Cobalt(I)-Catalyzed (3 + 2 + 2) Cycloaddition between Alkylidenecyclopropanes, Alkynes, and Alkenes.

Cobalt(I) catalysts equipped with bisphosphine ligands can be used to promote formal (3 + 2 + 2) intramolecular cycloadditions of enynylidenecyclopropanes of type 1. The method provides synthetically appealing 5,7,5-fused tricyclic systems in good yields and with complete diastereo- and chemoselectivity. Interestingly, its scope differs from that of previously reported annulations based on precious metal catalysts, specifically rhodium and palladium. Noticeably, density functional theory calculations confirm that the mechanism of the reaction is also different from those proposed for these other catalysts.

Straightforward Synthesis of Bis[(trifluoromethyl)sulfonyl]ethylated Isocoumarins from 2-Ethynylbenzoates.

Herein, we report a facile isocoumarin and isoquinolone preparation by taking advantage of an initial bis(triflyl)ethylation [triflyl = (trifluoromethyl)sulfonyl] reaction, followed by heterocyclization, which contrasts with our previous results on cyclobutene formation. The efficiency of the catalyst- and irradiation-free heterocyclization/bis(triflyl)ethylation sequence showed exquisite dependence on the electronic nature of the substituents at the 2-ethynylbenzoate(benzamide) precursors. Molecular docking of model bis(triflyl)ethylated isocoumarins on human acetylcholinesterase (hAChE) revealed promising biological activities through selective coordination on both the catalytic active site and peripheral active site.

Synthesis of Polycyclic Aromatic Hydrocarbons Decorated by Fluorinated Carbon Acids/Carbanions.

The carboarylation reaction of biphenyl-alkynes was successfully triggered by electrophilic attack of 1,1-bis(triflyl)ethylene on the alkyne moiety to give polycyclic aromatic hydrocarbons (PAHs) decorated by superacidic carbon acid functionality. Neutralisation of thus obtained acids with NaHCO3 yielded the corresponding sodium salts, which showed improved solubility in both aqueous and organic solvents.

A Convenient Formal [4+2] Heterocylization Route to Bis(triflyl)tetrahydroquinolines.

We report the sustainable and efficient synthesis of a new type of quinoline derivatives bearing one or two SO2 CF3 groups. The protocol is metal-, catalyst- and irradiation-free, involves the use of readily available and stable precursors, and avoids the formation of side products. Also, the mild conditions of the process allow the tolerance of a wide range of functional groups.

Pd-catalyzed C(sp3)-C(sp) bond formation in iodocyclobutenes.

A synthesis of skipped 1,4-enynes through functionalization of the cyclobutene core with alkynes has been achieved, suggesting an unusual pathway of oxidative addition in tertiary iodoalkanes.

Metal-Free C-C/C-N/C-C Bond Formation Cascade for the Synthesis of (Trifluoromethyl)sulfonylated Cyclopenta[b]indolines.

A bis(triflyl)ethylation [triflyl = (trifluoromethyl)sulfonyl] inserted into a sequential cyclization cascade resulted in the direct formation of gem-bis(triflyl)ated cyclopenta[b]indolines from anilide-derived allenols and alkenols. This catalyst- and irradiation-free sequence facilitated the efficient preparation of functionalized tricyclic indoline cores bearing two contiguous stereocenters. The formed cyclopenta[b]indolines can be easily transformed into a wide variety of triflylated indolines, including the tetracycle ring system found in polyveoline.

Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues.

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1-3) or a bioisosteric analogue core (compounds 4-6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones.

Herein, we report investigations embodying the first example of reversal of the native regioselectivity in the reaction of allenols with electrophiles. The effortlessness of C-C bond formation, mild reaction conditions, neither catalysts nor light irradiation, and exquisite selectivity, both in terms of functional-group tolerance and chemo-, site-, and stereo-selectivity, converts this trifluorosulfonylation-rearrangement sequence into an appealing protocol for the preparation of novel functionalized enones. The synthetic utility of this method has been validated by the conversion of the initially prepared bis(triflyl)enones into a variety of bis(triflyl)-functionalized molecules such as 1,3-dienes, allylic alcohols, pyrroles, pyrazoles, and chromenes. Besides, DFT calculations have provided a reliable understanding of observed selectivity.

Triflyl-assisted reductive Pd-catalyzed Tsuji-Trost type reaction.

New (triflyl)cyclobutenes have been prepared by palladium-catalyzed hydrodetriflylation reaction using water and deuterium oxide as convenient hydrogen and deuterium sources. In addition, an investigation of the possible mechanism for this Tsuji-Trost type reaction of bis(triflyl)cyclobutenes has been facilitated by labelling studies and density functional theory (DFT) calculations.

Convenient Access to 2,3-Disubstituted-cyclobut-2-en-1-ones under Suzuki Conditions and Their Synthetic Utility.

