Efficient approach to 1,1'-bisindoles via copper(I)-catalyzed double domino reaction.

A highly efficient copper(I)-catalyzed approach for the synthesis of 1,1'-bisindoles that is based on the formation of four bonds in one step has been developed. The unprecedented three component reaction between one molecule of a 1,2-bis(2-bromoaryl)hydrazine and two molecules of a 1,3-diketone employing 10 mol% CuI as a catalyst and Cs2CO3 as a base in DMSO at 100 °C for 24 h delivers substituted 1,1'-bisindoles with yields up to 92%. The new method proceeds as a double domino condensation/Ullmann type C-C coupling. It allows an efficient and practical access to substituted 1,1'-bisindoles in one step from easily available starting materials.

Cleistanthin A causes peripheral vasoconstriction and myocardial depression in isolated tissue preparations.

BACKGROUND: Cleistanthus collinus is a poisonous shrub commonly used for deliberate self-harm in rural south India. Boiled decoction or a paste made from its leaves is used for suicide. Cleistanthoside A and Cleistanthin A are the major toxins identified from this plant. In this study, we disclose the mechanism of Cleistanthin A toxicity and concentrations of the two toxins in different extracts of Cleistanthus collinus. METHODS: The effect of Cleistanthin A was studied on isolated goat leg arteries using two different preparations namely transverse cylinder and longitudinal strip. The influence of Cleistanthin A on peripheral vascular resistance and myocardial contractility was evaluated by rat hind limb and isolated rat heart experiments, respectively. For the quantification of toxins, five different extracts of C. collinus leaves were prepared. The extracts were subjected to analytical HPLC to quantify Cleistanthoside A and Cleistanthin A. RESULTS AND CONCLUSION: Cleistanthin A increased vascular tension in transverse cylinder preparation and increased peak, trough and mean aortic pressures in the rat hind limb preparations. In isolated rat heart experiments, there was an increase in diastolic and mean ventricular pressure with a significant decrease in ventricular pulse pressure. These observations suggest that the hypotension in C. collinus poisoning patients may be due to cardiotoxicity and not due to vasodilation as is currently believed. Quantification of different extracts showed that boiled extracts had higher quantities of Cleistanthoside A whereas crushed leaf extracts yielded significantly higher amounts of Cleistanthin A.

Flexible Approach for the Synthesis of Annulated 4H-Pyrans Based on a Cu(I)-Catalyzed C-Allylation/O-Vinylation Reaction of Cyclic 1-Bromoallyl Tosylates with Cyclic and Acyclic 1,3-Dicarbonyls.

The Cu(I)-catalyzed reaction between five-, six-, seven-, and eight-membered cyclic 1-bromoallyl tosylates and five- and six-membered cyclic 1,3-dicarbonyls in DMF at 80 °C using Cs2CO3 as a base and 2-picolinic acid as an additive selectively delivers a wide array of bisannulated 4H-pyrans in a single step with yields up to 92%. The transformations are considered to proceed as intermolecular C-allylations/intramolecular O-vinylations. With six-membered cyclic 1-bromoallyl tosylates and acyclic ß-ketoesters as substrates, the corresponding 5,6,7,8-tetrahydro-4H-chromene-3-carboxylates are obtained with yields up to 59%.

Direct Formation of 2-Substituted 2H-Indazoles by a Pd-Catalyzed Reaction between 2-Halobenzyl Halides and Arylhydrazines.

A direct and operationally simple method for the regioselective synthesis of 2-aryl-substituted 2H-indazoles is reported. The Pd-catalyzed reaction between easily available 2-bromobenzyl bromides and arylhydrazines employing Cs2CO3 as the base and t-Bu3PHBF4 as the ligand in DMSO at 120 °C in a sealed tube delivers the 2-substituted-2H-indazoles in a single synthetic step with yields up to 79%. The new method is based on a regioselective intermolecular N-benzylation followed by intramolecular N-arylation and oxidation.

