Unique Substitution Pattern Research Articles

Divergent Annulation Modes of (Z)-4-Aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile and Methyl Nitroacetate: Selective Access to 2-Acyl-4H-quinolizin-4-one, Isoxazole, and 2-Acylindolizine.

Three different annulation modes of (Z)-4-aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile in the reaction with methyl nitroacetate were discovered, allowing selective access to diverse heterocycles such as quinolizin-4-one, isoxazole, and indolizine with unique substitution patterns in good yields. Ease of operation, good chemical yields, and good functional group tolerance of our protocol enabled us to rapidly construct a number of synthetic analogs based on each scaffold under three reaction conditions.

Refining hospitality in a post-pandemic landscape: Tourist food choices through a latent class nested logit lens

In the post-pandemic landscape, scant research has been conducted on the timely, in-depth examination of how food-related attributes affect tourist food choices. To tackle this issue, this study employed a discrete choice experiment and latent class nested logit models for a nuanced exploration of tourist food preferences. This approach captured both tourists’ preference heterogeneity and substitution effects among fast, local, and hometown-style food options. Findings reveal that price, food taste rating, waiting time, service, and environment are key determinants of tourists’ food choices. Our model identified two distinct tourist classes, Local-food-image class and Anti-price-quality class, each displaying unique food preferences and substitution patterns. This research contributes to tourism and hospitality literature by offering an updated and nuanced understanding of post-pandemic tourists’ food preferences and decision-making trade-offs. It offers practical recommendations for targeted marketing and effective resource allocation, ultimately strengthening resilience and fostering sustainable development within hospitality, catering, and tourism sectors.

Dihydropyrazinoquinazolinones via SN2 Sulfamidate Ring-Opening and a Sequential Quinazolinone-Amidine Rearrangement Strategy (SQuAReS).

A synthesis of dihydropyrazino-[2,1-b]-quinazolinones is described using a 2-alkylaminoquinazolinone-mediated ring opening of a-/chiral sulfamidates, followed by a tandem quinazolinone-amidine rearrangement termed SQuAReS. This approach takes advantage of sulfamidates whose regioselective ring opening, after hydrolysis, appends an optimally distanced nucleophilic amine to a quinazolinone such that subsequent domino rearrangements are favored, integrating unique substitution patterns on a privileged core. This three-step protocol integrated five telescoped transformations and generated 20 pyrazinoquinazolinones in up to 74% yield with high enantiomeric fidelity and diastereoselectivity.

Molecular Characterization of a New Ecotype of Holoparasitic Plant Orobanche L. on Host Weed Xanthium spinosum L.

A species of Orobanche was observed on spiny cocklebur (Xanthium spinosum) for the first time in Iran and tentatively was named IR-Iso.This study was conducted to make a phylogenetic analysis of the Orobanche using 5.8S rRNA region sequences, and also to better understand its sequence pattern. The full-length ITS1-ITS2 region of the new Orobanche isolate was PCR-amplified from the holoparasitic plant parasitizing X. spinosum. Sequences of the amplicons from the isolate were 100% identical but differed by 5.6–6.7% from most homologous GenBank accessions to 37.9% divergence from distant species. The analysis of the molecular variance showed that variation between-population (61.9%, SE = 0.04) was larger than within-population. Neighbor-joining analysis placed the Iranian isolate in the same clade as most of the Orobanche and Phelipanche species. The isolate was more closely related to Orobanche aegyptiaca (from China), and this was confirmed by using a structure analysis. However, complementary analyses showed that the Iranian isolate has a unique nucleotide substitution pattern, and hence it was considered as an ecotype of O. aegyptiaca (ecotype Alborzica). In this paper we report on the association between this new ecotype of Orobanche and X. spinosum.

Differential Selection on Caste-Associated Genes in a Subterranean Termite.

