Presence Of Trifluoroacetic Acid Research Articles

Synthetic Transformations of Higher Terpenoids. 38.* Synthesis of Conjugates Containing β-Carboline and Tricyclic Diterpenoids

The synthesis and properties of tricyclic pimaranes containing a C-16 β-carboline are reported. A Pictet–Spengler reaction of methyl 15-oxo-16-formylisopimarate (prepared in situ from the 15-oxo-15,16-dihydroisopimarate) and tryptamine or tryptophan methyl ester in the presence of trifluoroacetic acid formed a mixture of terpenoid 1,2,3,4-tetrahydro-β-carbolines, 3,4-dihydro-β-carbolines, and β-carbolines. Tetrahydro- and dihydro-β-carbolines in CHCl3 were oxidized to the corresponding β-carbolines by treatment in air with basic Al2O3.

Synthesis and Investigation of Linker-Free BODIPY-Gly Conjugates Substituted at the Boron Atom.

An efficient synthesis of boron-functionalized cyclic BODIPY-Gly conjugates, using commercially available N-protected glycine amino acids and a BF2-BODIPY moiety as starting materials, is reported. The existence of two conformers (up and down) is revealed through comprehensive DFT calculations and 1H and 11B NMR analyses. The experimental and computational results indicate that all BODIPYs are stable in aqueous solutions at neutral pH and that Fmoc-BODIPY (4) is more stable than Ac-BODIPY (6) in the presence of trifluoroacetic acid (TFA). In part due to their enhanced rigidity, all BODIPY-Gly conjugates display increased fluorescence quantum yields (0.6 < Φ < 0.9) relative to the corresponding BF2-BODIPY, making them excellent candidates for fluorescence imaging applications.

Synthesis of 2-(pyrrolidin-1-yl)pyrimidines by reactions of N-(4,4-diethoxybutyl)pyrimidin-2-amine with (hetero)aromatic C-nucleophiles

A method was developed for the synthesis of 2-(pyrrolidin-1-yl)pyrimidines and 2-[(4,4-diarylbutyl)amino]pyrimidines by reactions of (hetero)aromatic C-nucleophiles with N-(4,4-diethoxybutyl)pyrimidin-2-amine in the presence of trifluoroacetic acid. The structures of the obtained products were confirmed by methods of IR spectroscopy, 1H and 13C NMR spectroscopy, and X-ray structural analysis.

A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing

Continuous-flow processing has become one of the fastest-growing research areas in chemistry in the last 10 years. Herein we disclose an automated and scalable continuous-flow route for the quick introduction of trifluoromethyl groups on a variety of heterocycles, with application in drug discovery and manufacturing. This involves the direct alkylation-cyclization of amines in the presence of trifluoroacetic acid or anhydride, cheap and readily available CF3-containing building blocks. Compared to traditional batch reactions involving an intermediate purification step, the continuous-flow reactions occurred quickly and at mild conditions, with high yield and broad functional-group tolerance. The practical utility of the method was demonstrated by a gram-scale synthesis and by the estimation of modern green metrics.

A new type of bicyclic phosphonates of unsymmetrical structure

Condensation of phenols or resorcinol and its derivatives with 2-(ethoxyvinyl)phosphonic dichloride in boiling toluene in the presence of trifluoroacetic acid has resulted in high yields of new unsymmetrical bicyclic phosphonates.

Metal-free, room temperature, acid-K2S2O8 mediated method for the nitration of olefins: an easy approach for the synthesis of nitroolefins.

Here, we have developed a simple, room temperature method for the nitration of olefins by using inexpensive sodium nitrite as a source of nitro groups in the presence of trifluoroacetic acid (TFA) and potassium persulfate (K2S2O8) under an open atmosphere. Styrenes and mono-substituted olefins give stereo-selective corresponding E-nitroolefins under optimized conditions, however, 1,1-bisubstituted olefins give a mixture of E- and Z-nitroolefins. The optimized conditions work well with electron-donating, electron-withdrawing, un-substituted and heterocyclic styrenes and mono-substituted olefins and give corresponding nitroolefins with good to excellent yields.

