Chemodivergent Tandem Radical Cyclization of Alkene-Substituted Quinazolinones: Rapid Access to Mono- and Di-Alkylated Ring-Fused Quinazolinones.

Chemodivergent tandem radical cyclization offers exciting possibilities for the synthesis of structurally diverse cyclic compounds. Herein, we revealed a chemodivergent tandem cyclization of alkene-substituted quinazolinones under metal- and base-free conditions, this transformation is initiated by alkyl radicals produced from oxidant-induced α-C(sp3 )-H functionalization of alkyl nitriles or esters. The reaction resulted in the selective synthesis of a series of mono- and di-alkylated ring-fused quinazolinones by modulating the loading of oxidant, reaction temperature, and reaction time. Mechanistic investigations show that the mono-alkylated ring-fused quinazolinones is constructed by the key process of 1,2-hydrogen shift, whereas the di-alkylated ring-fused quinazolinones is mainly achieved through crucial steps of resonance and proton transfer. This protocol is the first example of remote second alkylation on the aromatic ring via α-C(sp3 )-H functionalization and difunctionalization achieved by association of two unsaturated bonds in radical cyclization.

The construction of benzimidazo[2,1-a]isoquinolin-6(5H)-ones from N-methacryloyl-2-phenylbenzoimidazoles through radical strategies.

Benzimidazo[2,1-a]isoquinolin-6(5H)-one constitutes a structurally unique class of tetracyclic N-heterocycles that are found throughout a myriad of biologically active natural products, pharmaceutical compounds, and functional materials. Various synthetic routes for the preparation of benzimidazo[2,1-a]isoquinolin-6(5H)-ones have been reported. In particular, the use of N-methacryloyl-2-phenylbenzoimidazoles to construct benzimidazo[2,1-a]isoquinolin-6(5H)-ones through various radical strategies have attracted widespread attention due to the versatility and simple preparation of raw materials, as well as the step-economy and mild reaction conditions. Using representative examples, we highlight significant progress in the synthesis of benzimidazo[2,1-a]isoquinolin-6(5H)-ones, including the selection of the catalytic system, substrate scope, mechanistic understanding, and applications. The contents of this review focus on the development of C-, S-, P-, and Si-centered radical addition-intramolecular cyclization strategies.

Recent progress in the radical α-C(sp3)-H functionalization of ketones.

The direct use structurally simple ketones as α-ketone radical sources for α-C(sp3)-H functionalization is a sustainable and powerful approach for constructing complex and multifunctional chemical scaffolds with diverse applications. The reactions of α-ketone radicals with alkenes, alkynes, enynes, imides, and imidazo[1,2-a]pyridines have broadened the structural diversity and complexity of ketones. Through chosen illustrative examples, we outline the recent progress in the development of methods that enable the radical α-C(sp3)-H functionalization of ketones, with an emphasis on radical initiation systems and possible mechanisms of the transformations. The application of these strategies is illustrated by the synthesis of several biologically active molecules and drug molecules. Further subdivision is based on substrate type and reaction type.

Selective divergent radical cyclization of 1,6-dienes with alkyl nitriles.

An efficient, selective, and step economical radical cyclization of 1,6-dienes with alkyl nitriles initiated by α-C(sp3)-H functionalization under the Sc(OTf)3 and Ag2CO3 system is described here. The selective divergent cyclization relies on the substitution effect at the α-position of the acrylamide moiety and nitriles, which is terminated by hydrogen abstraction, direct cyclization with the aryl ring, or further cyclization with the CN bond and hydrolysis, respectively.

Base-promoted domino radical cyclization of 1,6-enynes.

A good regioselective, high atom-economical and transition-metal-free method for the synthesis of α-functionalized ether derivatives via the domino radical cyclization of 1,6-enynes is described. A series of α-functionalized ether derivatives could be easily obtained in good yields with wide functional group tolerance by using less toxic and inexpensive Cs2CO3 as the base. The control experiment results show that the reaction involves a radical process. This strategy provides a regioselective way toward the formation of dual C-C bonds in one step.

