Double Insertion Research Articles

Synthesis of Quinoxaline‐2,3‐diamines via Palladium‐Catalysed Double Isocyanide Insertion Cyclization

An approach for the synthesis of quinoxaline‐2,3‐diamines is reported using a palladium‐catalyzed cyclization reaction of o‐phenylenediamines and isocyanides. Various quinoxaline‐2,3‐diamines could be obtained in 25%‐95% yields at 100 °C for 3 h. The key to the success of this protocol involves the formation of two C‐N and one C‐C bonds via the double insertion of isocyanide.

Alkene Isomerization Catalyzed by a Mn(I) Bisphosphine Borohydride Complex.

An additive-free manganese-catalyzed isomerization of terminal alkenes to internal alkenes is described. This reaction is implementing an inexpensive nonprecious metal catalyst. The most efficient catalyst is the borohydride complex cis-[Mn(dippe)(CO)2(κ2-BH4)]. This catalyst operates at room temperature, with a catalyst loading of 2.5 mol %. A variety of terminal alkenes is effectively and selectively transformed into the respective internal E-alkenes. Preliminary results show chain-walking isomerization at an elevated temperature. Mechanistic studies were carried out, including stoichiometric reactions and in situ NMR analysis. These experiments are flanked by computational studies. Based on these, the catalytic process is initiated by the liberation of "BH3" as a THF adduct. The catalytic process is initiated by double bond insertion into an M-H species, leading to an alkyl metal intermediate, followed by β-hydride elimination at the opposite position to afford the isomerization product.

Synthesis of Heptacyclic Compounds through C-H Bond Activation-Initiated Cascade Reactions.

Presented herein is an atom- and step-economical method enabling the precise assembly of a heptacyclic scaffold containing both azocine and indoline units through the cascade reactions of indolin-1-yl(aryl)methanimines with diazo indanediones. The formation of products involves C-H bond activation and double carbene insertion followed by intramolecular condensation, retro-[2 + 2] cycloaddition, and recyclization. This cascade reaction not only provided a concise and straightforward strategy for the synthesis of the otherwise difficult to obtain heptacyclic compounds from readily available substrates but also disclosed an unprecedented reaction mode for indoline derivatives and diazo compounds. In general, this novel synthetic protocol has advantages, such as easily obtainable substrates, structurally sophisticated products, concise synthetic procedure, good compatibility with diverse functional groups, and ready scalability. Moreover, the products thus obtained showed decent antiproliferative activity against three human cancer cell lines.

Synthesis of β-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes.

An unprecedented trimethylsilyl trifluoromethanesulfonate (TMSOTf)-promoted selective double insertion of isocyanides into aldehydes was developed, providing an efficient protocol for synthetically challenging β-carbonyl α-iminoamides. The given approach is applicable for a diverse selection of readily accessible aldehydes, along with isocyanides serving as essential precursors for "amide" and "imine" scaffolds. The versatile transformations of the given products were demonstrated, and the pivotal intermediates for the plausible mechanism were identified.