1-(3,3-Diethoxypropyl)-1-[(dihexylphosphoryl)methyl]-3-phenylurea in the Synthesis of 4-Aryl-Substituted Tetrahydropyrimidin-2-ones

First specimens of 4-aryl-substituted tetrahydropyrimidin-2(1H)-ones containing a phosphoryl group were obtained through the reaction of 1-(3,3-diethoxypropyl)-1-[(dihexylphosphoryl)methyl]-3-phenylurea with resorcinol and its derivatives in the presence of trifluoroacetic acid.

New bicyclic phosphonates of unsymmetrical structure

New unsymmetrical bicyclic cage phosphonates have been obtained by refluxing two different phenols with (2-ethoxyvinyl) phosphonic dichloride in toluene in the presence of trifluoroacetic acid.

Reduction of cysteine-S-protecting groups by triisopropylsilane.

Triisopropylsilane (TIS), a hindered hydrosilane, has long been utilized as a cation scavenger for the removal of amino acid protecting groups during peptide synthesis. However, its ability to actively remove S-protecting groups by serving as a reductant has largely been mischaracterized by the peptide community. Here, we provide strong evidence that TIS can act as a reducing agent to facilitate the removal of acetamidomethyl (Acm), 4-methoxybenzyl (Mob), and tert-butyl (But ) protecting groups from cysteine (Cys) residues in the presence of trifluoroacetic acid (TFA) at 37°C. The lability of the Cys protecting groups in TFA/TIS (98/2) in this study are in the order: Cys(Mob)>Cys(Acm)>Cys(But ), with Cys(Mob) being especially labile. Unexpectedly, we found that TIS promoted disulfide formation in addition to aiding in the removal of the protecting group. Our results raise the possibility of using TIS in orthogonal deprotection strategies of Cys-protecting groups following peptide synthesis as TIS can be viewed as a potential deprotection agent instead of merely a scavenger in deprotection cocktails based on our results. We also tested other common scavengers under these reaction conditions and found that thioanisole and triethylsilane were similarly effective as TIS in enhancing deprotection and catalyzing disulfide formation. Our findings reported herein show that careful consideration should be given to the type of scavenger used when it is desirable to preserve the Cys-protecting group. Additional consideration should be given to the concentration of scavenger, temperature of the reaction, and reaction time.

Synthesis, characterization, antioxidant, antidiabetic, anticholinergic, and antiepileptic properties of novel N-substituted tetrahydropyrimidines based on phenylthiourea.

In the presence of trifluoroacetic acid, on the basis of three-component condensation of phenylthiourea with its salicylaldehyde and methyl-3-oxobutanoate, an efficient method for the synthesis of 1-(4-(2-hydroxyphenyl)-6-methyl-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (I) has been worked out. These novel N-substituted tetrahydropyrimidines based on phenylthiourea showed good inhibitory action against acetylcholinesterase (AChE), α-glycosidase, and human carbonic anhydrase (hCA) isoforms I and II. K i values of AChE enzyme were in the range of 0.48 to 7.46 nM. The hCA I and II were effectively inhibited by the compounds, with K i values in the range of 502.44 to 923.11 nM for hCA I and 400.32 to 801.57 nM for hCA II, respectively. The antioxidant activity of the novel N-substituted tetrahydropyrimidines based on phenylthiourea was investigated by using different in vitro antioxidant assays; including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging,Cu 2+ and Fe 3+ reducing activities.

Synthesis and X-Ray Single Crystal Study of 5-(4,4,5,5 – Tetramethyl – 1,3,2 – Dioxoborolane) – 10,20 – Diphenylporphyrin

Borylated porphyrin is one of building blocks in coupling reactions to obtain the multiporphyrin containing two, three or more subunits of porphyrins. In this study, one of borylated porphyrin derivatives, 5-(4,4,5,5 – tetramethyl – 1,3,2 – dioxoborolane) -10,20 – diphenylporphyrin (B-DPP) was synthesized through four steps of reactions. The building block of porphyrin, dipyrromethane was synthesized through a condensation reaction in the presence of trifluoroacetic acid as catalyst. Subsequently, A2B2 type of porphyrin was obtained by Lindsey condensation reaction followed by bromination reaction to produce porphyrin halide. Suzuki cross coupling reaction between porphyrin halide and pinacolborane with Pd (II) catalyst afforded 40% of borylayed porphyrin. The product was successfully characterized by using nuclear magnetic resonance spectroscopy (NMR) and UV-Visible spectroscopy (UV-Vis). This compound crystallized from a mixture of dichloromethane/methanol to give violet needle-like crystal. Crystallographic studies showed this compound crystallized in monoclinic system with space group of P21/c.