Iodine Catalyzed Oxidative Coupling of Diaminoazines and Amines for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles.

A simple, convenient, transition metal-free one pot synthesis of 3,5-disubstituted-1,2,4-triazoles has been established. The innovation in this reaction is the use of easily available 1,1-diaminoazines as substrates. This method provides the products with wider substrate scope, at an expedited rate, and with relatively better yields in comparison to the reported methods. The reaction mechanism involves an initial intermolecular nucleophilic addition (facilitated by I2) followed by intramolecular nucleophilic cyclization.

An unprecedented intramolecular to intermolecular mechanistic switch in 1,1-diaminoazines leading to differential product formation during the I2-induced tandem oxidative transformation.

The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to intermolecular mechanistic switch during the I2-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This intramolecular to intermolecular cyclization shift was established through control experiments and was attributed to the high energy demand (∼22 kcal mol-1) for the azine tautomer to adopt the s-cis conformation which is essential for the intramolecular reaction. An I2 induced protocol for an efficient and straightforward synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially existing azine tautomeric form) with distinct advantages such as wide substrate scope, use of substoichiometric amounts of iodine, no requirement of external oxidizing agents, base free reaction conditions, short reaction time and moderate to good yields. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.

Base-Promoted Domino Reaction of 5-Substituted 2-Nitrosophenols with Bromomethyl Aryl Ketones: A Transition-Metal-Free Approach to 2-Aroylbenzoxazoles.

The reaction of 5-substituted 2-nitrosophenols with bromomethyl aryl ketones and related compounds employing K2CO3 as a base in refluxing THF and DMF at 80 °C, respectively, delivers 2-aroylbenzoxazoles in a single step with yields up to 85%. The new method involves an intermolecular nucleophilic substitution followed by intramolecular 1,2-addition and elimination. It allows an efficient and practical access to 2-aroylbenzoxazoles under transition-metal-free conditions.

From nitrobenzenes to substituted tetrahydroquinolines in a single step by a domino reduction/imine formation/aza-diels-alder reaction.

The three-component reaction between a nitrobenzene, an aldehyde, and a dienophile in the presence of iron powder as a reductant and montmorillonite K10 as a catalyst in aqueous citric acid delivers the products of an aza-Diels-Alder (Povarov) reaction with high endo-selectivity and yields up to 99%.

Synthesis of fucosylated lacto-N-tetraose using whole-cell biotransformation.

Fucosylated oligosaccharides present a predominant group of free oligosaccharides found in human milk. Here, a microbial conversion of lactose, D-glucose and L-fucose to fucosylated lacto-N-tetraose by growing Escherichia coli cultures is presented. The recombinant expression of genes encoding for the ß1,3-N-acetylglucosaminyltransferase (LgtA) and the ß1,3-galactosyltransferase (WbgO) enables the whole-cell biotransformation of lactose to lacto-N-tetraose. By the additional expression of a recombinant GDP-L-fucose salvage pathway together with a bacterial fucosyltransferase, lacto-N-tetraose is further converted into the respective fucosylated compounds. The expression of a gene encoding the α1,2-fucosyltransferase (FutC) in the lacto-N-tetraose producing E. coli strain led to the formation of lacto-N-fucopentaose I, whereas the expression of a gene encoding the α1,4-fucosyltransferase (FucT14) mainly led to the conversion of lacto-N-tetraose to lacto-N-difucohexaose II.

Transition-metal-free synthesis of imidazo[2,1-b]thiazoles and thiazolo[3,2-a]benzimidazoles via an S-propargylation/5-exo-dig cyclization/isomerization sequence using propargyl tosylates as substrates.