Study of liver abscess in pediatrics patients in tertiary health care institute

liver abscess is mostly occurring due to the infection of bacteria, parasite like amoeba. The incidence of amoebic liver abscess varies all over the world and most of cases found in developing countries remain unreported. study of liver abscess in pediatric patients in tertiary health care institute. This was a prospective study, carried out in 64 at our tertiary care center, J K Lon Hospital, SMS Medical College, Jaipur from May 2022 to April 2023. We collect all data related to patients like demography, clinical features, laboratory finding, and imaging records and recorded on a pre-decided proforma. There were 64 patients (36 male, 56.25% and 28 females, 43.75%), The male to female ratio was 1.25:1. The mean age of presentation was 7.5 years. The common presenting symptom was anorexia in 55 (85.93%) cases. Most common symptom was abdominal pain in 60 (93.75%) cases, fever 58 (90.625%), and vomiting in 40 (62.5%%) cases. Diarrhoea was present in 5 patients. Anemia was most common clinical sign in present in 40 (62.5%) patients, weight loss 38 (59.37%). Respiratory distress was present in 4 (6.25%) due to pleural effusion and peritonitis cases. Jaundice was present in 5 (7.81%) . 5 case [7.81%] of patients had raised bilirubin and 28 patients [43.75%] had raised alkaline phosphatase levels. Raised SGOT and SGPT was 43.75 %. 34 patients of Amoebic liver abscess and 30 of Pyogenic liver abscess. 53.12% (34 cases) patients had amoebic liver abscess in the right lobe. less than 50 cc size of abscess was present in 24 patients (37.5%) cases. Most of the patients have cavity size 50-150cc. more than 200cc cavity found only in 10 cases. Average cavity size is 166cc. peritoneal ruptured liver abscess in 2 cases [3.12%%] had features of peritonitis, pleural effusion in 2 cases with complain of respiratory difficulties. Conservative medical management was done in 2 patients, USG guided needle aspiration 20 patients and 40 patients underwent pigtail catheter insertion. 12 fr pigtail catheter insertion was done in 30 patients and 10 patients underwent double pigtail catheter insertion. Exploration and drainage of liver abscess was done in 2 patients. In present study, mean hospital stay was 10.28 days. Hospital stays ranges from 5 to 17 days. Most of the patients stays 5 to 10 days [56.25%]. all amoebic liver abscesses were sterile. Most commonly found organism on pus culture was Staphylococcus in 25% cases followed by E. coli in 21.87% cases in pyogenic liver abscesses. from this study we found that ultrasonography is the standard modality for diagnostic and therapeutic management as well as for drainage and follow up. We also found that USG guided pigtail catheter drainage is a superior therapeutic approach than needle aspiration for large liver abscess, and abscess cavity resolves better in case of pigtail catheter drainage. We also concluded that ruptured liver abscess can also be managed with two pig tail catheter insertion.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

A toolbox to engineer the highly productive cyanobacterium Synechococcus sp. PCC 11901.

Synechococcus sp. PCC 11901 (PCC 11901) is a fast-growing marine cyanobacterial strain that has a capacity for sustained biomass accumulation to very high cell densities, comparable to that achieved by commercially relevant heterotrophic organisms. However, genetic tools to engineer PCC 11901 for biotechnology applications are limited. Here we describe a suite of tools based on the CyanoGate MoClo system to unlock the engineering potential of PCC 11901. First, we characterized neutral sites suitable for stable genomic integration that do not affect growth even at high cell densities. Second, we tested a suite of constitutive promoters, terminators, and inducible promoters including a 2,4-diacetylphloroglucinol (DAPG)-inducible PhlF repressor system, which has not previously been demonstrated in cyanobacteria and showed tight regulation and a 228-fold dynamic range of induction. Lastly, we developed a DAPG-inducible dCas9-based CRISPR interference (CRISPRi) system and a modular method to generate markerless mutants using CRISPR-Cas12a. Based on our findings, PCC 11901 is highly responsive to CRISPRi-based repression and showed high efficiencies for single insertion (31% to 81%) and multiplex double insertion (25%) genome editing with Cas12a. We envision that these tools will lay the foundations for the adoption of PCC 11901 as a robust model strain for engineering biology and green biotechnology.

Ru(II)-Catalyzed Deoxygenative Formal [3 + 1 + 2] Benzannulation of Allyl Alcohols and Acetylenediesters via C-H Activation and Selective Carbon-Carbon Triple Bond Cleavage.

An unprecedented Ru(II)-catalyzed deoxygenative, site-selective formal [3 + 1 + 2] benzannulation reaction for the efficient synthesis of highly substituted benzene molecules is reported. This reaction between allyl alcohols and acetylenedicarboxylate esters proceeds via cascade C-H activation, consecutive double migratory insertion with alkynes, and cycloaromatization followed by an unusual specific C-C triple bond cleavage.

