Synthesis of bis‐ and tris‐organophosphorus substituted amines and amino acids with PCH2N Fragments

The aminomethylation of the derivatives of trivalent organophosphorus acids, containing PH and POSiMe₃ fragments with various bis‐ and tris(alkoxymethyl)amines and bis(alkoxymethyl)amino acids, is proposed as a convenient method for the synthesis of new bis‐ and trisphosphorylated amines and amino acids as well as their derivatives with four and five coordinated phosphorus. Also the three‐components systems of phosphorous acid, paraformaldehyde, and amines are thoroughly investigated via the treatment of reaction mixtures with bis(trimethylsilyl)amine. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:430–440, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20616     

Synthesis of new 5‐acetyl(arylmethyliden)‐4‐thiazolidones

A new approach to the synthesis of new heterocyclic compounds with triazine and 4‐thiazolidone fragments in one molecule is developed. The synthesis methods comprise [2+3]‐cyclocondensation reactions essential in the preparative synthesis of 4‐thiazolidone derivatives. The reactions of S,N‐nucleophiles with C₂‐cyclization agents for the synthesis of a number of biologically active 2‐triazin‐4‐thiazolidones were investigated. The interaction of thiosemicarbazone of sym‐triazine with derivatives of α‐halogencarboxylic acids and maleic anhydride resulted in correspondent (2‐[2‐(4,6‐dichloro‐1,3,5‐triazin‐2‐yl)hydrazino]‐5‐(3,4,5‐ R‐p‐phenyl‐methyliden)‐1,3‐thiazol‐4‐ones obtained in the one‐step synthesis. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:392–396, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20631     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Liquid chromatography/tandem mass spectrometric analysis of 7,10‐dihydroxyoctadecenoic acid,its isotopomers,and other 7,10‐dihydroxy fatty acids formed by Pseudomonas aeruginosa 42A2

Pseudomonas aeruginosa is an opportunistic pathogen, which oxidizes oleic acid to 7(S),10(S)‐dihydroxy‐8(E)‐octadecenoic acid (7,10‐(OH)₂‐18:1) of biological and industrial interest. Electrospray tandem mass spectrometric (MS/MS) analysis of hydroxylated fatty acids usually generates characteristic fragments containing the carboxylate anion and formed by α‐cleavage at the oxidized carbon. These fragments indicate the positions of the hydroxyl group. In contrast, liquid chromatography (LC)/MS/MS analysis of 7,10‐(OH)₂‐18:1 yielded a series of other ions with structural information. To study the fragmentation mechanism, we prepared ²H‐ and ¹⁸O‐labeled isotopomers. We also performed MS³ analysis of the major ions, and for comparison we generated the corresponding 7,10‐dihydroxy metabolites of 16:1n‐7, 18:2n‐6, and 20:1n‐11 with a protein extract of P. aeruginosa. The MS/MS spectra of 7,10‐(OH)₂‐18:1 and its isotopomers, 7,10‐(OH)₂‐16:1, and 7,10‐(OH)₂‐20:1, contained a series of prominent fragments that all hold the omega end. The 8,9‐double bond was not essential for this fragmentation, as 7,10‐(OH)₂‐18:0, and its isotopomers, formed essentially the same fragments in the lower mass range. In contrast, 7,10‐dihydroxy‐8(E),12(Z)‐octadecadienoic acid (7,10‐(OH)₂‐18:2) fragmented by α‐cleavage at the oxidized carbons with formation of carboxylate anions. Our results demonstrate that C₁₆–C₂₀ fatty acids with a 7,10‐dihydroxy‐8(E) functionality undergo charge‐driven fragmentation after charge migration to the ω‐end, whereas the main ions of 7,10‐(HO)₂‐18:2 retain charge at the carboxyl group. Copyright © 2010 John Wiley & Sons, Ltd.     