Severity of acute gastrointestinal injury grade is a predictor of all-cause mortality in critically ill patients: a multicenter, prospective, observational study.

BACKGROUND: In 2012, the European Society of Intensive Care Medicine proposed a definition for acute gastrointestinal injury (AGI) based on current medical evidence and expert opinion. The aim of the present study was to evaluate the feasibility of using the current AGI grading system and to investigate the association between AGI severity grades with clinical outcome in critically ill patients. METHODS: Adult patients at 14 general intensive care units (ICUs) with an expected ICU stay ≥24 h were prospectively studied. The AGI grade was assessed daily on the basis of gastrointestinal (GI) symptoms, intra-abdominal pressures, and feeding intolerance (FI) in the first week of admission to the ICU. RESULTS: Among the 550 patients enrolled, 456 patients (82.9%) received mechanical ventilation, and 470 patients were identified for AGI. The distribution of the global AGI grade was 24.5% with grade I, 49.4% with grade II, 20.6% with grade III, and 5.5% with grade IV. AGI grading was positively correlated with 28- and 60-day mortality (P < 0.0001). Univariate Cox regression analysis showed that age, sepsis, diabetes mellitus, coronary artery disease, the use of vasoactive drugs, serum creatinine and lactate levels, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the global AGI grade were significantly (P ≤ 0.02) associated with 60-day mortality. In a multivariate analysis including these variables, diabetes mellitus (HR 1.43, 95% CI 1.03-1.87; P = 0.05), the use of vasoactive drugs (HR 1.56, 95% CI 1.12-2.11; P = 0.01), serum lactate (HR 1.15, 95% CI 1.06-1.24; P = 0.03), global AGI grade (HR 1.65, 95% CI 1.28-2.12; P = 0.008), and APACHE II score (HR 1.04, 95% CI 1.02-1.06; P < 0.001) were independently associated with 60-day mortality. In a subgroup analysis of 402 patients with 7-day survival, in addition to clinical predictors and the AGI grade on the first day of ICU stay, FI within the first week of ICU stay had an independent and incremental prognostic value for 60-day mortality (χ2 = 41.9 vs. 52.2, P = 0.007). CONCLUSIONS: The AGI grading scheme is useful for identifying the severity of GI dysfunction and could be used as a predictor of impaired outcomes. In addition, these results support the hypothesis that persistent FI within the first week of ICU stay is an independent determinant for mortality. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-OCS-13003824 . Registered on 29 September 2013.

Four-Component Radical 1,2-Selenosulfonylation of Allenes.

Selenosulfones, as pivotal pharmaceutical molecule frameworks, have become a research hotspot in modern organic synthesis due to their vital need for efficient preparation. Herein, we have developed an iron-catalyzed four-component controllable radical tandem reaction of allenes involving cycloketone oxime esters, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and diphenyl diselenides for the synthesis of complex selenosulfones. This is the first case of achieving the 1,2-selenosulfonylation of allenes via a radical process, wherein precise control of radical rates and polarity matching enhance high regioselective conversion. The reaction conditions are ecofriendly and mild with step-efficiency by forming two new C-S bonds and one C-Se bond in one pot. Moreover, the 1,2-selenosulfonylation of allenes can be achieved by replacing cycloketone oxime esters with aryldiazonium tetrafluoroborates in this system.

(Acetyl-acetonato-κ(2)O,O')bis-{5-fluoro-2-[3-(4-fluoro-phen-yl)pyrazin-2-yl]phenyl-κ(2)N(1),C(1)}iridium(III).

In the title complex, [Ir(C(16)H(9)F(2)N(2))(2)(C(5)H(7)O(2))], the Ir(III) atom, lying on a twofold rotation axis, is hexa-coordinated in a distorted octa-hedral geometry by two C,N-bidentate 5-fluoro-2-[3-(4-fluoro-phen-yl)pyrazin-2-yl]phenyl ligands and one O,O'-bidentate acetyl-acetonate ligand. The dihedral angles between the benzene rings and the pyrazine ring are 14.66 (8) and 49.76 (12)°.