Slow Deep Breathing in Patients Following Double Lumen Catheter Insertion Experiencing Acute Pain Nursing Problems: A Case Report

Inserting a double-lumen catheter (CDL) in hemodialysis patients results in adverse effects, specifically pain. Pain is a disagreeable sensation caused by tissue injury involving sensory and emotional components. Pain management is a nursing care option for individuals experiencing pain. Pain can be managed by non-pharmacological methods, such as the Slow Deep Breathing (SDB) technique. This case study aims to assess the intervention for sleep-disordered breathing in patients with chronic renal disease following central venous catheter installation, focusing on acute pain nursing issues. This article used a case report style focused on a single patient in the treatment room. The effectiveness of the SDB intervention was evaluated by the Numeric Rating Scale (NRS) and by monitoring the patient's blood pressure, pulse, and respiration. The intervention resulted in a decrease in the NRS score from 2 to 0. Additionally, the blood pressure value decreased to normal, the pulse remained within the normal range, and there was no change in the patient's respiratory value for three days post-intervention. Expanding the use of SDB therapies to a more diverse group of patients will enhance the evidence supporting the effectiveness of these interventions.

Efficient Synthesis of Highly Fused Quinazolinone Derivatives via Multiple C−C Bond Formations and 1,4‐Palladium Migration

AbstractAn efficient palladium‐catalyzed annulation of 3‐arylquinazolinones with mono and double alkyne insertion was developed for the synthesis of fused quinazolinone derivatives in 43–80 % yields. A notable effect was observed in product yield, when bases/additives were modulated. The reaction mechanism is believed to proceed through C−X cleavage/alkyne insertion/1,4‐Pd migration and C−H annulation in a one‐pot manner.

Disparate reactivity of a chiral iron(II) tetracarbene complex with organic azides.

A chiral tetra-NHC iron(II) complex and its disparate reactivity with multiple organic azides is reported. Both aryl and alkyl azides react with the iron(II) complex yielding three distinct products: an iron(IV) imide, an iron(IV) tetrazene, and a surprising and unprecedented double imide insertion complex.

A Comparison of the Success of Intubation Using C-MAC D-Blade and McGrath MAC X3 Blade Videolaryngoscopes during Double Lumen Tube Insertion in One-Lung Ventilation: A Prospective, Randomized Clinical Trial

Objective: To compare the effects of C-MAC D-Blade and McGrath MAC X3 Blade videolaryngoscopes (VLs) during double lumen tube (DLT) insertion in one-lung ventilation (OLV) in patients who underwent chest surgery in terms of intubation durations, hemodynamic responses, and intubation-induced complications. Materials and methods: Fifty patients aged 18−65 years who were scheduled for OLV were included in this study. The patients were divided randomly into two groups: a Storz C-MAC D-Blade VL group (C-MAC group, n = 25) and a McGrath MAC X3 Blade VL group (McGrath group, n = 25). The results of a preoperative airway assessment, number of intubation attempts and incidence of success at the first attempt, glottic view times, intubation times, Cormack−Lehane scores, percentage of glottic opening (POGO) scores, ease of intubation, comorbidities, hemodynamic responses, and adverse intubation-related events were recorded. Results: The demographic characteristics and comorbidities of both groups were similar. The intubation characteristics of both groups were similar in terms of Cormack−Lehane scores, thyromental and intergingival distances, and POGO scores. In the C-MAC group, the glottic view times (p = 0.001) and intubation times (p = 0.001) were significantly shorter than those in the McGrath group. As shown by ease of intubation scores, ease of intubation in the C-MAC group was significantly better than that in the McGrath group (p = 0.001). All the patients in the C-MAC group were intubated at the first attempt, without a statistically significant difference. The two groups were similar with respect to intubation-related complications and hemodynamic responses (mean arterial pressure [MAP] and heart rate [HR]). Conclusion: We conclude that the C-MAC D-Blade VL is more beneficial for airway management due to shorter glottic view and intubation times, high success rates at the first attempt, and ease of intubation in patients intubated with a DLT in OLV.

Four-component radical-polar crossover cyclization involving double insertion of SO2 to β-sulfonyl sultines

An unprecedented four-component radical-polar crossover cyclization (RPCC) protocol involving double insertion of SO2 was developed. Various sulfonium salts and alkyl boronic acids were transformed into functionalized β-sulfonyl sultines with S(iv) and S(vi) centers.

