Presence Of TFA Research Articles

Synthesis and metalation of dimethoxybenziporphyrins, thiabenziporphyrins, and dibenziporphyrins.

Dimethoxybenzitripyrranes were prepared in excellent yields by reacting benzene dicarbinols with BF3·Et2O and excess pyrrole in refluxing 1,2-dichloroethane. Reaction with a pyrrole dialdehyde in the presence of TFA, followed by oxidation with DDQ, afforded good yields of meso-diphenyldimethoxybenziporphyrins. These dimethoxyporphyrinoids exhibited weakly diatropic properties that were enhanced upon protonation. The dimethoxybenzitripyrranes also reacted with a thiophene dicarbinol to give dimethoxythiabenziporphyrins, and the nonplanar nature of this system was demonstrated by X-ray crystallography. The dimethoxybenziporphyrins reacted with palladium(II) acetate to give the related organometallic derivatives, but the thiabenziporphyrins underwent a demethylation to afford palladium(II) thiaoxybenziporphyrins. Related palladium(II) complexes were also prepared from previously reported thiacarbaporphyrinoids. The X-ray structure for one of the complexes showed that the six-membered ring is very distorted and the thiophene ring is strongly tilted out of the plane of the macrocycle. The dimethoxybenzitripyrranes also reacted with dimethoxybenzene dicarbinols to give the first examples of dibenziporphyrins, thereby further demonstrating the versatility of this synthetic methodology.

Electrocatalytic reduction of CO2 with palladium bis-N-heterocyclic carbene pincer complexes.

A series of pyridine- and lutidine-linked bis-N-heterocyclic carbene (NHC) palladium pincer complexes were electrochemically characterized and screened for CO2 reduction capability with 2,2,2-trifluoroethanol, acetic acid, or 2,2,2-trifluoroacetic acid (TFA) as proton sources. The lutidine-linked pincer complexes electrocatalytically reduce CO2 to CO at potentials as low as -1.6 V versus Ag/AgNO3 in the presence of TFA. The one-electron reduction of these complexes is shown to be chemically reversible, yielding a monometallic species, with density functional theory studies indicating charge storage on the redox-active ligand, thus addressing a major source of deactivation in earlier triphosphine electrocatalysts.

Tropone-Fused Carbaporphyrins

Previous attempts to prepare tropone-fused carbaporphyrins by reacting peroxides with azuliporphyrins under basic conditions afforded benzocarbaporphyrins instead. In this study, a methoxyazulitripyrrane condensed with a pyrrole dialdehyde in the presence of TFA, followed by oxidation with ferric chloride, to give a tropone-fused carbaporphyrin following a spontaneous demethylation. The porphyrinoid gave a modified UV-vis spectrum showing multiple bands in the Soret region, and the proton NMR spectrum showed that it has a reduced diamagnetic ring current in comparison to other carbaporphyrins. The tropone-fused derivative failed to react with tert-butyl hydroperoxide and potassium hydroxide, demonstrating that this type of structure is not an intermediate in the formation of benzocarbaporphyrins. However, the reaction with silver(I) acetate gave the corresponding silver(III) complex. Condensation of the methoxyazulitripyrrane with 2,5-thiophenedicarbaldehyde gave a related tropone-fused thiacarbaporphyrin together with a methoxythiaazuliporphyrin. Treatment of the carbaporphyrins with DBU resulted in the formation of anionic species, while addition of acid afforded dicationic structures. DFT studies were performed on a series of tautomers, protonated species, and anionic structures related to these tropone-fused carbaporphyrins, and NICS calculations were carried out. These results allowed favorable conjugation pathways to be identified. In addition, these studies predicted that protonation initially occurs on the carbonyl moiety rather than on the expected interior pyrrolenine nitrogen atom.

Structural and medium effects on the reactions of the cumyloxyl radical with intramolecular hydrogen bonded phenols. The interplay between hydrogen-bonding and acid-base interactions on the hydrogen atom transfer reactivity and selectivity.

A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO(•)) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO(•) and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO4)2, protonation or Mg(2+) complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO(•) exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Brønsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.

ChemInform Abstract: The Acid‐Catalyzed Synthesis of 7‐Azaindoles from 3‐Alkynyl‐2‐aminopyridines and Their Antimicrobial Activity.

AbstractA series of 7‐azaindoles is prepared by Sonogashira coupling of 3‐halopyridines (I) with alkynes followed by ring‐closure reaction of resulting 3‐alkynyl‐2‐aminopyridines (III) in the presence of TFA and TFAA.

