Cyclopropyl Ring Research Articles

Electrosynthesis of Highly Functionalized Quinolines through Radical Annulation-Polar Addition Cascade.

Synthesis of diversely functionalized quinoline-2-carboxylates is illustrated through electrochemical cross-dehydrogenative coupling between N-aryl glycinates and methylenecyclopropanes. An extensive range of distinct functionalities is well-compatible under these transition-metal- and oxidant-free mild electrochemical conditions, contributing to a broad substrate scope and practical applicability. Cyclic voltammetric measurements and control experiments suggested a formal [4 + 2] cycloaddition involving radical intermediates, followed by a cyclopropyl ring opening through nucleophilic polar addition, consecutively fabricating C-C and C-N bonds.

Rearrangement, Elimination, and Ring-Opening Reactions of Cyclopropyl-Substituted Nitrenium Ions: A Computational and Experimental Investigation.

N-(4-Biphenylyl)-N-cyclopropyl nitrenium ion 5 and N-benzyl-N-cyclopropyl nitrenium ion (6) were generated through photolysis of their corresponding N-aminopyridinium ion photoprecursors. In the case of 5, stable products result from a combination of cyclopropyl ring expansion (N-biphenylazetium ion) and ethylene elimination (biphenylisonitrilium ion). When present in high concentrations, methanol can add to the cyclopropyl ring-forming N-3-methoxypropyl-N-biphenyl iminium ion. In contrast, the only detectable product from the N-benzyl-N-cyclopropyl nitrenium ion (6) is benzylisonitrile, resulting from the elimination of ethylene. Density functional theory (DFT) calculations predict the product distributions from the more stable biphenyl system 5 with reasonable accuracy. However, product distributions from the less stable benzyl system 6 are forecast with less accuracy.

Comprehensive Strategies for the Synthesis of 1,3-Enyne Derivatives

AbstractThe synthesis of 1,3-enyne has widespread appeal in organic synthesis due to their proven adaptability as intermediates in routes to compounds of significant biological and material interest. A variety of methods have been designed to formulate 1,3-enynes from diverse substrates, such as alkynes, 1,3-diynes, alkynyl-substituted cyclopropanes, and propargyl alcohols. This review covers the synthesis of 1,3-enynes utilizing the homo- and cross-coupling of alkynes, nucleophilic metal/acid-induced cyclopropane ring opening, and rearrangement/dehydration of propargyl alcohols. A key concern in procedures starting from alkynes and 1,3-diynes is the management of regio-, stereo-, and, where fitting, chemoselectivity. In contrast, in cyclopropyl ring opening nucleophile orientation determines the 1,3-enynes formed. Efficient methods for the broad and selective synthesis of 1,3-enynes are highlighted and specific examples are given to demonstrate the efficacy of these processes.1 Introduction and Scope2 Synthesis2.1 Synthesis of 1,3-Enynes from Alkynes2.1.1 Metal-Catalyzed Cross-Coupling/Additions of Alkynes with Alkenes or Vinyl or Aryl Halides2.1.1.1 Palladium Catalysis2.1.1.2 Rhodium Catalysis2.1.1.3 Copper Catalysis2.1.1.4 I ron Catalysis2.1.1.5 Nickel Catalysis2.1.1.6 Miscellaneous2.2 Synthesis of Enynes from Propargyl Alcohols2.3 Metal/Acid-Catalyzed Ring Opening of Cyclopropanes3 Conclusion

Reactivity of α-diazo sulfonium salts: rhodium-catalysed ring expansion of indenes to naphthalenes.

In the presence of catalytic amounts of the paddlewheel dirhodium complex Rh2(esp)2, α-diazo dibenzothiophenium salts generate highly electrophilic Rh-coordinated carbenes, which evolve differently depending on their substitution pattern. Keto-moieties directly attached to the azomethinic carbon promote carbene insertion into one of the adjacent C-S bonds, giving rise to highly electrophilic dibenzothiopyrilium salts. This intramolecular pathway is not operative when the carbene carbon bears ester or trifluoromethyl substituents; in fact, these species react with olefins delivering easy to handle cyclopropyl-substituted sulfonium salts. When indenes are the olefins of choice, the initially formed cyclopropyl rings smoothly open with concomitant departure of dibenzothiophene, enabling access to a series of 2-functionalized naphthalenes.