Simple SummarySocial insects can sometimes boldly invade new habitats, including areas of human habitation where they can become unwanted domestic or agricultural pests. In this study, we use molecular sequence analysis to study genetic patterns associated with the invasion and division of labour in the Eastern subterranean termite Reticulitermes flavipes. By studying how genes vary by caste and by population, we show that even termites invasive to a metropolitan city can still harbour plenty of genetic variation, as much or more as native termite populations. We suggest therefore that invasive termites do not necessarily suffer long term loss-of-variation upon invasion. Second, we show that genes associated in their expression with the soldier caste evolve approximately twice as fast as genes expressed by other castes of this species, regardless of from what population the castes were sampled. Why termite soldier genes evolve quickly is not known, but it seems unrelated to invasion or the invaded habitat. Given that soldiers are sterile and thus have no direct fitness, the evidence for gene-level selection in the soldier caste is an intriguing example of kin selection.Analyzing the information-rich content of RNA can help uncover genetic events associated with social insect castes or other social polymorphisms. Here, we exploit a series of cDNA libraries previously derived from whole-body tissue of different castes as well as from three behaviourally distinct populations of the Eastern subterranean termite Reticulitermes flavipes. We found that the number (~0.5 M) of single nucleotide variants (SNVs) was roughly equal between nymph, worker and soldier caste libraries, but dN/dS (ratio of nonsynonymous to synonymous substitutions) analysis suggested that some of these variants confer a caste-specific advantage. Specifically, the dN/dS ratio was high (~4.3) for genes expressed in the defensively specialized soldier caste, relative to genes expressed by other castes (~1.7–1.8) and regardless of the North American population (Toronto, Raleigh, Boston) from which the castes were sampled. The populations, meanwhile, did show a large difference in SNV count but not in the manner expected from known demographic and behavioural differences; the highly invasive unicolonial population from Toronto was not the least diverse and did not show any other unique substitution patterns, suggesting any past bottleneck associated with invasion or with current unicoloniality has become obscured at the RNA level. Our study raises two important hypotheses relevant to termite sociobiology. First, the positive selection (dN/dS > 1) inferred for soldier-biased genes is presumably indirect and of the type mediated through kin selection, and second, the behavioural changes that accompany some social insect urban invasions (i.e., ‘unicoloniality’) may be detached from the loss-of-diversity expected from invasion bottlenecks.

Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)-Methyl-(2R,6R)-hydroxynorketamines.

(R,S)-Ketamine is rapidly metabolized to form a range of metabolites in vivo, including 12 unique hydroxynorketamines (HNKs) that are distinguished by a cyclohexyl ring hydroxylation at the 4, 5, or 6 position. While both (2R,6R)- and (2S,6S)-HNK readily penetrate the brain and exert rapid antidepressant-like actions in preclinical tests following peripheral administration, the pharmacokinetic profiles and pharmacodynamic actions of 10 other HNKs have not been examined. We assessed the pharmacokinetic profiles of all 12 HNKs in the plasma and brains of male and female mice and compared the relative potencies of four (2,6)-HNKs to induce antidepressant-relevant behavioral effects in the forced swim test in male mice. While all HNKs were readily brain-penetrable following intraperitoneal injection, there were robust differences in peak plasma and brain concentrations and exposures. Forced swim test immobility rank order of potency, from most to least potent, was (2R,6S)-, (2S,6R)-, (2R,6R)-, and (2S,6S)-HNK. We hypothesized that distinct structure-activity relationships and the resulting potency of each metabolite are linked to unique substitution patterns and resultant conformation of the six-membered cyclohexanone ring system. To explore this, we synthesized (5R)-methyl-(2R,6R)-HNK, which incorporates a methyl substitution on the cyclohexanone ring. (5R)-Methyl-(2R,6R)-HNK exhibited similar antidepressant-like potency to (2R,6S)-HNK. These results suggest that conformation of the cyclohexanone ring system in the (2,6)-HNKs is an important factor underlying potency and that additional engineering of this structural feature may improve the development of a new generation of HNKs. Such HNKs may represent novel drug candidates for the treatment of depression.

Efficient synthesis of pentasubstituted pyrroles via intramolecular C-arylation.

Immobilized L-aspartic acid beta-methyl ester (Fmoc-Asp(OMe)-OH) was reacted with 4-nitrobenzenesulfonyl chloride, followed by alkylation with various α-haloketones. The resulting intermediates were treated with potassium trimethylsilanolate, which yielded tetrasubstituted pyrroles after a one-step transformation consisting of sequential C-arylation, aldol condensation and spontaneous aromatization. The discovered synthetic strategy enables fast and simple access to pentasubstituted and functionalized pyrroles from a number of readily available starting materials.

α-Cationic Phosphines: from Curiosities to Powerful Ancillary Ligands

AbstractThe distinguishing feature of α-cationic phosphines is the presence of at least one substituent, normally (hetero)cyclic and positively charged, which is directly attached to the phosphorus atom. As result from this unique substitution pattern, the thus designed ligands depict significantly diminished donor properties if compared with their neutral counterparts. Thus, if in a hypothetical catalytic cycle, the step that determines the rate is facilitated by an increase of the electrophilicity at the metal center; then, the use of α-cationic ancillary phosphines can be highly beneficial. This fact, combined with their easy syntheses and stability, which allows an easy handling, make α-cationic phosphines a useful tool for the synthetic practitioner. Our research on the topic demonstrates that generally a remarkable ligand acceleration effect is observed when α-cationic phosphines are employed in Au(I)- and Pt(II)-promoted cycloisomerizations; moreover, in some cases even otherwise not operative transformations can be promoted. This Account describes how we entered into the topic, our efforts, and those of others to understand the coordination behavior of α-cationic phosphines and further develop their range of applications in catalysis; but it also identifies the drawbacks associated with their use, which limit their range of application.1 Introduction2 Polycationic Phosphines: Stronger Acceptors than Phosphites3 Inconveniences Derived from the Use of (Poly)cationic phosphines4 A Second Generation of Cationic Ligands: α-Pyridiniophosphines5 Chiral α-Cationic Phosphines6 α-Radical Phosphines and (Poly)cationic Phosphine Oxides7 Conclusions and Outlook

