought to exert their carcinogenicity via metabolic activation of proximally carcinogenic dihydrodiols to diol epoxides as ultimate carcinogens. Benzo[c] chrysene (B[c]C) is structurally intriguing among the PAH because it features both a bay region and a fjord region. Although B[c]C is carcinogenic and mutagenic, few data are available on its metabolic activation or the nature of its metabolites.

We have synthesized the B[c]C trans-1,2-, 7,8-, and 9,10-dihydrodiols from the appropriate methoxy-substituted bisnaphthyl olefins by photochemical cyclization. B[c]C was metabolized with S9 liver fraction from phenobarbital/β-naphthoflavone-treated rats. Dihydrodiols were formed on both terminal rings as well as in the K-region. 2-, 3-, and 10-HydroxyB[c]C were also identified as metabolites. In mutagenicity studies toward S. typhimurium TA100, 1,2-dihydrodiol was more mutagenic than B[c]C at doses above 1.25 μg/plate, whereas 9,10-dihydrodiol was toxic at doses above 1.25 μg/plate.