6,7-Diphenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one 5,5-dioxide.

The racemic mixture of the title compound, C19H19NO3S, crystallizes in space group P with two homochiral mol-ecules in each asymmetric unit. The seven-membered ring in both mol-ecules is in a pucker-chair conformation. The extended structure exhibits C-H⋯O hydrogen bonds, of which two connect crystallographically independent mol-ecules to generate a chain propagating along the b-axis direction. One C-H grouping of the cyclo-propyl ring is in close contact with the phenyl ring of the neighboring independent mol-ecule in C-H⋯π type inter-actions with carbon atom-ring-centroid distances of 3.544 (5) and 3.596 (4) Å. Other inter-actions are of the parallel-reciprocal type, with the chiral carbon atom of one mol-ecule donating a proton to an oxygen atom of the sulfone group of a symmetry-related mol-ecule and vice-versa. Symmetry-related mol-ecular pairs also exhibit T-type inter-actions between aromatic rings with inter-planar angles of 74.2 (2) and 69.2 (2)° and inter-centroid distances of 4.965 (4) and 5.114 (4) Å.

When Phenyl and Cyclopropyl Rings Meet: Spectroscopic Shifts and Conformational Questions.

The electronic and vibrational spectra of cyclopropylbenzene (CPB) and 1,3-bromocyclopropylbenzene (BrCPB) in the gas phase were investigated using quantum chemical calculations in combination with resonance-enhanced multi-photon ionization REMPI techniques including 1c-R2PI, UV-UV holeburning, and IR-UV ion depletion in the CH stretch region. The electronic spectra revealed the presence of a single conformer for both species, with the absence of any perpendicular conformer attributed to low computed barriers to conformer interconversion. Assignment of CPB to the bisected conformer was made through interpreting distinctive CH stretch bands in the IR-UV spectrum in conjunction with quantum chemical calculations. A local anharmonic model based on DFT calculations was adapted to reproduce the cyclopropyl CH stretch spectrum successfully. It was not feasible to definitively assign which bisected conformer of BrCPB was observed using vibrational information alone due to the close similarity of their predicted IR spectra. However, conformational sensitivity of the S1 ← S0 transition dipole moment (TDM) alignments leads to simulated rotational contours that display stark differences, which prompted assignment to the "B1" bisecting conformer with the cyclopropyl ring directed away from the bromine atom. The absence of the energetically comparable "B2" conformer is unexpected. The analysis of the convolution of aromatic and aliphatic modes serves as a basis for assignment in constrained aliphatic systems.

Study on the initial pyrolysis kinetics of strained polycyclic hydrocarbons

Strained polycyclic hydrocarbons are one of the most important classes of high-energy density fuels. In this work, the thermodynamics and initial pyrolysis kinetics of five strained polycyclic hydrocarbons, which are isomers of JP-10 and are linearly aggregates of two cyclopropyl rings and one cyclobutyl ring, were investigated using quantum chemical computations. The initial pyrolysis reactions include ring bond breaking and bridge bond breaking. The ring bond breaking reactions include a diradical pathway which is the direct C-C bond breaking to produce a diradical and an isomerization pathway involving concert bond breaking and H-atom transfer, and the bridge bond breaking reactions lead to two radicals. Our potential energy calculation shows that the ring bond breaking reactions are much more energetically favorable than the bridge bond breaking reactions, which can be neglected in the initial pyrolysis process of strained polycyclic hydrocarbons. The rate constants of the ring bond breaking reactions were computed using variational transition state theory (VTST) or transition state theory (TST). Our calculated results demonstrated that ring bond breaking reactions of the three-membered ring are competitive with that of the four-membered ring. The studied reactions are divided into classes depending on the size of the rings (three- or four-membered ring) and the types of the carbon atoms of the breaking C-C bond (Cs-Cs, Cs-Ct, Ct-Ct and Cq-Cs). Reaction rate rules are established for each class, which are useful for the mechanism generation for analogous strained polycyclic hydrocarbons. Thermodynamic properties including net calorific values per mole, gravimetric net heat of combustion and impulse time of our studied strained polycyclic hydrocarbons are higher than those of JP-10. A comparison of the initial pyrolysis kinetics of our studied strained polycyclic hydrocarbons with the isomer JP-10 indicates that these compounds may be easier to pyrolyze.

