Triflate Moiety Research Articles

Aluminum-Catalyzed Intramolecular Vinylation of Arenes by Vinyl Cations.

This study addresses the challenges associated with vinyl cation generation, a process that traditionally requires quite specific counterions. Described herein is a novel intramolecular vinylation of arenes catalyzed by aluminum(III) chloride, utilizing practical conditions and readily available vinyl triflates derived from 2-aceto-3-arylpropionates. Comprehensive experimental data support diverse carbocycle synthesis, exemplified by indenes and higher analogues. Control experiments verify the applicability of the vinylation protocol, and synthetic applications showcase a potent tubulin polymerization inhibitor with anticancer properties. Density functional theory computations reveal a Lewis-acid-driven mechanism involving triflate moiety abstraction to generate a reactive vinyl cation.

Palladium‐Catalyzed Cyclization of a Pyryne Precursor to Higher Pyrenylenes

AbstractThe palladium catalyzed cyclotrimerization of ortho‐silylaryl triflates as aryne precursors is meanwhile an established method to synthesize polycyclic aromatic hydrocarbons (PAHs) with triphenylene cores. During the palladium‐catalyzed reaction of a pyrene with an o‐silylaryl triflate moiety in the K‐region higher homologues with central eight‐ and ten‐membered rings (the pyrenylenes) were found, besides the expected trimer and a protocol was developed to isolate all members of this series. This unprecedented new class of PAHs was fully investigated by all means, including X‐ray diffraction of single‐crystals, UV/Vis and fluorescence spectroscopy and theoretical calculations. Supported by density‐functional theory (DFT) calculations, a mechanism of all higher cyclooligomers is proposed.

Palladium-Catalyzed Cyclization of a Pyryne Precursor to Higher Pyrenylenes.

The palladium catalyzed cyclotrimerization of ortho-silylaryl triflates as aryne precursors is meanwhile an established method to synthesize polycyclic aromatic hydrocarbons (PAHs) with triphenylene cores. During the palladium-catalyzed reaction of a pyrene with an o-silylaryl triflate moiety in the K-region, besides the expected trimer higher homologues with central eight- and ten-membered rings (the pyrenylenes) were found and a protocol developed to isolate all members of this series. This unprecedented new class of PAHs was fully investigated by all means, including X-ray diffraction of single-crystals, UV/vis and fluorescence spectroscopy and theoretical calculations. Furthermore, supported by density-functional theory (DFT) calculations, a mechanism of all higher cyclooligomers is proposed.

Synthesis and Biological Evaluation of Water‐Soluble Esterase‐Activated CO‐Releasing Molecules Targeting Mitochondria

Due to the beneficial effects of carbon monoxide as a cell‐protective and anti‐inflammatory agent, CO‐releasing molecules (CORMs) offer some promising potential applications in medicine. In this context, we synthesized a set of acyloxy‐cyclohexadiene‐Fe(CO)3 complexes, all displaying a N‐methyl‐pyridinium triflate moiety in the ester side chain, as mitochondria‐targeting esterase‐triggered CORM prodrugs. Whereas the compounds in which the acyloxy substituent is attached to the 2‐position of the diene‐Fe(CO)3 unit (A series) spontaneously release CO upon dissolution in phosphate buffer, which remarkably is partly suppressed in the presence of porcine liver esterase (PLE), the 1‐substituted isomers (B series) show the expected PLE‐induced release of CO (up to 3 equiv.). The biological activity of Mito‐CORMs 2/3‐B and their isophorone‐derived analogs 2/3‐A’, which also displayed PLE‐induced CO release, was assessed by using human umbilical vein endothelial cells (HUVEC). Whereas Mito‐CORMs 2/3‐B were not cytotoxic up to 500 μM (MTT assay), Mito‐CORMs 2/3‐A’ caused significant toxicity at concentrations above 50 μM. The anti‐inflammatory potential of both Mito‐CORM variants was demonstrated by concentration‐dependent down‐regulation of the pro‐inflammatory markers VCAM‐1, ICAM‐1 and CXCL1 as well as induction of HO‐1 in TNFα‐stimulated human umbilical vein endothelial cells (HUVECs; western blotting and qPCR). Energy phenotyping by seahorse real‐time cell metabolic analysis, revealed opposing shifts of metabolic potentials in cells treated either with Mito‐CORMs 2/3‐B (increased mitochondrial respiration and glycolytic activity) or Mito‐CORMs 2/3‐A’ (suppressed mitochondrial respiration and increased glycolytic activity). Thus, the Mito‐CORMs represent valuable tools for the safe and targeted delivery of CO to mitochondria as a subcellular compartment to induce positive anti‐inflammatory effects with only minor shifts in cellular energy metabolism. Also, due to their water solubility, these compounds provide a promising starting point for further pharmacological studies.