Syntheses of 4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones from Sydnone Derivatives and Their Fragments

4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 11 and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 13 have been obtained from a‐chloroformylarylhydrazine hydrochloride 2 . Moreover, the intermediates, including 3, 4 , 9 and 10 , in this study are synthetically informative and valuable. It is also noteworthy that three reactants, 1, 2 and sydnonecarbaldehydes, were prepared from sydnone derivatives and their fragments. The oxidative cyclizations of sydnonecarbaldehyde semicarbazones 9 and carbazones 10 with two different oxidizing agents (Cu(ClO₄)₂ and Fe(ClO₄)₃) have been extensively examined. The reaction time and the yields of cyclizations were affected by the substituents of semicarbazones 9 and carbazones 10.     

The N‐Terminal Nonapeptide of Cephaibols A and C: A Naturally Occurring Example of Mismatched Helical Screw‐Sense Control

The N‐terminal nonapeptide domain of the fungal nonribosomal peptide antibiotics cephaibol A and cephaibol C (AcPheAib₄LeuIvaGly‐ Aib) is reported to adopt a right‐handed helical conformation in the crystalline state. However, this conformation is at odds with the left‐handed helicity observed in solution in related synthetic oligomers capped with Ac‐L ‐PheAib₄ fragments. We report the synthesis of four diastereoisomers of the cephaibol N‐terminal nonapeptide, and show by NMR and CD spectroscopy that the peptide containing the chiral amino acids Phe and Leu in the naturally occurring relative configuration exists in solution as an interconverting mixture of helical screw‐sense conformers. In contrast, the nonapeptide containing the unnatural relative configuration at Phe and Leu adopts a single, stable helical screw‐sense, which is left handed when the N‐terminal Phe residue is L and right‐handed when the N‐terminal Phe residue is D .     

Ultrasound‐Promoted Catalyst‐Free Synthesis of 2,2′‐(1,4‐Phenylene)bis[1‐acetyl‐1,2‐dihydro‐4H‐3,1‐benzoxazin‐4‐one] Derivatives

A convenient approach to 2,2′‐(1,4‐phenylene)bis[1‐acetyl‐1,2‐dihydro‐4H‐3,1‐benzoxazin‐4‐one] derivatives 4 was explored employing the one‐pot condensation of anthranilic acids (=2‐aminobenzoic acids) 1 with terephthalaldehyde (=benzene‐1,4‐dicarboxaldehyde; 2 ) under ultrasound‐irradiation conditions (Scheme 1). The reactions proceeded smoothly in the presence of excess Ac₂O in the absence of any other catalyst and solvent to afford the respective products in high yields.     

Palladium‐catalyzed three‐component cyclization of 2‐bromocyclohex‐1‐enecarboxylic acids with carbon monoxide and arylhydrazines leading to 2‐anilinohydroisoindoline‐1,3‐diones

2‐Bromocyclohex‐1‐enecarboxylic acids are carbonylatively cyclized with arylhydrazines or their hydrochlorides in tetrahydrofuran at 120 °C under carbon monoxide pressure in the presence of a catalytic amount of PdCl₂ and 1,3‐bis(diphenylphosphino)propane along with Et₃N to give 2‐anilinohydroisoindoline‐1,3‐diones. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis of Organophosphorus‐Substituted Amides of Carbonic Acids with PCHNC(O) and 2,6‐Di‐tert‐butyl‐4‐methylphenol Fragments

Convenient procedures for the synthesis of new organophosphorus‐substituted amides of various carbonic acids with PCHNC(O) and 2,6‐di‐tert‐butyl‐4‐methylphenol (ionol) fragments, starting from the adducts of imines and acyl chlorides, are proposed. Some properties of the new synthesized organophosphorus amides are presented. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:733–737, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20502     

Me‐BIPAM for the Synthesis of Optically Active 3‐Aryl‐3‐hydroxy‐2‐oxindoles by Ruthenium‐catalyzed Addition of Arylboronic Acids to Isatins

A chiral O‐linked C₂‐symmetric bidentate phosphoramidite (Me‐BIPAM) was found to be efficient for the ruthenium‐catalyzed addition of arylboronic acids to isatins. Asymmetric synthesis of 3‐aryl‐3‐hydroxy‐2‐oxindoles by 1,2‐addition of arylboronic acids to isatins was carried out in the presence of [RuCl₂(PPh₃)₃]/(R,R)‐Me‐BIPAM and KF, resulting in an enantioselectivity as high as 90 % ee. It was found that the reaction with N‐protected isatins proceeds with high yields and good enantioselectivities. The best protective groups on the nitrogen atom were different depending on the substituents on the aromatic ring. The use of a N‐benzyl group resulted in excellent enantioselectivities in many substrates compared with other groups.     