Metal-free cascade O–H double insertion between I(III)/S(VI)-ylides, carboxylic acids, and alcohols: modular access to unsymmetrical α,α-O,O-substituted ketones

Herein, we present a cascade O–H double insertion reaction between I(III)/S(VI)-ylides, carboxylic acids, and alcohols under metal-free conditions, enabling the modular synthesis of unsymmetrical α,α-O,O-substituted ketones.

Induction of Labour with a Double Balloon Catheter - Comparison of Effectiveness of Six Versus Twelve Hours Insertion Time: a Prospective Case Control Study.

Induction of labour is a common obstetric procedure to initiate or augment contractions when labour is delayed or uncertain. The double balloon catheter is a safe and effective mechanical method for cervical ripening during induction of labour. This study evaluates the effectiveness of reducing double balloon catheter insertion time from 12 to 6 hours. 248 women undergoing induction with a double balloon catheter at term were divided into two groups: catheter placed for 12 hours at 8pm in the first half of 2021 (P12) and catheter placed for 6 hours at 7am in the second half of 2021 (P6). T-tests, chi-squared tests, and Wilcoxon signed rank test were used for statistical analysis. Primary and secondary endpoints included induction to delivery interval, prostaglandin to delivery interval, mode of delivery, and maternal and neonatal outcomes. The P6 group had a significantly reduced induction to delivery interval of 558min (P6: 1348min, P12: 1906min, p<0.01, 95% CI: 376-710) within demographically comparable groups. Multiparous women also showed a significant reduction in prostaglandin to delivery interval of 260min (P6: 590min, P12: 850min, p=0.038, 95% CI: 9-299). There were no significant differences in mode of delivery, maternal blood loss, or neonatal outcome. Reducing double balloon catheter placement time from 12 to 6 hours resulted in almost 9 hours less induction to delivery interval without adverse effects on maternal and neonatal outcome.

A Journey from Benzoborirene to Benzoborole-Supported 1,2-Diimine and Antiaromatic Borolediide.

The reaction of benzoborirene with one equivalent of isocyanides leads to benzene-fused boretes bearing one imine function, while the reaction with two equivalents of isocyanide affords 2,3-dihydro-2,3-diiminoboroles with perfect regioselectivity. The isocyanide double insertion products represent a novel type of 1,2-diimine with a benzoborole backbone. The reduction chemistry of the benzoborole-supported 1,2-diimine was investigated. Single- and two-electron reduction allow for the isolation and full characterization of a radical anion and a dianion, respectively. In stark contrast to the ordinary boroles, which should turn aromatic by accepting two electrons, the antiaromatic character of the benzoborole backbone is highlighted upon reduction, thus presenting a rare example of antiaromatic borole dianion. Detailed quantum chemical calculations provide a rationale for the observed regioselectivity and the electronic structure of the reduced borole diimine species.

Von Benzoborirenen zu Benzoborol‐basierenden 1,2‐Diiminen und antiaromatischen Boroldiiden

AbstractDie Reaktion von Benzoborirenen mit einem Äquivalent Isocyanid führt zu benzolkondensierten Boreten mit einer Iminfunktion, während die Reaktion mit zwei Äquivalenten Isocyanid 2,3‐Dihydro‐2,3‐diiminoborole mit perfekter Regioselektivität ergibt. Die Isocyanid‐Doppelinsertionsprodukte stellen einen neuen Typ von 1,2‐Diiminen mit einem Benzoborol‐Rückgrat dar. Die Reduktionschemie des Benzoborol‐basierenden 1,2‐Diimins wurde untersucht. Die Reduktion mit einem und zwei Elektronen ermöglicht die Isolierung und vollständige Charakterisierung eines radikalischen Anions bzw. eines Dianions. Im Gegensatz zu gewöhnlichen Borolen, die durch die Aufnahme von zwei Elektronen aromatisch werden sollten, wird der antiaromatische Charakter des Benzoborol‐Rückgrats bei der Reduktion verstärkt und stellt somit ein seltenes Beispiel für ein antiaromatisches Borol‐Dianion dar. Detaillierte quantenchemische Berechnungen liefern eine Erklärung für die beobachtete Regioselektivität und die elektronische Struktur der reduzierten Borol‐Diimin‐Spezies.