Proton-Coupled Redox Switching in an Annulated π-Extended Core-Modified Octaphyrin.

Proton-coupled electron transfer (PCET) is an important chemical and biological phenomenon. It is attractive as an on-off switching mechanism for redox-active synthetic systems but has not been extensively exploited for this purpose. Here we report a core-modified planar weakly antiaromatic/nonaromatic octaphyrin, namely, a [32]octaphyrin(1.0.1.0.1.0.1.0) (1) derived from rigid naphthobipyrrole and dithienothiophene (DTT) precursors, that undergoes proton-coupled two-electron reduction to produce its aromatic congener in the presence of HCl and other hydrogen halides. Evidence for the production of a [4 n + 1] π-electron intermediate radical state is seen in the presence of trifluoroacetic acid. Electrochemical analyses provide support for the notion that protonation causes a dramatic anodic shift in the reduction potentials of octaphyrin 1, thereby facilitating electron transfer from halide anions (viz. I-, Br-, and, Cl-). Electron-rich molecules, such as tetrathiafulvene (TTF), phenothiazine (PTZ), and catechol, were also found to induce PCET in the case of 1. Both the oxidized and two-electron reduced forms of 1 were characterized by X-ray diffraction analyses in the solid state and in solution via spectroscopic means.

Near-White Light Emission from Lead(II) Metal-Organic Frameworks.

Reaction of bpy (bpy = 4,4'-bipyridine) with Pb(OAc)2·3H2O in DMF (DMF = dimethylformamide) afforded a metal-organic framework (MOF), [Pb2(μ-bpy)(μ-O2CCH3)2(μ-O2CCH3)2]·H2O (1). Reaction of bpy with Pb(O2CCF3)2 in a methanol and chloroform mixture furnished another MOF, [Pb(μ-bpy)(μ-O2CCF3)2]·1/2CHCl3 (2). However, the reaction of bpy with Pb(OAc)2·3H2O in the presence of trifluoroacetic acid in a similar reaction condition yielded a hydrogen-bonded zwitter-ionic complex of Pb(II), [Pb(bpy-H)2(O2CCF3)4] (3). All compounds have been characterized by single crystal X-ray crystallography, FT-IR, and 1H NMR spectroscopies. Compound 1 forms four heptacoordinated Pb(II) joined by (OCCH3)-O- linkages, resulting in a 3D noninterpenetrated MOF net with a four-connected uninodal sra (SrAl2) topology. However, in 2, tetra-connected Pb4(O2CCF3)8 cluster units are linked further through eight bpy ligands to furnish a doubly interpenetrated MOF with a new topology but having the very similar connectivity of 1, whereas 3 forms a zigzag hydrogen-bonded chain structure. The variation of carboxylate anions, pH of the reaction medium, and the ratio of the reactants profoundly affected the final topological structure of the compounds synthesized. The solid-state photoluminescence of 1-3 was investigated at room temperature. Interestingly 1, 2, and 3 achieved close to white light emission when excited at 329, 376, and 330 nm, respectively. The systematic understanding of the photophysical properties of analogous Pb-based compounds may open new perspectives for developing single-phase white-light-emitting materials using Pb(II) based MOFs.

Effective synthesis of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

A highly effective method for the preparation of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines was developed on the basis of condensation reaction between aryl(hetaryl) α-bromo ketones and commercially available thiocarbohydrazide, followed by treatment of the obtained 2-hydrazinyl-6H-1,3,4-thiadiazine hydrobromides with ortho esters in the presence of trifluoroacetic acid under mild conditions.

First Examples of Povarov Reaction of Cyclopentadienones

We describe herein the first examples of Povarov reaction of tetrasubstituted cyclopentadienones in the preparation of quinoline compounds. Polycyclic compounds bearing tetrahydro‐3H‐cyclopenta[c]quinoline and dihydro‐1H‐cyclopenta[c]naphtha[2,3‐h]quinoline moieties have been synthesized by one pot reaction of tetrasubstituted cyclopentadienones with N‐arylamines and formaldehyde in the presence of trifluoroacetic acid. The control of the regioselectivity was total as well with symmetrical and non symmetrical cyclopentadienones. The X‐ray structures of new quinolines were reported.