Photocatalytic degradation of the antiviral drug abacavir using titania-graphene oxide nanocomposites in landfill leachate

The photocatalytic treatment of the antiviral drug abacavir has been studied using graphene oxide (GO)-titania (TiO2) nanocomposites as catalysts under simulated solar irradiation. A mild ultrasonically assisted synthetic route was followed for the preparation of the GO-TiO2 composites. Their characterization and determination of their physicochemical properties was conducted employing Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), BET analysis and X-ray Diffraction (XRD). Six different nanocomposites were tested towards their photocatalytic efficiency containing a varying amount of GO ranging from 1 % to 20 %. The degradation kinetics followed the first-order kinetic law. The synthesized composite with 2 % GO appeared to be the most effective achieving complete disappearance of the target compound within 20 min. The photocatalytic degradation of the target compound proceeded in slower rates when using a landfill leachate as a water matrix due to its increased complexity. The identification of the transformation products (TPs) revealed the formation of forty-six intermediates arising from different transformation routes. The cyclopropyl ring appears to be the main site of reaction although hydroxylation, dehydrogenation, deamination/hydroxylation and isomerization of the parent compound may be also observed. The evolution profiles of the most abundant TPs in the two matrices (ultrapure water and leachate) revealed that different transformation routes may be more favored in each matrix.

Picolinamide Ligands: Nickel-Catalyzed Reductive Cross-Coupling of Aryl Bromides with Bromocyclopropane and Beyond.

The arylcyclopropane motif as the combination of aryl and cyclopropyl ring systems can be found in an increasing amount of approved and investigational drugs. Herein, we have developed a mild, efficient nickel-catalyzed reductive cross-coupling protocol, featuring a simple Ni(II) precatalyst and a novel picolinamide NN2 pincer ligand. A variety of (hetero)aryl bromides could successfully couple with cyclopropyl bromide to furnish the valued arylcyclopropanes in good to excellent yields. This method is applicable to other alkyl bromides as well. Notably, the reaction is tolerant of a broad range of functionalities including free amines. Furthermore, the synthesis of several significant intermediates of bioactive molecules was achieved in grams, proving the practicability of this method.

Stereoselective Preparation of CF3-Containing Cyclopropanes.

A regio- and diastereoselective carbometalation of easily accessible CF3-substituted cyclopropenes is developed with a diastereoselectivity of the addition opposite to the CF3 group. This simple strategy allows the preparation of polysubstituted (up to penta-) cyclopropyl rings possessing two adjacent quaternary carbon stereocenters with excellent diastereoselectivities.

Synthesis of Bicyclo[3.2.1]octanones by Regioselective Cyclopropyl Ring Cleavage of Tricyclo[3.3.0.02,8]octanones in an Ionic Liquid

AbstractThe synthesis of bicyclo[3.2.1]octanones by the regioselective cyclopropyl ring cleavage of bicyclo[3.3.0.02,8]octanes using hydrochloric acid in an ionic liquid BMImCl is reported herein. The reaction provides the products regioselectively in very good yields in much faster times compared to such reactions in traditional solvents. Direct head to head comparison of the ring cleavage reaction in BMImCl with other conventional organic solvents clearly demonstrate the advantages of the former as the medium for the ring cleavage reactions.

Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs

Members of the HEPT class are potential non-nucleoside inhibitors of HIV-1 reverse transcriptase. Our previously disclosed one representative HEPT analog 2 produced potent inhibitory activity against wild-type HIV-1 (EC50 = 63.0 nM), but its high cytotoxicity and low selectivity index still needs to be improved (CC50 = 34.0 μM, SI = 565). In this work, a series of novel cyclopropyl-substituted HEPT analogs were developed by substituting a cyclopropyl ring for the isopropyl group at the C-5 position of 2 with the purpose of improving its potency and safety. Of this series, the most potent compound 9h featuring a 2,5-fluoro substitution on the C-6 benzene ring exerted significantly increased inhibitory activity toward wild-type HIV-1 (EC50 = 0.017 μM), which was 4-fold more active than the lead compound 2. The cytotoxicity of 9h was also reduced with much higher selectivity index (SI > 2328). This compound possessed good pharmacokinetics profiles and potential safety: (1) No obvious in vitro inhibition effect toward CYP enzyme and hERG was observed in 9h; (2) The single-dose acute toxicity test did not induce mice death and obvious pathological damage; (3) Excellent oral bioavailability of 9h (F= 86%) in rats was unveiled. These results provide valuable guidance for further development of HEPT anti-HIV-1 drugs.

Directed Diastereoselective Cyclopropanation and Epoxidation of Alkenyl Cyclopropyl Carbinol Derivatives.

We report the directed diastereoselective Simmons-Smith cyclopropanation and vanadium-catalyzed epoxidation reactions of alkenyl cyclopropyl carbinol derivatives. The reaction furnished densely substituted stereodefined bicyclopropanes and cyclopropyl oxiranes as a single diastereomer in each case. The remarkable selectivity is obtained thanks to the rigidity of the cyclopropyl core, allowing diastereoselective reactions on the alkenyl moiety. This emphasizes the uniqueness of the cyclopropyl ring as a central platform in stereoselective synthesis.

Conformationally Locked Carbocyclic Nucleosides Built on a 4'-Hydroxymethyl-3'-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity.

Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a-e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.

Bench-Stable Dinuclear Mn(I) Catalysts in E-Selective Alkyne Semihydrogenation: A Mechanistic Investigation.

Dinuclear manganese hydride complexes of the form [Mn2 (CO)8 (μ-H)(μ-PR2 )] (R=Ph, 1; R=iPr, 2) were used in E-selective alkyne semi-hydrogenation (E-SASH) catalysis. Catalyst speciation studies revealed rich coordination chemistry and the complexes thus formed were isolated and in turn tested as catalysts; the results underscore the importance of dinuclearity in engendering the observed E-selectivity and provide insights into the nature of the active catalyst. The insertion product obtained from treating 2 with (cyclopropylethynyl)benzene contains a cis-alkenyl bridging ligand with the cyclopropyl ring being intact. Treatment of this complex with H2 affords exclusively trans-(2-cyclopropylvinyl)benzene. These results, in addition to other control experiments, indicate a non-radical mechanism for E-SASH, which is highly unusual for Mn-H catalysts. The catalytically active species are virtually inactive towards cis to trans alkene isomerization indicating that the E-selective process is intrinsic and dinuclear complexes play a critical role. A reaction mechanism is proposed accounting for the observed reactivity which is fully consistent with a kinetic analysis of the rate limiting step and is further supported by DFT computations.

Beyond the cyclopropyl ring formation: fungal Aj_EasH catalyzes asymmetric hydroxylation of ergot alkaloids.

Ergot alkaloids (EAs) are among the most important bioactive natural products. FeII/α-ketoglutarate-dependent dioxygenase Aj_EasH from Aspergillus japonicus is responsible for the formation of the cyclopropyl ring of the ergot alkaloid (EA) cycloclavine (4). Herein we reconstituted the biosynthesis of 4 in vitro from prechanoclavine (1) for the first time. Additionally, an unexpected activity of asymmetric hydroxylation at the C-4 position of EA compound festuclavine (5) for Aj_EasH was revealed. Furthermore, Aj_EasH also catalyzes the hydroxylation of two more EAs 9,10-dihydrolysergol (6) and elymoclavine (7). Thus, our results proved that Aj_EasH is a promiscuous and bimodal dioxygenase that catalyzes both the formation of cyclopropyl ring in 4 and the asymmetric hydroxylation of EAs. Molecular docking (MD) revealed the substrate-binding mode as well as the catalytic mechanism of asymmetric hydroxylation, suggesting more EAs could potentially be recognized and hydroxylated by Aj_EasH. Overall, the newly discovered activity empowered Aj_EasH with great potential for producing more diverse and bioactive EA derivatives. KEY POINTS: • Aj_EasH was revealed to be a promiscuous and bimodal FeII/α-ketoglutarate-dependent dioxygenase. • Aj_EasH converted festuclavine, 9,10-dihydrolysergol, and elymoclavine to their hydroxylated derivatives. • The catalytic mechanism of Aj_EasH for hydroxylation was analyzed by molecular docking.