Palladium‐Catalyzed Chemoselective Borylation of (Poly)halogenated Aryl Triflates and Their Application in Consecutive Reactions

AbstractThis study reports the palladium‐catalyzed chemoselective borylation of (poly)halogenated aryl triflates with a reactivity order of C−Cl>C−OTf. A catalyst system comprising Pd(OAc)2 and SelectPhos (L1) enables a reaction with high reactivity and chemoselectivity. The consecutively chemoselective borylation reaction followed by the chemoselective intermolecular Suzuki‐Miyaura reaction can be performed using a one‐pot two‐step approach to synthesize unsymmetrical biaryl compounds containing the triflate moiety. The reaction can be scaled up to the gram scale without diminishing the yield and chemoselectivity.magnified image

A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 3: Iodophenyltriflate Core Fragments Featuring Side Chains of Proteinogenic Amino Acids.

Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd‐catalyzed cross‐coupling used for teraryl assembly. In previous publications we have introduced the methodology of 4‐iodophenyltriflates decorated with the side chains of some of the proteinogenic amino acids. We herein report the core fragments corresponding to the previously missing amino acids Arg, Asn, Asp, Met, Trp and Tyr. Therefore, our set now encompasses all relevant amino acid analogues with the exception of His. In order to be compatible with the triflate moiety, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks. Additionally, cross‐coupling procedures for the assembly of teraryls were investigated.

Consecutive Aryne Generation Strategy for the Synthesis of 1,3-Diarylpyrazoles.

An efficient method for the synthesis of diverse 1,3-diarylpyrazoles via consecutive aryne generation has been developed. The bisaryne precursors bearing o-iodo- and o-silylaryl triflate moieties were prepared by sequential Suzuki-Miyaura and Chan-Lam-Evans cross-coupling reactions. The selective generation of the first aryne triggered by a silylmethyl Grignard reagent followed by the second aryne generation mediated by a fluoride ion allowed for the synthesis of diverse multisubstituted 1,3-diarylpyrazoles in a modular synthetic manner with various arynophiles.

Rapid Access to Bi‐ and Tri‐Functionalized Dibenzofurans and their Application in Selective Suzuki–Miyaura Cross Coupling Reactions

Syntheses of 1,2‐, 1,3‐, 1,4‐, 1,8‐, 2,4‐, 3,4‐, 4,8‐, 1,2,4‐, 1,2,8‐ and 1,3,4‐functionalized dibenzofurans in few steps with good to excellent yields starting from dibenzofuran‐1‐ol or ‐4‐ol are presented. These rapidly accessible bi‐ or tri‐functionalized building blocks are of great interest for the synthesis of bioactive substances or functional material development. Furthermore, for intermediates containing both a bromine and a triflate moiety, a selective mono‐substitution by means of Suzuki–Miyaura reaction (SMR) is described.

A rod-like phenolic π-conjugated polymer with pillar[5]arene units in its main chain

A new rigid rod-like phenolic π-conjugated polymer containing pillar[5]arene units in its main chain was prepared. First, a pillar[5]arene-containing π-conjugated polymer was prepared by Pd-catalyzed copolymerization of 4,4’-diphenyldiboronic acid with a pillar[5]arene bearing two triflate moieties in one hydroquinone unit and eight ethoxy groups in the other units. Then, deprotection of the ethyl moieties using BBr3 gave a rigid rod-like phenolic π-conjugated polymer. The phenolic polymer showed high thermal stability, with a 10 wt% loss temperature (T10) of 300 °C in a nitrogen atmosphere, which is higher than that of a pillar[5]arene containing 10 phenolic moieties (T10 = 164 °C). Moreover, the phenolic π-conjugated polymer showed selective gas adsorption properties: it was highly selective for the adsorption of CO2, but did not take up N2 or methane.

Efficient synthesis of rigid ladder polymers via palladium catalyzed annulation.

We report a new method to synthesize rigid ladder polymers using efficient palladium catalyzed annulation reactions with low catalyst loading (1 mol %). Rigid ladder polymers with benzocyclobutene backbone linkages can be synthesized from copolymerization of readily accessible aryl dibromides and norbornadiene or polymerization of AB type monomers bearing norbornene and aryl bromide or triflate moieties. High molecular weight (10-40 kDa) rigid ladder polymers can be obtained with complete monomer conversions. Diverse monomers also gave different, fixed ladder polymer conformations. The ladder polymers exhibited excellent thermal stability, high carbonization yield, and large intrinsic porosity.