Conversion of 1,3‐Dimethyl‐5‐(Arylazo)‐6‐Amino‐Uracils to 1,3‐Dimethyl‐5‐(Arylazo)‐Barbituric Acids: Spectroscopic Characterization,Photophysical Property and Determination of pKa of the Products

The study of inter‐conversion between molecules, especially biologically and pharmaceutically important molecules, is extremely important. This study reports the inter‐conversion between two azo‐derivtives: azo‐6‐aminouracils to azo‐barbituric acids. We successfully converted the 1,3‐dimethyl‐5‐(arylazo)‐6‐aminouracils ( Uazo‐1 to Uazo‐4 ) to 1,3‐dimethyl‐5‐(arylazo)‐barbituric acids ( BAazo‐1 to BAazo‐4 ) (where aryl?C₆H₅‐( 1 ); p‐MeC₆H₄‐( 2 ), p‐ClC₆H₄‐( 3 ), and p‐NO₂C₆H₄‐( 4 )) following an acid‐hydrolysis path. The products were characterized using spectroscopic tools like UV‐vis, IR, and NMR spectroscopy. UV‐vis spectra of the as‐prepared dyes reveal that in contrast to the azo‐6‐aminouracils they are hardly responsive towards solvatochromism. IR spectra exhibit three characteristic >C?O frequencies for as‐prepared azobarbituric acids instead of two for mother azo‐6‐aminouracils. ¹H NMR spectra which reflect the existence of solution species evidence the absence of >C?NH group (characteristic imido‐H at the 6‐position of hydrazone species of azo‐6‐aminouracils) and consequence presence of >C?O group at the same position in as‐prepared azobarbituric acids. They exhibit structural emissions in the range of 400–440 nm upon excitation at 360 nm. The determined acid dissociation constant (pKa) values of BAazos increase according to the following sequence: BAazo ‐ 2 > 1 > 3 > 4 .     

Oxygenated Metabolites of n‐3 Polyunsaturated Fatty Acids as Potential Oxidative Stress Biomarkers: Total Synthesis of 8‐F3t‐IsoP, 10‐F4t‐NeuroP and [D4]‐10‐F4t‐NeuroP

A wide variety of metabolic products of polyunsaturated fatty acids is of paramount importance for improving our medical knowledge in the field of oxidized lipids. Two novel metabolites of n‐3 polyunsaturated fatty acids, 8‐F_3t‐IsoP and 10‐F_4t‐NeuroP as well as a deuterated derivative thereof were synthesized based on an acetylenic intermediate. An original approach achieved lateral chain insertion of 8‐F_3t‐IsoP by a ring‐closing alkyne metathesis/semi‐reduction strategy together with a temporary tether.     

Reaction of tellurium tetraiodide with 2,3‐dihydro‐1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene

2,3‐Dihydro‐1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene 1 (Carb, R¹ = ⁱPr, R² = Me) reacts with TeI₄ to give the carbene adduct CarbTeI₂ ( 3 ). The crystal structure of 3 consists of T‐shaped monomeric fragments linked by weak Te. I interactions to form infinite helical chains. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:316–319, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20090     

Rose Bengal‐Sensitized Photooxidation of the Dipeptides l‐Tryptophyl‐l‐Phenylalanine,l‐Tryptophyl‐l‐Tyrosine and l‐Tryptophyl‐l‐Tryptophan: Kinetics,Mechanism and Photoproducts¶