Direct/Reversible Amidation of Troponyl Alkylglycinates via Cationic Troponyl Lactones and Mechanistic Insights.

The conversion of troponyl alkylglycinate acid/ester/amide derivatives (Trag acid/ester/amide) into cationic troponyl lactones (CTLs) in the presence of trifluoroacetic acid and their amidation with amines is described. The reversible amidation of Trag amides, that is, the cleavage and reformation of the Trag amide bond via CTLs is demonstrated. The direct amidation of Trag esters with the amino group of amino acid esters/peptide esters via CTLs is achieved. The direct amidation of the amine group of hydroxyl amino acid esters is selective over esterification. The Trag amide bond is stable under basic ester hydrolysis and Fmoc removal conditions. Hence, the troponyl alkylglycinates could be applicable as protecting groups for amine functionality of amino acids and peptides. The reaction mechanism was investigated by using a deuterium probe and studied by NMR and electrospray ionisation mass spectrometry techniques. Deuterium incorporation at α-CH2 strongly supported the formation of CTLs via ketene intermediates.

Synthesis and Oxidation of Internally Chlorinated Carbachlorins

Chlorinated cyclohexene and cyclopentene dialdehydes, which can be prepared in one step from cyclohexanone or cyclopentanone, were condensed with a tripyrrane in the presence of trifluoroacetic acid and oxidized with DDQ to afford modest yields of internally halogenated carbachlorin‐type products. The new macrocycles retained strongly aromatic properties and gave UV/Vis spectra with intense Soret bands near 400 nm and moderately strong chlorin‐like absorptions at approximately 660 nm. Attempts to further oxidize a 21‐chlorocarbachlorin with DDQ in refluxing toluene gave a dehalogenated carbaporphyrin and two externally chlorinated products.

Synthesis, characterization and electrochemical properties of O-alkyldithiophosphate nickel complexes with dppf ligand

Four new O-alkyldithiophosphate nickel complexes [(dppf)Ni(S2P{O}OR)] with dppf ligand (1, R = CH3; 2, R = CH2CH3; 3, R = CH2Ph; 4, R = CH2CH2Ph; dppf = 1,1′-bis(diphenylphosphino)ferrocene) have been synthesized by treatment of (dppf)NiCl2 with (RO)2PS2NH2Et2 in good yields. All the four complexes were characterized by elemental analysis, spectroscopy (IR, UV–Vis, 1H, 13C and 31P NMR), thermogravimetric analysis and single crystal X-ray diffraction. The crystal structures of 1–4 reveal that the nickel atom lies at the center of a slightly distorted square-planar environment and all complexes display CH⋯Ni intramolecular anagostic interactions. Furthermore, the electrochemical properties for 1–4 were also investigated by cyclic voltammetry. The electrochemical studies indicate that all complexes can be used as eletrocatalysts for reduction proton to hydrogen in the presence of trifluoroacetic acid and acetic acid in CH2Cl2 solution, respectively.

Oxidative Rearrangement Coupling Reaction for the Functionalization of Tetrahydro-β-carbolines with Aromatic Amines.

The observation of an unexpected oxidative rearrangement coupling reaction led to the development of a novel method for the efficient functionalization of tetrahydro-β-carbolines (THβCs). The treatment of THβCs with photogenerated singlet oxygen (1 O2 ) afforded unstable dioxetanes, which underwent further transformation to form new bonds in the presence of trifluoroacetic acid. This operationally simple protocol exhibits broad functional-group tolerance and is suitable for the late-stage functionalization of complex druglike molecules.

Oxidative Rearrangement Coupling Reaction for the Functionalization of Tetrahydro‐β‐carbolines with Aromatic Amines

AbstractThe observation of an unexpected oxidative rearrangement coupling reaction led to the development of a novel method for the efficient functionalization of tetrahydro‐β‐carbolines (THβCs). The treatment of THβCs with photogenerated singlet oxygen (1O2) afforded unstable dioxetanes, which underwent further transformation to form new bonds in the presence of trifluoroacetic acid. This operationally simple protocol exhibits broad functional‐group tolerance and is suitable for the late‐stage functionalization of complex druglike molecules.