Sulfonyl-bridged oligo(benzoic acid)s: synthesis, X-ray structures, and properties as metal extractants

Sulfonyl-bridged oligo(benzoic acid)s 7 n (n = 2–4) are prepared from the corresponding triflate esters (8 n ) of sulfur-bridged oligophenols by palladium-catalyzed methoxycarbonylation of the triflate moieties, followed by hydrolysis of the resulting methyl esters, and subsequent oxidation of the sulfur bridges. X-ray analysis reveals that dimer 7 2 forms supramolecular zig-zag chains through intermolecular hydrogen bonds between the carboxy groups. As for the crystal of trimer 7 3 , two molecules are associated through two couples of intermolecular hydrogen bonds between terminal and central carboxy groups to form a cyclic dimer, which connects with two adjacent dimers with the remaining carboxy groups to construct an infinite columnar structure. Tetramer 7 4 adopts a monomolecular cyclic structure through intramolecular hydrogen bonds between the terminal carboxy groups, and a molecule connects with each of two adjacent molecules through two couples of intermolecular hydrogen bonds between inner carboxy and sulfonyl groups. Solvent extraction experiments reveal that the oligo(benzoic acid)s exhibit high extractability toward lanthanoid ions (Ln3+); the performance follows the order 7 4 ≈ 7 3 > 7 2 . Moderate extraction selectivity is observed for the extraction of Pr3+, Gd3+, and Yb3+ with 7 2 . X-ray crystallographic analysis of cluster [Tb4L4(H2O)6](Et3NH)4, which was prepared from 7 4 (H4L) and Tb(NO3)3·6H2O in the presence of Et3N, reveals that no sulfonyl oxygens coordinate to the metal centers. This indicates that the high extractability of 7 4 originates from the electron-withdrawing nature of the sulfonyl function, which increases the acidity of two adjacent carboxy groups.

Dissociative electron attachment to triflates

Gas phase studies of dissociative electron attachment to simple alkyl (CF(3)SO(3)CH(3)) and aryl (C(6)H(5)SO(3)CF(3) and CF(3)SO(3)C(6)H(4)CH(3)) triflates, model molecules of nonionic photoacid generators for modern lithographic applications, were performed. The fragmentation pathways under electron impact below 10 eV were identified by means of crossed electron-molecular beam mass spectrometry. Major dissociation channels involved C-O, S-O, or C-S bond scissions in the triflate moiety leading to the formation of triflate (OTf(-)), triflyl (Tf(-)), or sulfonate (RSO(3)(-)) anions, respectively. A resonance leading to C-O bond breakage and OTf(-) formation in alkyl triflates occurred at electron energies about 0.5 eV lower than the corresponding resonance in aryl triflates. A resonance leading to S-O bond breakage and Tf(-) formation in aryl triflates occurred surprisingly at the same electron energies as C-O bond breakage. In case of alkyl triflates S-O bond breakage required 1.4 eV higher electron energies to occur and proceeded with substantially lower yields than in aryl triflates. C-S bond scission occurred for all presently studied triflates at energies close to 3 eV.

New fluorescent isoquinoline derivatives

Various structural modifications of 3-amino and 3-hydroxyisoquinolines have been carried out to provide new fluorescent derivatives. The transformations involved nucleophilic substitution of a bromine atom or a triflate moiety at positions 1 and 3, respectively, as well as the condensation reaction of a 3-amino group with triethyl orthoformate and subsequent transformation with amines to give amidines. The new compounds have been studied by fluorescence spectroscopy.

Nanostructured Liquid Crystals Combining Ionic and Electronic Functions

New molecular materials combining ionic and electronic functions have been prepared by using liquid crystals consisting of terthiophene-based mesogens and terminal imidazolium groups. These liquid crystals show thermotropic smectic A phases. Nanosegregation of the pi-conjugated mesogens and the ionic imidazolium moieties leads to the formation of layered liquid-crystalline (LC) structures consisting of 2D alternating pathways for electronic charges and ionic species. These nanostructured materials act as efficient electrochromic redox systems that exhibit coupled electrochemical reduction and oxidation in the ordered bulk states. For example, compound 1 having the terthienylphenylcyanoethylene mesogen and the imidazolium triflate moiety forms the smectic LC nanostructure. Distinct reversible electrochromic responses are observed for compound 1 without additional electrolyte solution on the application of double-potential steps between 0 and 2.5 V in the smectic A phase at 160 degrees C. In contrast, compound 2 having a tetrafluorophenylterthiophene moiety and compound 3 having a phenylterthiophene moiety exhibit irreversible cathodic reduction and reversible anodic oxidation in the smectic A phases. The use of poly(3,4-ethylenedioxythiophene)-poly(4-styrene sulfonate) (PEDOT-PSS) as an electron-accepting layer on the cathode leads to the distinct electrochromic responses for 2 and 3. These results show that new self-organized molecular redox systems can be built by nanosegregated pi-conjugated liquid crystals containing imidazolium moieties with and without electroactive thin layers on the electrodes.