A regioselective synthesis of general applicability has been designed for the one-pot preparation of 2,3-disubstituted-cyclobutenones from iodoalkynes through cyclobutenylation, Suzuki CC coupling, and ketone formation. This one-pot methodology has been applied to the selective synthesis of an orally active cyclooxygenase II inhibitor. Furthermore, the obtained cyclobut-2-en-1-ones were used as synthons in several transformations, such as, the preparation of ß-lactams, phthalazines, cyclohexa-2,5-dien-1-ones, and cyclopent-3-en-1-ones.

Synthesis and Characterization of Stable Phosphorus Carbabetaines.

Phosphorus 1,3- and 1,4-carbabetaines with 'P(+)-C-C(-)' and 'P(+)-C-C-C(-)' structures, respectively, in which the carbanion moiety was significantly stabilized by two trifluoromethylsulfonyl groups, have been synthesized and characterized. Analysis of their X-ray crystal structures revealed that any attractive interactions between the anionic and cationic moieties were negligibly weak. This result was corroborated by using natural bond orbital (NBO) and Bader's quantum theory of atoms in molecules (QTAIM) models. In contrast, performing the same analysis of a known 1,3-carbabetaine equivalent, which can be drawn as a 'P(+)-C-C=C-O(-)' resonance structure, revealed pronounced charge-transfer interactions between the anionic and cationic moieties.

Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-Difunctionalization versus Rare Bis(cyclization).

Functionalized ynones can be activated by Tf2 C=CH2 , which was generated in situ, to form zwitterionic species. These species were trapped in an intramolecular fashion by several nucleophiles to generate two major types of triflones in a divergent manner. Through fine-tuning of the reaction temperature, bis(triflyl)-6-membered- or (triflyl)-5-membered-fused-heterocycles were achieved in reasonable yields in a totally selective manner. In this way, bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones, (triflyl)benzothienopyrans, (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and (triflyl)pyranoindoles were constructed. Conceivable mechanistic pathways were suggested on the basis of the isolation of several intermediates and the results from control experiments.

Photoinduced Gold-Catalyzed Domino C(sp) Arylation/Oxyarylation of TMS-Terminated Alkynols with Arenediazonium Salts.

A selective and convenient synthesis of tri- and tetrasubstituted α,ß-unsaturated ketones, as well as 2,3-diarylbenzofurans has been developed with the aid of light and taking advantage of a cooperative gold/photoredox-catalyzed 2-fold arylation reaction of TMS-terminated alkynols. The reaction of 3-(trimethylsilyl)prop-2-yn-1-ols was competent to generate diarylated α,ß-unsaturated ketones; whereas the photoredox sequence involving 2-[(trimethylsilyl)ethynyl]phenol exclusively afforded 2,3-diarylbenzofurans. The reaction of terminal alkynes proceeded in poor yields while the use of bulkier silyl groups, such as TIPS, resulted unproductive. Apparently, the C(sp) arylation reaction is the first event on the domino bis-arylative sequence. These results could be explained through the intermediation of arylgold(III) species and several single electron transfer processes.

Direct Metal-Free Entry to Aminocyclobutenes or Aminocyclobutenols from Ynamides: Synthetic Applications.

The [2+2] cycloaddition of ynamides with the highly polarized reagent Tf2 C=CH2 has been developed to regioselectively afford bis(triflyl)aminocyclobutenes in the absence of catalyst under mild conditions. Incidentally, with the ynamides bearing electron-rich aromatic rings at the C-terminal, an interesting reactivity switch was observed; a cyclization/hydroxylation sequence yielded 2-amino-3-(triflyl)cyclobut-2-enols. Aminocyclobutene construction with addition of alcohols resulted in the formation of aminocyclobutenyl ethers through a cyclization/hydroalkoxylation process. Moreover, the utility of functionalized aminocyclobutenes as precursors for further elaboration was demonstrated with the preparation of α-amino-ß,γ-unsaturated ketones and 3-(triflyl)buta-1,3-dien-2-amines through 4 π-electrocyclic ring opening.

Metal-free [3+2] cycloaddition of azides with Tf2C=CH2 for the regioselective preparation of elusive 4-(trifluoromethylsulfonyl)-1,2,3-triazoles.

1,2-Dipole Tf2C=CH2 is generated in situ and immediately reacts at room temperature with an azide to afford previously unknown 4-trifluoromethanesulfonyl 1,2,3-triazoles through a stepwise [3+2] cycloaddition reaction. Noteworthily, this mild and powerful uncatalyzed protocol is highly regio- and chemoselective.

Unveiling the uncatalyzed reaction of alkynes with 1,2-dipoles for the room temperature synthesis of cyclobutenes.

2-(Pyridinium-1-yl)-1,1-bis(triflyl)ethanides have been used as 1,2-dipole precursors in a metal-free direct [2+2] cycloaddition reaction of alkynes. Starting from stable zwitterionic pyridinium salts, the electron deficient olefin 1,1-bis(trifluoromethylsulfonyl)ethene is generated in situ and immediately reacted at room temperature with an alkyne to afford substituted cyclobutenes. Remarkably, this mild and facile uncatalyzed protocol requires neither irradiation nor heating.