A rhodium‐catalyzed C−H activation/annulation of N‐aryl‐pyrazolidinones with vinylene carbonate was developed. The utilization of vinylene carbonate as the acetylene surrogate furnished the ...successful construction of non‐substituted 5,6‐pyrazolo1,2‐acinnoline derivatives, which are difficult to synthesize through other procedures. In this work, a series of variously substituted pyrazolo1,2‐acinnolines were obtained in yields up to 98 % with broad substrate scope and excellent selectivity. Moreover, external oxidants were not required in this protocol with H2O and CO2 as the clean by‐products.
A rhodium‐catalyzed C−H activation/annulation of N‐aryl‐pyrazolidinones with vinylene carbonate was developed. The utilization of vinylene carbonate as the acetylene surrogate furnished the successful construction of non‐substituted 5,6‐pyrazolo1,2‐acinnoline derivatives. A series of variously substituted pyrazolo1,2‐acinnolines were obtained with a broad substrate scope and excellent selectivity. Moreover, external oxidants were not required in this protocol with H2O and CO2 as the clean by‐products.
A method to synthesize pyrazolo1,2‐acinnolines via rhodium(III)‐catalyzed C−H activation of pyrazolidinones and subsequent 4+2 annulation of sulfoxonium ylides was developed. 5‐Substituted or ...5,10‐disubstituted pyrazolo1,2‐acinnolines could be obtained by slightly adjusting the reaction conditions. Gram‐scale synthesis and practical transformations proved the practicability of this method. The mechanism of this method was proposed in the article on the basis of preliminary mechanistic results and previous reports. This method features simplified operation, metal‐oxidant free, and readily available reactants.
The transition‐metal‐catalyzed C−H activation and annulation reactions of pyrazolidinones with 4‐vinyl‐1,3‐dioxolan‐2‐one or vinylene carbonate are described herein. This protocol provided two types ...of pyrazolo1,2‐acinnolines as essential assets for the development of bioactive compounds, and the synthetic practicality was performed and explained with 44 examples. The possible mechanism of these two reactions is proposed based on preliminary studies and previous reports, and no oxidant was added to both reactions.
The cytoplasmic steps of peptidoglycan synthesis represent an important targeted pathway for development of new antibiotics. Herein, we report the synthesis of novel 3-oxopyrazolidin-4-carboxamide ...derivatives with variable amide side chains as potential antibacterial agents targeting MurA enzyme, the first committed enzyme in these cytosolic steps. Compounds 15 (isoindoline-1,3-dione-5-yl), 16 (4-(1H-pyrazol-4-yl)phenyl), 20 (5-cyanothiazol-2-yl), 21 and 31 (5-nitrothiazol-2-yl derivatives) exhibited the most potent MurA inhibition, with IC50 values of 9.8–12.2 μM. Compounds 15, 16 and 21 showed equipotent inhibition of the C115D MurA mutant developed by fosfomycin–resistant Escherichia coli. NMR binding studies revealed that some of the MurA residues targeted by 15 also interacted with fosfomycin, but not all, indicating an overlapping but not identical binding site. The antibacterial activity of the compounds against E. coli ΔtolC suggests that inhibition of MurA accounts for the observed effect on bacterial growth, considering that a few potent MurA inhibitors could not penetrate the bacterial outer membrane and were therefore inactive as proven by the bacterial cell uptake assay. The most promising compounds were also evaluated against a panel of Gram-positive bacteria. Remarkably, compounds 21 and 31 (MurA IC50 = 9.8 and 10.2 μM respectively) exhibited a potent activity against Clostridioides difficile strains with MIC values ranging from 0.125 to 1 μg/mL, and were also shown to be bactericidal with MBC values between 0.25 and 1 μg/mL. Furthermore, both compounds were shown to have a limited activity against human normal intestinal flora and showed high safety towards human colon cells (Caco-2) in vitro. The thiolactone derivative (compound 5) exhibited an interesting broad spectrum antibacterial activity despite its weak MurA inhibition. Altogether, the presented series provides a promising class of antibiotics that merits further investigation.
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•15, 16 and 21 could equally inhibit wildtype and C115D MurA mutant developed by fosfomycin-resistant E. coli.•NMR studies revealed partial overlap between 15 and fosfomycin in binding to MurA.•21 and 31 were 2–8 folds more potent than vancomycin against some C. difficile clinical strains.•21 and 31 exhibited a bactericidal action and showed high stability in culture media and bacterial cell lysate.•21 and 31 exhibited restricted activity against representatives of the human normal microbiota.
A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid‐catalyzed formal 3+2‐ and 3+2+2‐cycloadditions of ketenes with azomethine imines is described. The methodology was found ...to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71–99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a 3+2+2‐cycloaddition to form structurally interesting bicyclic pyrazolo‐oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3‐dipole.
The catalytic asymmetric synthesis of bicyclic pyrazolidinones through alkaloid‐catalyzed formal 3+2‐ and 3+2+2‐cycloadditions of in situ‐generated and pre‐generated ketenes with azomethine imines is described. The method provides good to excellent yields (71–99 % for 24 examples, 39 examples in all), good to excellent diastereoselectivity (dr 3 : 1 to 27 : 1) and excellent enantioselectivity for most examples (≥93 % ee for 34 products).
Herein a rhodium (III)‐mediated catalysis was demonstrated for approaching the structurally divergent N,N‐bicyclic pyridazine analogues. The pyrazolidinone moiety was used to direct the ortho C−H ...activation and this led to a general synthesis of benzopyridazine analogues with satisfactory yields. The crucial effect of the base was illustrated in the sequential dehydration process. For mechanistic insight, control experiments were performed for illustration of the catalytic circle. Gram scale synthesis and several practical transformations were conducted for further applications.
Copper‐catalyzed sequential 1,3‐dipolar cycloadditions of azomethine imines and alkynes and electrophilic thiolations are described. The C−S, C−N, and C−C bonds were simultaneously formed in one pot, ...leading to N,N‐bicyclic pyrazolidinones in good to excellent yields. The process is proposed to proceed via reaction of a cuprate pyrazolidinonate intermediate and benzenesulfonothioate.
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We report herein a new pyrazolidinone chiral auxiliary and its utility in Lewis acid-mediated conjugate addition followed by diastereoselective trapping of the intermediate radical by ...an allyl group. The allylated products were obtained in good yields (up to 89%) and high diastereoselectivities (up to 94/6).
3+2 Cycloaddition reactions of 2-(trifluoroacetyl)vinyl ethyl ether (1) to substituted and unsubstitued 2-arylidene-5-oxopyrazolidin-2-ium-1-ides (2a?e) were studied using density functional theory ...(DFT) methods at the cc-pVDZ level. The mechanistic details of these reactions, especially with respect to regio- and stereoselectivity, were analyzed. Analysis of the relative energies that are associated with the different reaction pathways indicated that the presence of the trifluoroacetyl group in the dipolarophile and substituents on the aryl ring in the dipolar have a remarkable effect on selectivity. In addition, it was found that the ortho?endo pathway with the lowest activation energy is preferred, which is in good agreement with the experimental data. Moreover, the elimination of ethanol from the 3+2 cycloadducts and the formation of bicyclic pyrazolidinones are explained in order to give a total description of the complete domino processes. The inclusion of solvent effects increased the activation energies and the exothermic character of the cycloadducts, but did not change the gas phase selectivity. The DFT-based reactivity indices clearly predicted the experimental regiochemistry.
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