Spectroscopic signatures of bilayer ordering in native biological membranes

Membrane proteins and polycyclic lipids like cholesterol and hopanoids coordinate phospholipid bilayer ordering. This phenomenon manifests as partitioning of the liquid crystalline phase into liquid-ordered (Lo) and liquid-disordered (Ld) regions. In Eukaryotes, microdomains are rich in cholesterol and sphingolipids and serve as signal transduction scaffolds. In Prokaryotes, Lo microdomains increase pathogenicity and antimicrobial resistance. Previously, we identified spectroscopically distinct chemical shift signatures for all-trans (AT) and trans-gauche (TG) acyl chain conformations, cyclopropyl ring lipids (CPR), and hopanoids in prokaryotic lipid extracts and used Polarization Transfer (PT) SSNMR to investigate bilayer ordering. To investigate how these findings relate to native bilayer organization, we interrogate whole cell and whole membrane extract samples of Burkholderia thailendensis to investigate bilayer ordering in situ. In 13C-13C 2D SSNMR spectra, we assigned chemical shifts for lipid species in both samples, showing conservation of lipids of interest in our native membrane sample. A one-dimensional temperature series of PT SSNMR and transverse relaxation measurements of AT versus TG acyl conformations in the membrane sample confirm bilayer ordering and a broadened phase transition centered at a lower-than-expected temperature. Bulk protein backbone Cα dynamics and correlations consistent with lipid-protein contacts within are further indicative of microdomain formation and lipid ordering. In aggregate, these findings provide evidence for microdomain formation in vivo and provide insight into phase separation and transition mechanics in biological membranes.

Potent biological investigation into a new class of sulfone derivatives endowed with quinolinyl–cyclopropane analogue

Novel series of quinoline derivatives incorporating cyclopropyl ring and sulfone linkage as substituents have been synthesized, and oxidation of ethyl-2-cyclopropyl-4-(substituted phenylthio)quinoline-3-carboxylate was carried out to set ethyl-2-cyclopropyl-4-(substituted phenyl sulfonyl)quinoline-3-carboxylate. An ecofriendly synthesis of sulfone derivatives was carried out by the reaction of glacial acetic acid and 30% hydrogen peroxide at room temperature. The synthesized quinoline incorporating sulfone linkage derivatives was evaluated for their anticipated antimicrobial activity as well as characterized by their melting point, mass spectra, IR, 1H NMR and 13C NMR spectra. For proving the structural biological activity, herein we have carried out SAR and HOMO–LUMO studies. From these studies, we have found some best results as their energy gap is very low which makes their activity higher, i.e. compounds 11a, 11b, 11h, 11k and 11m.Graphical abstract

QSCR Analysis of Cytotoxicity of 6-Fluoro-3-(4H-1,2,4-triazol-3- yl)quinolin-4(1H)-ones on Chinese Hamster Ovary Cell Line: Design of REPUBLIC1986.

6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computerassisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4- triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity, and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (μM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin- 4(1H)-ones as seed compounds.

Synthesis of 1,4-Dihydropyridines and Related Heterocycles by Iodine-Mediated Annulation Reactions of N-Cyclopropyl Enamines.

The annulation of N-cyclopropyl enamines to produce 1,4-dihydropyridine (1,4-DHP) derivatives is described. In the presence of molecular iodine (I2), an N-cyclopropyl enamine substrate undergoes iodination, opening of the cyclopropyl ring, and annulation with a second molecule of the substrate to form the 1,4-DHP product. This reaction is amenable to gram-scale operations under mild reaction conditions with no transition metals being required. Further transformations of the 1,4-DHPs leads to related pyridine and bicyclic frameworks.