Stabilization of a 12-π electrons diamino-benzoquinonediimine tautomer.

The first example of diamino-benzoquinonediimine bearing both electron-donating and electron-withdrawing groups on the same 6-π electron subunit was synthesized using a straightforward one pot strategy. Photophysical analysis and theoretical calculations demonstrate that this unique substitution pattern is efficient to favour the establishment of a single tautomeric structure in solution.

Polyhalonitrobutadienes as Versatile Building Blocks for the Biotargeted Synthesis of Substituted N-Heterocyclic Compounds.

Substituted nitrogen heterocycles are structural key units in many important pharmaceuticals. A new synthetic approach towards heterocyclic compounds displaying antibacterial activity against Staphylococcus aureus or cytotoxic activity has been developed. The selective synthesis of a series of 64 new N-heterocycles from the three nitrobutadienes 2-nitroperchloro-1,3-butadiene, 4-bromotetrachloro-2-nitro-1,3-butadiene and (Z)-1,1,4-trichloro-2,4-dinitrobuta-1,3-diene proved feasible. Their reactions with N-, O- and S-nucleophiles provide rapid access to push-pull substituted benzoxazolines, benzimidazolines, imidazolidines, thiazolidinones, pyrazoles, pyrimidines, pyridopyrimidines, benzoquinolines, isothiazoles, dihydroisoxazoles, and thiophenes with unique substitution patterns. Antibacterial activities of 64 synthesized compounds were examined. Additionally, seven compounds (thiazolidinone, nitropyrimidine, indole, pyridopyrimidine, and thiophene derivatives) exhibited a significant cytotoxicity with IC50-values from 1.05 to 20.1 µM. In conclusion, it was demonstrated that polyhalonitrobutadienes have an interesting potential as structural backbones for a variety of highly functionalized, pharmaceutically active heterocycles.

The LANCA three-component reaction to highly substituted β-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to β-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-β-ketoenamides. β-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of β-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of β-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile β-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key β-ketoenamides show a unique substitution pattern – not easily accomplishable by alternative methods – and therefore many subsequent reactions are possible.

Mercuration of calix[4]arenes immobilized in the 1,2- and 1,3-alternate conformations

Calix[4]arenes immobilized in the 1,2-alternate and 1,3-alternate conformations were directly mercurated using Hg(TFA)2. The reaction regioselectivity was compared with the thermodynamic stability of the corresponding products obtained by theoretical calculations (wB97XD/def2tzvp method). Both experimental and theoretical data suggest that para substitution is slightly preferred over meta attack for the 1,2-alternate conformer, while in the case of the 1,3-alternate conformation the situation is reversed. The usefulness of the mercury intermediates was demonstrated by the synthesis of a rigid upper-rim-bridged calixarene in the 1,2-alternate conformation possessing a highly distorted cavity. A simple transformation of the organomercury compounds afforded the corresponding iodo derivatives, which are potentially applicable as building blocks for further synthesis. Moreover, many products are inherently chiral representing unique substitution patterns inaccessible by common “mercury-free” chemistry.

Diazatetracenes Derived from the Benzannulation of Acetylenes: Electronic Tuning via Substituent Effects and External Stimuli.

Functionalized diazatetracenes are prepared using a new two-step sequence. The use of a dichlorobenzaldehyde in a Cu-catalyzed benzannulation of acetylenes provides functionalized dichloronaphthalenes that afford diazatetracenes using Buchwald-Hartwig aminations. This approach provides unique substitution patterns and rapid access to covalently linked dimeric diazatetracenes. Their electronic properties are characterized by UV-vis absorption/emission and cyclic voltammetry, revealing strong effects from both external stimuli by acid and internal substituent effects.