Vicinal bis(trifluoroacetimidoyl chloride)s: novel building blocks for the synthesis of benzo-fused eight-membered rings via [2 + 2 + 2] cycloadditions

Vicinal bis(trifluoroacetimidoyl chloride)s, a novel kind of fluorinated building block, were obtained from o-phenylenediamines in the presence of TFA, triethylamine, triphenylphosphine and tetrachloromethane. Based on these blocks, a new synthesis involving [2 + 2 + 2] cycloaddition reactions for trifluoromethylated benzo-fused eight-membered rings was disclosed.

Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio of catalyst and TFA=1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the formation of the major enantiomer in this reaction.

Synthesis and Evaluation of New Phthalazine Urea and Thiourea Derivatives as Carbonic Anhydrase Inhibitors

A new series of phthalazine substituted urea and thiourea derivatives were synthesized, and their inhibitory effects on the activity of purified human carbonic anhydrases (hCAs I and II) were evaluated. 2H‐Indazolo[2,1‐b]phthalazine‐trione derivative (1) was prepared with 4‐nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and nitro group was reduced to amine derivative (2) with SnCl2·2H2O. The compound was reacted with isocyanates and isothiocyanates to get the final products (3a–p). The results showed that all the synthesized compounds inhibited the CA isoenzymes activity. 3a (IC50 = 6.40 µM for hCA I and 6.13 µM for hCA II) has the most inhibitory effect. The synthesized compounds are very bulky to be able to bind near the zinc ion, and they much more probably bind as the coumarin derivatives.

Functionalized 3-pyrrolyl boron-dipyrromethenes

A series of mono-functionalized 3-pyrrolyl boron-dipyrromethenes containing functional groups such as bromo, formyl, cyano, nitro and trimethylsilylacetylene groups at the α-position of the uncoordinated pyrrole group were synthesized. Further to show the use of functionalized 3-pyrrolyl BODIPY, we treated α-bromo BODIPY with four different boronic acids such as phenyl, biphenyl, phenylacetyl and thienyl boronic acids under mild Pd(0) coupling conditions to afford α-aryl substituted 3-pyrrolyl BODIPYs. α-Dipyrromethanyl substituted 3-pyrrolyl BODIPY was synthesized by treating α-formyl 3-pyrrolyl BODIPY with pyrrole in the presence of TFA in CHCl3. The 3-pyrrolyl BODIPY appended with BODIPY (BODIPY dyad) at the α-position of uncoordinated pyrrole was synthesized by oxidizing 3-dipyrromethanyl BODIPY with DDQ followed by complexation with BF3·Et2O. All compounds were characterized by HRMS mass, NMR, absorption, electrochemical and fluorescence techniques. The spectral studies indicated that the presence of substituent at the α-position of uncoordinated pyrrole of 3-pyrrolyl BODIPY alter the electronic properties of the BODIPY core. The photophysical studies on BODIPY dyad indicated a possibility of energy transfer from the appended BODIPY unit to the 3-pyrrolyl BODIPY unit in BODIPY dyad.

Identification and optimization of novel pyrimido-isoxazolidine and oxazine as selective hydride donors

Two novel carbon skeletons (3S,3a′R)-6′-(methylthio)-5′,7a′-dihydro-1′H-spiro[indoline-3,3′-isoxazolo[3,4-d]pyrimidine]-2,4′(3a′H)-dione (11a) and 3-(methylthio)-4a,5,7,11c-tetrahydropyrimido[4′,5′:3,4][1,2]oxazino[6,5-b]indol-1(2H)-one (12a) are characterized as hydride donors. The generation of these hydride sources during the spiroannulation reaction between isatin (4) and pyrimidine (5) through the free radical mechanism, was confirmed by (i) the increase in the stoichiometric yields of 11 and 12 when the same reaction was carried out in the presence of free radical initiators (e.g., mCPBA) and (ii) the formation of oxazepine (14) when AIBN was used as free radical initiator. The PKIE [KH/KD] values 4.5 and 4.9 obtained when deuterated 11a (d) was used in the presence of TFA and TFA-d, respectively, suggest the hydride transfer step to be the rate determining step. These hydrides donors selectively reduce aldehyde in the presence of other reducible groups.

Fused Arene Ring Construction Around Pyrrole To Form 4,7‐Disubstitued Indole

AbstractA method for synthesizing 4,7‐diarylindoles and 4,7‐di(thien‐2‐yl)indole by applying a strategy where the fused benzene ring was built on an existing pyrrole in an acid‐catalyzed rearrangement of 1,4‐diaryl‐1,4‐di(pyrrol‐2‐yl)but‐2‐yne and 1,4‐di(pyrrol‐2‐yl)‐1,4‐di(thien‐2‐yl)but‐2‐yne, respectively, is presented. In the presence of TFA (30 equiv.), 4,7‐diarylindoles undergo thermodynamically equilibrated dimerization at 240 K as determined by 1H NMR spectroscopy and substantiated by DFT calculations.