A transition-metal-free route for the synthesis of several N-fused heterocycles, including thiazolo[3,2-a]benzimidazoles and imidazo[2,1-b]thiazoles, is reported. The reaction between propargyl tosylates and 2-mercaptobenzimidazoles under basic conditions results in 3-substituted thiazolo[3,2-a]benzimidazoles, in yields up to 92% in a single synthesis step. With 2-mercaptoimidazoles as the substrate, the corresponding imidazo[2,1-b]thiazoles were exclusively obtained. The transformation is considered to proceed as an intermolecular S-propargylation that is followed by 5-exo-dig ring closure and double-bond isomerization.

Crematoenones - a novel substance class exhibited by ants functions as appeasement signal.

BACKGROUND: Parasitic, commensalistic, and mutualistic guests in social insect colonies often circumvent their hosts' nestmate recognition system to be accepted. These tolerance strategies include chemical mimicry and chemical insignificance. While tolerance strategies have been studied intensively in social parasites, little is known about these mechanisms in non-parasitic interactions.Here, we describe a strategy used in a parabiotic association, i.e. two mutualistic ant species that regularly share a common nest although they have overlapping food niches. One of them, Crematogaster modiglianii, produces an array of cuticular compounds which represent a substance class undescribed in nature so far. They occur in high abundances, which suggests an important function in the ant's association with its partner Camponotus rufifemur. RESULTS: We elucidated the structure of one of the main compounds from cuticular extracts using gas chromatography, mass spectrometry, chemical derivatizations and nuclear magnetic resonance spectroscopy (NMR). The compound consists of two fused six-membered rings with two alkyl groups, one of which carries a keto functionality. To our knowledge, this is the first report on the identification of this substance class in nature. We suggest naming the compound crematoenone.In behavioural assays, crematoenones reduced interspecific aggression. Camponotus showed less aggression to allospecific cuticular hydrocarbons when combined with crematoenones. Thus, they function as appeasement substances. However, although the crematoenone composition was highly colony-specific, interspecific recognition was mediated by cuticular hydrocarbons, and not by crematoenones. CONCLUSIONS: Crematenones enable Crematogaster to evade Camponotus aggression, and thus reduce potential costs from competition with Camponotus. Hence, they seem to be a key factor in the parabiosis, and help Crematogaster to gain a net benefit from the association and thus maintain a mutualistic association over evolutionary time.To our knowledge, putative appeasement substances have been reported only once so far, and never between non-parasitic species. Since most organisms associated with social insects need to overcome their nestmate recognition system, we hypothesize that appeasement substances might play an important role in the evolution and maintenance of other mutualistic associations as well, by allowing organisms to reduce costs from antagonistic behaviour of other species.

Synthesis of 2-aryl-1,2-dihydrophthalazines via reaction of 2-(bromomethyl)benzaldehydes with arylhydrazines.

The reaction of 2-(bromomethyl)benzaldehydes with arylhydrazines employing K(2)CO(3) as a base and FeCl(3) as a catalyst in CH(3)CN at 100 °C delivers 2-aryl-1,2-dihydrophthalazines with yields ranging from 60 to 91%. The transformation is considered to proceed as an intermolecular condensation/intramolecular nucleophilic substitution.

Laccase-catalyzed domino reaction between catechols and 6-substituted 1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinecarbonitriles for the synthesis of pyrimidobenzothiazole derivatives.

The laccase-catalyzed domino reaction between catechols and 6-substituted 1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinecarbonitriles using aerial O2 as the oxidant delivers new pyrimidobenzothiazole derivatives. The complete structure elucidation of the ring-proton deficient heterocyclic products and the unambiguous determination of the regioselectivity of the reactions have been achieved by extended NMR spectroscopic methods including HSQMBC, super long-range HMBC, and (15)N measurements.

Reaction of 1-nitroso-2-naphthols with α-functionalized ketones and related compounds: the unexpected formation of decarbonylated 2-substituted naphtho[1,2-d][1,3]oxazoles.