(Acetyl-acetonato-κO,O')bis-[2-(5-methyl-3-phenyl-pyrazin-2-yl-κN)phen-yl-κC]iridium(III).

In the title complex, [Ir(C(17)H(13)N(2))(2)(C(5)H(7)O(2))], the Ir(III) atom is hexa-coordinated in a distorted octa-hedral geometry by two C,N-bidentate 2-(5-methyl-3-phenyl-pyrazin-2-yl)phenyl (mdpp) ligands and one O,O-bidentate acetyl-acetonate ligand. The dihedral angles between the phenyl rings and the pyrazine ring are 9.56 (14) and 58.99 (14)° for one mdpp ligand and 9.34 (14) and 79.94 (15)° for the other.

Sulfonyl radical triggered selective iodosulfonylation and bicyclization of 1,6-dienes.

A novel sulfonyl radical triggered selective iodosulfonylation and bicyclization of 1,6-dienes has been described for the first time. High selectivity and efficiency, mild reaction conditions, excellent functional group compatibility, and broad substrate scope are the attractive features of this synthetic protocol, which provides a unique platform for precise radical cyclization.

Prognostic Value of Prolonged Feeding Intolerance in Predicting All-Cause Mortality in Critically Ill Patients: A Multicenter, Prospective, Observational Study.

BACKGROUND: The 2012 European Society of Intensive Care Medicine (ESICM) guidelines provided a clear definition of feeding intolerance (FI). The study aimed to investigate the association between FI based on the current ESICM definition and clinical outcome and to further explore the effect of the duration of FI on mortality. METHODS: Adult patients from 14 general intensive care units (ICUs) with an expected ICU stay ≥24 hours were prospectively studied. Based on FI duration in the first week of admission to the ICU, FI was categorized as 7-day persistent feeding tolerance (FT), delayed FT, delayed FI, and 7-day persistent FI. The primary outcomes were 28-day and 60-day all-cause mortality. RESULTS: Of 499 patients, the prevalence of 3-day and 7-day persistent FI was 39.2% (n = 196) and 25.4% (n = 106), respectively. The patients with 3-day FT had lower risk of 28-day and 60-day mortality rates and higher prevalence in ventilator weaning and vasoactive medication on the seventh day of ICU admission than those with 3-day FI. Three-day FI remained an independent predictor for 60-day mortality. In a subgroup analysis including 418 patients with 7-day survival, compared with those with 7-day persistent FT, the odds ratios of 60-day mortality were 1.67, 1.97, and 2.62 in the patients with delayed FT, delayed FI, and 7-day persistent FI, respectively. CONCLUSION: FI was associated with increased mortality and longer duration of mechanical ventilation and vasoactive support. Prolonged or relapsing FI represented an incremental risk of adverse outcomes in critically ill patients.

Data-based approach for feedback-feedforward controller design using closed-loop plant data.

Feedforward control of measurable disturbances is a useful complement to feedback control because feedforward control performs control actions before a disturbance response occurs in a process output. In contrast to the typical model-based design approach, a novel data-based method for designing both the feedback and feedforward controllers is presented in this paper. The controller design directly exploits closed-loop plant data and does not require an identification of process and disturbance models. A feedback proportional-integral-derivative controller and feedforward lead-lag compensator are sequentially designed on the basis of the closed-loop response data for a set-point change and for a disturbance input, respectively. Because the controller design process uses plant data integrals, the proposed method is robust against measurement noise. Moreover, the proposed design method can be applied to improve existing underperforming feedback and feedforward controllers using routine closed-loop operating data. Simulation studies demonstrated that the proposed method outperforms existing methods in designing a feedback-feedforward control system.

Competition-derived FRET-switching cationic conjugated polymer-Ir(III) complex probe for thrombin detection.