Practical Demethylation of Podophyllotoxin and Efficient Preparation of 4-Amino-4-deoxy-4′-demethylepipodophyllotoxin

4′-Demethylepipodophyllotoxin (4′-DMEP) was readily available through demethylation of podophyllotoxin using methionine in methanesulfonic acid in the presence of TFA (or acetone/water). Thus, 4-amino-4-deoxy-4′-demethylepipodophyllotoxin was obtained in three steps in excellent yield by a Ritter reaction on 4′-DMEP, followed by treatment with thiourea in AcOH.

ChemInform Abstract: Novel Synthesis of Oxonine Derivatives from 3‐[(2‐Aminophenyl)amino]‐5,5‐dimethyl‐2‐cyclohexene‐1‐one and o‐Quinones.

AbstractThe reaction of unsymmetrical o‐quinones (I) and (V) with title compound (II) in the presence of TFA gives novel 9‐membered lactones (III) and (VI), respectively.

Enantioselective Pd-catalyzed hydrogenation of tetrasubstituted olefins of cyclic β-(arylsulfonamido)acrylates

Asymmetric hydrogenation of tetrasubstituted olefins of cyclic β-(arylsulfonamido)acrylates produces the corresponding cyclic β-(arylsulfonamido)propionates using Pd(OCOCF3)2/diphosphine complexes as catalysts in the presence of TFA with up to 96% ee.

A direct introduction of 18O isotopes into peptides and proteins for quantitative mass spectroscopy analysis

The method of direct introduction 18O isotopes in peptides and proteins carboxylic groups through the exchange with H218O in the presence of TFA is shown. The isotope label is steady enough in awide range of pH. Because the labeled compounds retain their physical and chemical characteristics, they can be used as an internal standard in quantitative determination of authentic compounds in the analyzed sites by mass spectrometry methods. The technique may be applicable for quantitative analysis of peptides and proteins in biological environments, for quantitative study of the kinetics of metabolism and enzymatic activity. For polypeptides and proteins the quantitative analysis is combined with trypsinolysis. If necessary, the isotope label may be introduced simultaneously in all peptides and proteins control bioassays, making it suitable for use as a standard for the comparative analysis of experimental bioassays.

Preparation of hydrophilic polymer-grafted polystyrene beads for hydrophilic interaction chromatography via surface-initiated atom transfer radical polymerization

A one-step procedure based on surface-initiated atom transfer radical polymerization (SI-ATRP) to hydrophilize monodisperse poly(chloromethylstyrene-co-divinylbenzene) beads has been presented in this work, using 2-hydroxyl-3-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]propyl 2-methylacrylate (HTMA) as a monomer. The chain length of the grafted poly(HTMA) was controlled via varying the ratio of HTMA to initiator on the surface of the beads. When using the grafted beads as a stationary phase in hydrophilic interaction chromatography (HILIC), good resolution for nucleobases/nucleosides was obtained with acetonitrile aqueous solution as an eluent; while for phenolic acids and glycosides, they could be eluted and separated in the presence of TFA. The retention time of the solutes increased with the amount of the grafted HTMA. The retention mechanisms of solutes were investigated by the effects of mobile phase composition and buffer pH on the retention of solutes. The results illustrated that the retention behaviors of the tested solutes were dominated by hydrogen bonding interaction and electrostatic interaction. From the chemical structure of the ligands, the modified beads could not only be used as a stationary phase in HILIC, but also act as a useful building block to develop new stationary phases for other chromatographic modes such as affinity media.