Reactions between 1-nitroso-2-naphthols and α-functionalized ketones such as α-bromo-, α-chloro-, α-mesyloxy-, α-tosyloxy-, and α-hydroxy ketones under basic conditions delivered 2-substituted naphtho[1,2-d][1,3]oxazoles in a single synthetic operation. The product formation was accompanied by the unexpected loss of the C═O group from the α-functionalized ketones. With aryl bromides, allyl bromides, α-bromo diketones, α-bromo cyanides, α-bromoesters, and α-bromo ketoesters as substrates the formation of naphtho[1,2-d][1,3]oxazoles was also observed. The transformations were performed in 1,2-dichloroethane or acetonitrile under reflux and gave the corresponding naphthoxazoles with yields ranging between 52% and 85%.

Combination of enzyme- and Lewis acid-catalyzed reactions: a new method for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting from 2,5-dimethylfuran and 1,3-cyclohexanediones.

The Lewis acid-catalyzed domino 1,2-addition/1,4-addition/elimination between (Z)-3-hexene-2,5-dione and 1,3-dicarbonyls delivers 3-methyl-6,7-dihydrobenzofuran-4(5H)-ones exclusively with yields up to 82%. The combination of this new process with the laccase-catalyzed formation of (Z)-3-hexene-2,5-dione by oxidative cleavage of 2,5-dimethylfuran allows for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting directly from 2,5-dimethylfuran.

Root exudate fingerprint of Brachiaria humidicola reveals vanillin as a novel and effective nitrification inhibitor.

Introduction: Biological Nitrification Inhibition (BNI) is defined as the plant-mediated control of soil nitrification via the release of nitrification inhibitors. BNI of Brachiaria humidicola (syn. Urochloa humidicola) has been mainly attributed to root-exuded fusicoccane-type diterpenes, e.g., 3-epi-brachialactone. We hypothesized, however, that BNI of B. humidicola is caused by an assemblage of bioactive secondary metabolites. Methods: B. humidicola root exudates were collected hydroponically, and metabolites were isolated by semi-preparative HPLC. Chemical structures were elucidated by HRMS as well as 1D and 2D NMR spectroscopy. Nitrification inhibiting potential of isolated metabolites was evaluated by a Nitrosomonas europaea based bioassay. Results and discussion: Besides previously described brachialactone isomers and derivatives, five phenol and cinnamic acid derivatives were identified in the root exudates of B. humidicola: 2-hydroxy-3-(hydroxymethyl)benzaldehyde, vanillin, umbelliferone and both trans- and cis-2,6-dimethoxycinnamic acid. Notably, vanillin revealed a substantially higher nitrification inhibiting activity than 3-epi-brachialactone (ED50 ∼ 12.5 µg·ml-1, ED80 ∼ 20 µg·ml-1), identifying this phenolic aldehyde as novel nitrification inhibitor (NI). Furthermore, vanillin exudation rates were in the same range as 3-epi-brachialactone (1-4 µg·h-1·g-1 root DM), suggesting a substantial contribution to the overall inhibitory activity of B. humidicola root exudates. In relation to the verification of the encountered effects within soils and considering the exclusion of any detrimental impact on the soil microbiome, the biosynthetic pathway of vanillin via the precursor phenylalanine and the intermediates p-coumaric acid/ferulic acid (precursors of further phenolic NI) might constitute a promising BNI breeding target. This applies not only to Brachiaria spp., but also to crops in general, owing to the highly conserved nature of these metabolites.

Copper-catalyzed synthesis of quinazolines in water starting from o-bromobenzylbromides and benzamidines.

Water makes it possible: The Cu(2)O-catalyzed reaction between easily available o-bromobenzylbromides and benzamidines by using Cs(2)CO(3) as the base and N,N'-dimethylethylenediamine (DMEDA) as the additive in water as the solvent gives access to substituted quinazolines in a single step with yields ranging from 57 to 85 % (see scheme).

Mammalian-specific OR37 receptors are differentially activated by distinct odorous fatty aldehydes.