A Carbene Relay Strategy for Cascade Insertion Reactions

AbstractInsertion reactions that involve stabilized electrophilic metallocarbenes are of great importance for installing α‐heteroatoms to carbonyl compounds. Nevertheless, the limited availability of carbene precursors restricts the introduction of only a single heteroatom. In this report, we describe a new approach based on an I(III)/S(VI) reagent that promotes the cascade insertion of heteroatoms. This is achieved by sequentially generating two α‐heteroatom‐substituted metal carbenes in one reaction. We found that this mixed I(III)/S(VI) ylide reacts efficiently with a transition metal catalyst and an X−H bond (where X=O, N). This transformation leads to the sequential formation of a sulfoxonium‐ and an X‐substituted Rh‐carbenes, enabling further reactions with another Y−H bond. Remarkably, a wide range of symmetrical and unsymmetrical α,α‐O,O‐, α,α‐O,N‐, and α,α‐N,N‐subsituted ketones can be prepared under mild ambient conditions. In addition, we successfully demonstrated other cascades, such as CN/CN double amidation, C−H/C−S double insertion, and C−S/Y−H double insertion (where Y=S, N, O, C). Notably, the latter two cascades enabled the simultaneous installation of three functional groups to the α‐carbon of carbonyl compounds in a single step. These reactions demonstrate the versatility of our approach, allowing for the synthesis of ketones and esters with multiple α‐heteroatoms using a common precursor.

A Carbene Relay Strategy for Cascade Insertion Reactions.

Insertion reactions that involve stabilized electrophilic metallocarbenes are of great importance for installing α-heteroatoms to carbonyl compounds. Nevertheless, the limited availability of carbene precursors restricts the introduction of only a single heteroatom. In this report, we describe a new approach based on an I(III) /S(VI) reagent that promotes the cascade insertion of heteroatoms. This is achieved by sequentially generating two α-heteroatom-substituted metal carbenes in one reaction. We found that this mixed I(III) /S(VI) ylide reacts efficiently with a transition metal catalyst and an X-H bond (where X=O, N). This transformation leads to the sequential formation of a sulfoxonium- and an X-substituted Rh-carbenes, enabling further reactions with another Y-H bond. Remarkably, a wide range of symmetrical and unsymmetrical α,α-O,O-, α,α-O,N-, and α,α-N,N-subsituted ketones can be prepared under mild ambient conditions. In addition, we successfully demonstrated other cascades, such as CN/CN double amidation, C-H/C-S double insertion, and C-S/Y-H double insertion (where Y=S, N, O, C). Notably, the latter two cascades enabled the simultaneous installation of three functional groups to the α-carbon of carbonyl compounds in a single step. These reactions demonstrate the versatility of our approach, allowing for the synthesis of ketones and esters with multiple α-heteroatoms using a common precursor.

HIV Protease Hinge Region Insertions at Codon 38 Affect Enzyme Kinetics, Conformational Stability and Dynamics.

HIV-1 protease is essential for the production of mature, infectious virions and is a major target in antiretroviral therapy. We successfully purified a HIV-1 subtype C variant, L38↑N↑L- 4, containing an insertion of asparagine and leucine at position 38 without the four background mutations - K20R, E35D, R57K, V82I using a modified purification protocol. Isothermal titration calorimetry indicated that 50% of the variant protease sample was in the active conformation compared to 62% of the wild type protease. The secondary structure composition of the variant protease was unaffected by the double insertion. The specific activity and kcat values of the variant protease were approximately 50% lower than the wild type protease values. The variant protease also exhibited a 1.6-fold increase in kcat/KM when compared to the wild type protease. Differential scanning calorimetry showed a 5°C increase in Tm of the variant protease, indicating the variant was more stable than the wild type. Molecular dynamics simulations indicated the variant was more stable and compact than the wild type protease. A 3-4% increase in the flexibility of the hinge regions of the variant protease was observed. In addition, increased flexibility of the flaps, cantilever and fulcrum regions of the variant protease B chain was observed. The variant protease sampled only the closed flap conformation indicating a potential mechanism for drug resistance. The present study highlights the direct impact of a double amino acid insertion in hinge region on enzyme kinetics, conformational stability and dynamics of an HIV-1 subtype C variant protease.