The Rose Bengal‐sensitized photooxidations of the dipeptides l ‐tryptophyl‐l ‐phenylalanine (Trp‐Phe), l ‐tryptophyl‐l ‐tyrosine (Trp‐Tyr) and l ‐tryptophyl‐l ‐tryptophan (Trp‐Trp) have been studied in pH 7 water solution using static photolysis and time‐resolved methods. Kinetic results indicate that the tryptophan (Trp) moiety interacts with singlet molecular oxygen (O₂(¹Δ_g)) both through chemical reaction and through physical quenching, and that the photooxidations can be compared with those of equimolecular mixtures of the corresponding free amino acids, with minimum, if any, influence of the peptide bond on the chemical reaction. This is not a common behavior in other di‐ and polypeptides of photooxidizable amino acids. The ratio between chemical (k_r) and overall (k_t) rate constants for the interaction O₂(¹Δ_g)‐dipeptide indicates that Trp‐Phe and Trp‐Trp are good candidates to suffer photodynamic action, with k_rlk_t values of 0.72 and 0.60, respectively (0.65 for free Trp). In the case of Trp‐Tyr, a lower k_rlk_t value (0.18) has been found, likely as a result of the high component of physical deactivation of O₂(¹Δ_g) by the tyrosine moiety. The analysis of the photooxidation products shows that the main target for O₂(¹Δ_g) attack is the Trp group and suggests a much lower accumulation of kynurenine‐type products, as compared with free Trp. This is possibly because of the occurrence of another accepted alternative pathway of oxidation that gives rise to 3a‐oxidized hydrogenated pyrrolo[2,3‐b]indoles.     

Nickel‐Catalyzed Cross‐Coupling of Redox‐Active Esters with Boronic Acids

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross‐coupling between alkyl‐carboxylic acids and boronic acids is described. This Ni‐catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox‐active ester derivatives, specifically N‐hydroxy‐tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl₂?6 H₂O—$9.5 mol^?1, Et₃N) coupled to the virtually unlimited commercial catalog of available starting materials bodes well for its rapid adoption.     

Pyrazole‐4‐carboxylic Acids from Vanadium‐catalyzed Chemical Transformation of Pyrazole‐4‐carbaldehydes

The conversion of aldehydes into carboxylic acids using oxidizing agents is a common protocol in transformation chemistry. An efficient oxidation strategy of transformation of pyrazole‐4‐aldehydes to the corresponding acids using vanadium catalysts in the presence of 30% H₂O₂ as an oxidant is described. The catalytic technology was successfully applied to a range of various 4‐formylpyrazoles, and plausible mechanism is also discussed.     

8‐Chloro‐7‐(2,6‐di­chloro­benzyl)‐1,3‐di­methyl‐7H‐purine‐2,6(1H,3H)‐dione

The title compound, C₁₄H₁₁Cl₃N₄O₂, consists of two planar fragments which are nearly perpendicular to one another. The crystal packing is controlled by intra‐ and intermolecular C—H·O hydrogen bonds, and Cl·phenyl‐ring‐centroid and weak stacking interactions.     

Microwave‐Accelerated Pd‐Catalyzed Desulfitative Direct C2‐Arylation of Free (NH)‐Indoles with Arylsulfinic Acids

The rapid and efficient direct C2‐arylation of free (NH)‐indoles with arylsulfinic acids proceeded through a microwave‐accelerated palladium‐catalyzed desulfitation reaction. By using PdCl₂ as a catalyst, silver acetate as an oxidant, and H₂SO₄ as an additive, arylsulfinic acids with both electron‐donating and electron‐withdrawing groups underwent desulfitative coupling with an array of free (NH)‐indoles, thereby selectively providing C2‐arylindoles in good yields.     

Functionalization of Quinazolin‐4‐ones Part 1: Synthesis of Novel 7‐Substituted‐2‐thioxo Quinazolin‐4‐ones from 4‐Substituted‐2‐Aminobenzoic Acids and PPh3(SCN)2

4‐(Nitro, amino, acetylamino)‐2‐aminobenzoic acid were allowed to react with PPh₃(SCN)₂ and gave the crossholding 7‐nitro, 7‐acetylamino‐ and 7‐amino‐2‐thioxo quinazolin‐4‐ones respectively. The nature of the substituent at position 4 of the 2‐aminobenzoic acids has significant influence on the outcome of the cyclisation reaction with PPh₃(SCN)₂. Similarly, the nature of the substituent at position 7 of the 2‐substituted quinazolin‐4‐ones significantly affected the ease with which alkylation reactions could be performed. The alkylation selectivity of the 7‐ substiuted‐2‐thioxo quinazolin‐4‐ones was found to depend on the nature of the alkyl halide and the nature of the substituent at position 2.