The capacity of the mammalian olfactory system to detect an enormous collection of different chemical compounds is based on a large repertoire of odorant receptors (ORs). A small group of these ORs, the OR37 family, is unique due to a variety of special features. Members of this subfamily are exclusively found in mammals, they share a high degree of sequence homology and are highly conserved during evolution. It is still elusive which odorants may activate these atypical receptors. We have reasoned that compounds from skin, hairs, or skin glands might be potential candidates. We have exposed mice to such compounds and monitored activation of glomeruli through the expression of the activity marker c-fos in juxtaglomerular cells surrounding ventrally positioned glomeruli in the olfactory bulb (OB). Employing this methodology it was found that stimulation with long-chain alkanes elicits activation in the ventral part of the OB, however, none of the OR37 glomeruli. Analyses of long-chain hydrocarbon compounds with different functional groups revealed that long-chain aliphatic aldehydes elicited an activation of defined OR37 glomeruli, each of them responding preferentially to an aldehyde with different chain lengths. These results indicate that OR37 receptors may be tuned to distinct fatty aldehydes with a significant degree of ligand specificity.

Nitric oxide, can it be only good? Increasing the antioxidant properties of nitric oxide in hepatocytes by YC-1 compound.

The aim of the study was to evaluate the effect of Nitric oxide (NO) on redox changes and fat accumulation in hepatocytes. AML-12 hepatocytes were exposed to the NO donor Diethylenetriamine-NONOate (DETA-NO). DETA-NO led to a dose- and time-dependent increase in lipid accumulation in the cells, measured by Nile red fluorescence. Exposure of the cells to 1mM DETA-NO for 24h increased reactive oxygen species production, mainly peroxides. At the same time, NO induced elevation of reduced glutathione (GSH) and a mild activation of the antioxidant transcription factors Hypoxia-inducible factor 1α (HIF1α) and NF-E2 related factor 2 (Nrf-2). We used 100 µM YC-1 to inhibit HIF1α activity and induce activation of soluble Guanylate Cyclase (sGC). YC-1 alone did not affect fat accumulation, and only moderately increased the expression of Nrf-2-targeted genes Heme oxygenase 1 (Hmox1), NAD(P)H dehydrogenase (quinone 1) (Nqo1) and Glutathione S-transferase α1 (Gstα1). However, YC-1 abolished the negative effect of NO on fat accumulation when administered together. Strikingly, YC-1 potentiated the effect of NO on Nrf-2 activation, thus increasing dramatically the antioxidant properties of NO. Moreover, YC-1 intensified the effect of NO on the expression of peroxisome-proliferator-activated receptor-gamma co-activator 1α (PGC1α) and mitochondrial biogenesis markers. This study suggests that YC-1 may shift the deleterious effects of NO into the beneficial ones, and may improve the antioxidant properties of NO.

Laccase-catalyzed domino reactions between hydroquinones and cyclic 1,3-dicarbonyls for the regioselective synthesis of substituted p-benzoquinones.

Highly substituted p-benzoquinones were obtained in yields ranging from 39% to 98% by laccase-catalyzed domino reactions between hydroquinones and cyclic 1,3-dicarbonyls using aerial oxygen as the oxidant. In almost all reactions bis-adducts with two adjacent 1,3-dicarbonyl substituents on the quinone moiety were formed selectively. The transformations can be regarded as domino oxidation/1,4-addition/oxidation/1,4-addition/oxidation processes. With unsubstituted hydroquinone as the substrate 2,3-disubstituted p-benzoquinones were isolated. Bis-adducts were also formed exclusively upon reaction with monosubstituted hydroquinones. In almost all cases the 2,3,5-trisubstituted p-benzoquinones were obtained. When 2,3-disubstituted hydroquinones were employed as starting materials the 2,3,5,6-tetrasubstituted p-benzoquinones were isolated. The unambiguous structure elucidation of all products has been achieved by NMR spectroscopic methods including spin pattern analysis of the long-range coupled C═O carbons and (13)C satellites analysis in (1)H NMR spectra.