A novel, label-free and convenient strategy for thrombin assay has been developed based on the fluorescence resonance energy transfer (FRET) from a cationic conjugated polymer (CCP) to Ir(III) complex. The energy donor (CCP) and acceptor (Ir(III) complex) were taken into close proximity through π-π stacking interaction and electrostatic interaction, leading to the occurrence of FRET. However, the introduction of the thrombin aptamer upset the status and blocked the FRET process, but afterwards the reappearance of FRET phenomenon was confirmed by the special binding interaction between aptamer and thrombin, thus achieving the quantitative detection of thrombin. This assay could detect thrombin as low concentration as about 0.05pM and provided a highly specific selectivity among other nonspecific proteins. Moreover, the strategy may allow our platform to provide similar sensitivity toward different targets in an aptamer-structure-independent manner. Furthermore, the assay can be used to detect thrombin in diluted real urine or serum samples with a satisfactory recovery, implying its great potential for rapid detection of thrombin in the clinic.

Synthesis of fluorescent composite macromolecules by using organic/inorganic assemblies as structural units.

A synthetic pathway is introduced to construct fluorescent composite macromolecules with supramolecular assemblies as structural units. The supramolecular assembly that contains polymerizable groups is used as a starting "monomer." The supramolecular assembly is composed of nanoparticle core of II - IV group semiconductor and organic ammonium shell. Polymerization of the assemblies yields soluble composite macromolecules. Light scattering data show that the macromolecule has an average size of about 310 nm in diameter in chloroform; AFM image illustrates that the macromolecule has an average diameter of 120 nm and an average height of 35 nm on a mica surface and photoluminescent spectra reveal that the macromolecule performs an extraordinary enhancement in fluorescence intensity of the semiconductor nanoparticles. These observations suggest that construction of macromolecules with supramolecular assembly as starting monomer may produce generations of materials with novel properties.

Disturbance-rejection-based tuning of proportional-integral-derivative controllers by exploiting closed-loop plant data.

A systematic data-based design method for tuning proportional-integral-derivative (PID) controllers for disturbance attenuation is proposed. In this method, a set of closed-loop plant data are directly exploited without using a process model. PID controller parameters for a control system that behaves as closely as possible to the reference model for disturbance rejection are derived. Two algorithms are developed to calculate the PID parameters. One algorithm determines the optimal time delay in the reference model by solving an optimization problem, whereas the other algorithm avoids the nonlinear optimization by using a simple approximation for the time delay term, enabling derivation of analytical PID tuning formulas. Because plant data integrals are used in the regression equations for calculating PID parameters, the two proposed algorithms are robust against measurement noises. Moreover, the controller tuning involves an adjustable design parameter that enables the user to achieve a trade-off between performance and robustness. Because of its closed-loop tuning capability, the proposed method can be applied online to improve (retune) existing underperforming controllers for stable, integrating, and unstable plants. Simulation examples covering a wide variety of process dynamics, including two examples related to reactor systems, are presented to demonstrate the effectiveness of the proposed tuning method.

A one-step electrochemiluminescence immunosensor preparation for ultrasensitive detection of carbohydrate antigen 19-9 based on multi-functionalized graphene oxide.

A one-step electrochemiluminescence (ECL) immunosensor for ultrasensitive detection of carbohydrate antigen 19-9 (CA19-9) was developed based on multi-functionalized graphene oxide (GO), which was prepared with N-(4-aminobutyl)-N-ethylisoluminol (ABEI) and CA19-9 antibody (anti-CA19-9) chemically bound to the surface of magnetic GO (nanoFe3O4@GO). ABEI and anti-CA19-9 acted as the electrochemiluminophore and the capture device for CA19-9 respectively. NanoFe3O4@GO enabled all the ABEI immobilized molecules electrochemically active due to its good conductivity, and brought multi-functionalized GO attracted on the surface of magnetic glass carbon electrode through magnetism. Thus the ECL immunosensor could be prepared through a one-step process that facilitates ultrasensitive detection of CA19-9. Under optimal conditions, the ECL intensity of the immunosensor decreased proportionally to the logarithmic concentrations of CA19-9 in the range of 0.001-5U/mL with a detection limit of 0.0005U/mL. This one-step ECL immunosensor showed good performance in specificity, stability, reproducibility, regeneration and application. It opened a new avenue to apply multi-functionalized bionanomaterials in ECL immunoassay.