Naphthiporphyrins

Benziporphyrins, cross-conjugated porphyrin analogues with a benzene ring in place of one of the usual pyrrole units, have varying degrees of macrocyclic aromaticity because the 6π electron arene needs to give up its aromatic characteristics to facilitate conjugation over the entire system. As naphthalene would lose less resonance stabilization energy in giving up one of its benzene units, it was proposed that naphthiporphyrins would exhibit enhanced diatropicity compared to the related benziporphyrins. A naphthiporphyrin was prepared using the "3 + 1" variant of the MacDonald condensation by reacting 1,3-naphthalenedicarbaldehyde with a tripyrrane in the presence of TFA, followed by oxidation with DDQ. Although the free base form of naphthiporphyrin showed no overall diatropicity, the corresponding dication in TFA-CDCl(3) demonstrated a significant diatropic ring current where the internal CH shifted upfield to between 4.0 and 4.6 ppm. Naphthiporphyrin was converted to the corresponding palladium(II) complexes by reaction with Pd(OAc)(2) in acetonitrile, and the complex was further characterized by X-ray crystallography. Oxynaphthiporphyrins were similarly prepared by the "3 + 1" methodology from 4-methoxy-1,3-naphthalene-dicarbaldehyde, and these showed slightly enhanced diatropic character compared to oxybenziporphyrins. Reaction of oxybenziporphyrins or oxynaphthiporphyrins with silver(I) acetate afforded the corresponding silver(III) organometallic derivatives. A meso-tetraphenyl naphthiporphyrin was also synthesized in 4% yield by reacting a 1,4-naphthalene dicarbinol with 2 equiv of benzaldehyde and 3 equiv of pyrrole in the presence of BF(3).Et(2)O, followed by oxidation with DDQ. However, this 1,4-naphthiporphyrin showed reduced diatropic character compared to the corresponding p-benziporphyrin system. The NMR spectra for the 1,4-naphthiporphyrin show that the naphthalene unit pivots over the macrocycle and this presumably leads to further steric interactions that reduce the planarity of the macrocycle. These results demonstrate that while naphthiporphyrins can show enhanced aromatic properties as predicted, other factors may overwhelm this effect.

ChemInform Abstract: Synthesis of 6‐Cyano and 6‐Unsubstituted 2‐Aryl‐8‐oxopurine from a Common 2‐Oxoimidazole Precursor.

AbstractIntramolecular cyclization of imines (III) in the presence of DBU results in formation of imidazole derivatives (IV) which are slowly transformed into 6‐cyano oxopurine (V) in the presence of TFA.

Pyrazole analogues of porphyrins and oxophlorins

A series of porphyrin analogues with pyrazole rings replacing one of the usual pyrrole subunits have been synthesized. This was accomplished by reacting 1-phenyl, 1-methyl and 1-ethyl pyrazole-1,3-dicarbaldehydes with a tripyrrane in the presence of TFA, followed by an oxidation step. The initially formed phlorin product was sufficiently stable for the N-phenyl system to be isolated and characterized, although the related N-alkyl phlorin analogues were less stable. Attempts to dehydrogenate the intermediary phlorins with DDQ resulted in decomposition, but the N-alkylphlorins could be oxidized with 0.2% aqueous ferric chloride solutions. Although the phenyl-substituted phlorin could not be oxidized under these conditions, it did afford the pyrazoloporphyrin upon treatment with silver acetate under acidic conditions. Oxidations with silver acetate also afforded oxophlorin analogues where the oxo-linkage was selectively formed at the 5-position. The pyrazole-containing porphyrin analogues are cross-conjugated and exhibit only a small degree of diatropic character. The internal CH resonances were observed between 5.27 and 5.87 ppm, while the external meso-protons fell into a range of 6.84-7.88 ppm. The borderline overall aromatic character was attributed to dipolar resonance contributors. Protonation considerably increased the diatropicity and the diprotonated dications formed from these porphyrin analogues gave the internal CH resonance at upfield values of 2.65-3.20 ppm. The aromatic character was enhanced by the presence of an electron-donating alkyl substituent on the nitrogen compared to the phenyl-substituted species. The pyrazoloporphyrins reacted with nickel(II) acetate in DMF, or palladium(II) acetate in acetonitrile, to give the corresponding organometallic derivatives. The metal complexes showed increased diatropic character but protonation afforded nonaromatic cations. The oxophlorin analogues were also nonaromatic in the free base and protonated forms. This work extends our understanding of carbaporphyrinoid systems and provides the first detailed studies on pyrazole-containing porphyrin analogues.

Ferrocene‐modified thiopyrimidines: synthesis, enantiomeric resolution, antitumor activity

AbstractFerrocenylalkyl thiopyrimidines (6a–d to 9a–d) were prepared via the reaction of the α‐(hydroxy)alkyl ferrocenes, FcCHR(OH) (1a–d; Fc = ferrocenyl; R = H, Me, Et, Ph), with 2‐thiopyrimidines (2–5) in acetone at room temperature in the presence of TFA, yielding 50–95%. The resulting enantiomers were resolved using HPLC on modified cellulose as chiral selector. The antitumor activities of S‐ferrocenylethyl 2‐thiopyrimidine (6b) against two murine solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were evaluated in vivo. The strong antitumor effect of compound 6b on Ca755 and LLC was demonstrated. The index of tumor growth inhibition on Ca755 equaled 95% in comparison with control. Copyright © 2010 John Wiley & Sons, Ltd.