Synthesis and study of calix[4]arenes bearing azo moieties at the meta position

Direct mercuration and subsequent transformation of organomercurial intermediates into the corresponding nitroso derivatives enabled the construction of calix[4]arenes bearing azo moieties at the meta position (to the alkoxy groups). These compounds, representing a unique substitution pattern in calixarene chemistry, showed very unusual dynamic behaviour in solution. Temperature dependent 1H NMR spectra confirmed that the introduction of two bulky moieties (or even just one) into the meta position of calix[4]arene led to the rigidification of the molecule as demonstrated by complete arrest of the typical pinched cone – pinched cone interconversion in solution. The rigidified molecules can be used as ligands capable of cation−π interactions with N-methylpyridinium salts.

Xanthones of Lichen Source: A 2016 Update.

An update of xanthones encountered in lichens is proposed as more than 20 new xanthones have been described since the publication of the compendium of lichen metabolites by Huneck and Yoshimura in 1996. The last decades witnessed major advances regarding the elucidation of biosynthetic schemes leading to these fascinating compounds, accounting for the unique substitution patterns of a very vast majority of lichen xanthones. Besides a comprehensive analysis of the structures of xanthones described in lichens, their bioactivities and the emerging analytical strategies used to pinpoint them within lichens are presented here together with physico-chemical properties (including NMR data) as reported since 1996.

ChemInform Abstract: Sequential Morita—Baylis—Hillman/Achmatowicz Reactions: An Expeditious Access to Pyran‐3(6H)‐ones with a Unique Substitution Pattern.

AbstractA simple and straightforward approach to the synthesis of hydroxy‐2H‐pyranones with a unique substitution pattern is described.

Sequential Morita–Baylis–Hillman/Achmatowicz reactions: an expeditious access to pyran-3(6H)-ones with a unique substitution pattern

We herein disclosed a novel approach to synthesize densely functionalized 6-hydroxy-2H-pyran-3(6H)-ones with moderate to good diastereoselectivity. The method is based on a two step sequence using Morita–Baylis–Hillman adducts as substrates for the Achmatowicz rearrangement, allowing the preparation of highly substituted pyran-3-ones with overall yields ranging from 17% to 80% and a unique substitution pattern.

Transition-metal-free access to primary anilines from boronic acids and a common (+)NH2 equivalent.

Diversely substituted anilines are prepared by treatment of functionalized arylboronic acids with a common, inexpensive source of electrophilic nitrogen (H2N-OSO3H, HSA) under basic aqueous conditions. Electron-rich substrates are found to be the most reactive by this method. However, even moderately electron-poor substrates are well tolerated under the room temperature conditions. Sterically hindered substrates appear to be equally effective compared to unhindered ones. Highly electron-deficient substrates afford product in very low yields at room temperature, but moderate to good yields are obtained at refluxing temperatures. Our method is also amenable to electrophilic amination of several common boronic acid derivatives (e.g., pinacol esters). We demonstrate that it can be combined with metal-halogen exchange reactions or a variety of directed ortho metalation protocols in a "one-pot" sequence for the synthesis of aromatic amines with unique substitution patterns. DFT studies, in combination with experimental results, suggest that the reaction occurs via base-mediated activation of HSA, followed by 1,2 aryl B-N migration. This mode of activation appears to be critical for the success of the reaction and allows, for the first time, a general, electrophilic amination of boronic acids at ambient temperature.

Metal‐Free Reagent Dependent SS and CC Homocoupling of α‐Enolic Dithioesters at Room Temperature: Direct Access to Fully Substituted Symmetrical Thiophenes via Chemoselective Paal–Knorr Approach

AbstractAn unprecedented metal‐free oxidative homodimerization of α‐enolic dithioesters has been achieved for the first time at room temperature within 5–10 min. Molecular iodine promotes the SS coupling leading to S,S′‐bis(dithioacetals), while N‐chlorosuccinimide facilitates CC coupling to give α,α′‐bis(β‐oxo dithioesters) in good to excellent yields. Furthermore, the newly generated α,α′‐bis(β‐oxo dithioesters) have been directly employed in the synthesis of fully substituted thiophenes with a unique symmetrical substitution pattern in a one‐pot, two‐step reaction sequence.magnified image

Zwitterionic Phosphirenium Borates Derived from Bis(alkynyl)mesityl Phosphanes and Tris(pentafluorophenyl)borane

ABSTRACTFrom a series of bis(alkynyl)mesityl phosphanes 5, we prepared phosphirenium borate compounds 6 in high yields by reaction with B(C6F5)3 at room temperature. The zwitterionic compounds 6 are conveniently accessible and can be obtained with unique substitution patterns by this route. For two examples, we show the conversion of 6 to the respective 3‐borylated phosphole derivatives 7 through multiple 1,1‐carboboration reactions. In a useful one‐pot methodology, the phosphirenium borates 6 are converted to air‐stable 3‐arylated phospholes 8 by a sequential 1,1‐carboboration/ Suzuki–Miyaura type cross‐coupling reaction.