Stereoselective Total Synthesis of (+)-Varitriol, (−)-Varitriol, 5′-epi-(+)-Varitriol, and 4′-epi-(−)-Varitriol from d-Mannitol

Stereoselective total syntheses of natural (+)-varitriol (1), (-)-varitriol (2), 5'-epi-(+)-varitriol (3), and 4'-epi-(-)-varitriol (4) have been accomplished with use of D-mannitol as a chiral pool material. The Heck reaction was used to assemble the olefinic sugar moiety and the aromatic triflate moiety.

Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2

Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.

Stille–Heck Coupling Sequences Applied in a Versatile New Access to Steroid Skeletons

A variety of enantiomerically pure steroidal compounds was synthesized utilizing a sequence of Stille and Heck cross-coupling reactions and subsequent thermal 6pi-electrocyclizations. Highly chemoselective Stille couplings on the triflate moiety of several 2-bromocyclohex-1-enyl triflates with cis- and trans-fused bicyclo[4.3.0]nonenylstannanes furnished the corresponding tricyclic bromobutadienes in good to excellent yields (70-97%). These were subjected to Heck reactions with tert-butyl acrylate to provide pentasubstituted tricyclic 1,3,5-hexatrienes. A significant increase in efficiency could be achieved by applying a novel protocol with a precatalyst on the basis of the palladacycle prepared from Pd(OAc)2 and P(o-Tol)3 with added triarylphosphines as co-ligands (73-90% yield). Upon heating to 205-215 degrees C in decalin or to 140 degrees C in toluene (for certain cases), these hexatrienes yielded (78-90%) various unsaturated steroid analogues as single diastereomers. A particular oxohexatriene, obtained after deprotection of an adjacent carbonyl group, underwent 6pi-electrocyclization at the unusually low temperature of 140 degrees C to yield (75%) an interesting 7-carboxyl-substituted steroidal dienone. Attempts to remove the remaining protecting groups from some of the other new steroidal compounds under acidic conditions furnished a novel 3-oxo-7-carboxyl steroid analogue and a 3-hydroxy-substituted steroidal diene. A novel estradiol derivative could be obtained in 69% yield from the synthesized steroidal dienone. Deprotection furnished the corresponding unprotected 7-carboxylestradiol in 81% yield.

An Enantioselective Access to an Anthracycline AB Synthon by a ­Desymmetrizing Heck Cyclization

A group-selective intramolecular Heck reaction of an acyclic prochiral cyclization precursor provides an entry into the catalytic asymmetric synthesis of the AB bicyclic skeleton of ­anthracyclines. Enantiotopic group selection is strongly influenced by the hydroxylation pattern relative to the triflate moiety of the B ring (47% ee for 3,6-dimethoxy, 76% ee for 3-methoxy, and 92% ee without substitution).

Tandem Nucleophilic Addition/Fragmentation Reactions and Synthetic Versatility of Vinylogous Acyl Triflates

A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the sigma-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 --> 6 or 8), is also illustrated.

Synthesis and Reactivities of Neutral and Cationic Indenyl−Palladium Complexes

The complexes [(1-R-Ind)Pd(PPh3)Me] (R = H (3), Me (4)), [(1-R-Ind)Pd(PPh3)2]BF4 (R = H (5[BF4]), Me (6)), and [(1-R-Ind)Pd(PPh3)(OSO2CF3)] (R = H (7), Me (8)) have been prepared by reacting their corresponding Pd−Cl derivatives with MeMgCl, AgBF4/PPh3, and AgOTf, respectively. These complexes have been characterized by NMR spectroscopy and, in the case of 3, 5[BF4], 6 and 7, by X-ray crystallography. The triflate moiety in complexes 7 and 8 is displaced readily by various ligands to give [(1-R-Ind)Pd(PPh3)L][OTf] (L = PPh3 (5[OTf]), PMe3 (9), CH3CN (10), PhCN (11), t-BuNC (12)). Reactions of 7 or 8 with various olefins result in isomerization (1-hexene), dimerization and/or trimerization (ethylene, styrene, and p-fluorostyrene), oligomerization (p-amino- and p-methylstyrene), or polymerization (p-methoxystyrene). Compounds 1−8 promote the addition of HSiCl3 to styrene and phenylacetylene.