Ruthenium‐catalyzed formation of quinolines via reductive cyclization of nitroarenes with tris(3‐hydroxypropyl)amine in an aqueous medium

Nitroarenes react with tris(3‐hydroxypropyl)amine in an aqueous medium (dioxane/H₂O) at 180° in the presence of a catalytic amount of a ruthenium catalyst and tin(II) chloride along with isopropanol as hydrogen donor to afford the corresponding quinolines in good yields. The presence of tin(II) chloride is essential for the formation of quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines, propanol group transfer from tris(3‐hydroxypropyl)amine to anilines to form 3‐anilino‐1‐propanols, N‐alkylation of anilines by 3‐anilino‐1‐propanol to form 1,3‐dianilinopropane and intramolecular heteroannulation of 1,3‐dianilinopropane is proposed for this catalytic process.     

Nonlinear Brønsted and Hammett Correlations Associated with Reactions of 4‐Chloro‐7‐nitrobenzofurazan with Anilines in Dimethyl Sulfoxide Solution

The kinetics and mechanism of nucleophilic aromatic substitution reactions of 4‐chloro‐7‐nitrobenzofurazan 1 with 4‐X‐substituted anilines 2a–g (X = OH, OCH₃, CH₃, H, I, Cl, and CN) are investigated in a dimethyl sulfoxide (Me₂SO) solution at 25°C. The Hammett plot of log k₁ versus σ is nonlinear for all the anilines studied due to positive deviations of the electron‐donating substituents. However, the corresponding Yukawa–Tsuno plot resulted in a good linear correlation with σ+r (σ⁺?σ). The corresponding Brønsted‐type plot is also nonlinear, i.e., the slope (β_nuc) changes from 1.60 to 0.56 as the basicity of anilines decreases. These results indicate a change in a mechanism from a polar S_NAr process for less basic nucleophiles (X = I, Cl, and CN) to a single electron transfer for more basic nucleophiles (X = OH, OCH₃, and CH₃). The satisfactory log k₁ versus E^o correlation obtained for the reactions of 1 with anilines 2a–d in the present system is consistent with the proposed mechanism. Interestingly, the β_nuc = 1.60 value measured for 1 in Me₂SO reflects one of the highest coefficients Brønsted ever observed for S_NAr reactions. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 152–160, 2013     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .     

7‐Iodo‐8‐aza‐7‐deaza‐2′‐deoxy­adenosine and 7‐bromo‐8‐aza‐7‐deaza‐2′‐deoxyadenosine

The isomorphous structures of the title molecules, 4‐amino‐1‐(2‐deoxy‐β‐d ‐erythro‐pento­furan­osyl)‐3‐iodo‐1H‐pyrazolo‐[3,4‐d]pyrimidine, (I), C₁₀H₁₂IN₅O₃, and 4‐amino‐3‐bromo‐1‐(2‐deoxy‐β‐d ‐erythro‐pento­furan­osyl)‐1H‐pyrazolo[3,4‐d]­pyrimidine, (II), C₁₀H₁₂BrN₅O₃, have been determined. The sugar puckering of both compounds is C1′‐endo (^1′E). The N‐­glycosidic bond torsion angle χ¹ is in the high‐anti range [?73.2 (4)° for (I) and ?74.1 (4)° for (II)] and the crystal structure is stabilized by hydrogen bonds.     

Hydrogen‐bonded dimers in 3‐amino‐4‐anilino‐1H‐isochromen‐1‐one and a hydrogen‐bonded sheet in 3‐amino‐4‐[methyl(phenyl)amino]‐1H‐isochromen‐1‐one

The molecules of 3‐amino‐4‐anilino‐1H‐isochromen‐1‐one, C₁₅H₁₂N₂O₂, (I), and 3‐amino‐4‐[methyl(phenyl)amino]‐1H‐isochromen‐1‐one, C₁₆H₁₄N₂O₂, (II), adopt very similar conformations, with the substituted amino group PhNR, where R = H in (I) and R = Me in (II), almost orthogonal to the adjacent heterocyclic ring. The molecules of (I) are linked into cyclic centrosymmetric dimers by pairs of N—H...O hydrogen bonds, while those of (II) are linked into complex sheets by a combination of one three‐centre N—H...(O)₂ hydrogen bond, one two‐centre C—H...O hydrogen bond and two C—H...π(arene) hydrogen bonds.     

Linear Free‐Energy Relationships Applied to the 13C NMR Chemical Shifts in 4‐Substituted N‐[1‐(Pyridine‐3‐ and ‐4‐yl)ethylidene]anilines

Two series of 4‐substituted N‐[1‐(pyridine‐3‐ and ‐4‐yl)ethylidene]anilines have been synthesized using different methods of conventional and microwave‐assisted synthesis, and linear free‐energy relationships have been applied to the ¹³C NMR chemical shifts of the carbon atoms of interest. The substituent‐induced chemical shifts have been analyzed using single substituent parameter and dual substituent parameter methods. The presented correlations describe satisfactorily the field and resonance substituent effects having similar contributions for C1 and the azomethine carbon, with exception of the carbon atom in para position to the substituent X. In both series, negative ρ values have been found for C1′ atom (reverse substituent effect). Quantum chemical calculations of the optimized geometries at MP2/6‐31G++(d,p) level, together with ¹³C NMR chemical shifts, give a better insight into the influence of the molecular conformation on the transmission of electronic substituent effects. The comparison of correlation results for different series of imines with phenyl, 4‐nitrophenyl, 2‐pyridyl, 3‐pyridyl, 4‐pyridyl group attached at the azomethine carbon with the results for 4‐substituted N‐[1‐(pyridine‐3‐ and ‐4‐yl)ethylidene]anilines for the same substituent set (X) indicates that a combination of the influences of electronic effects of the substituent X and the π₁‐unit can be described as a sensitive balance of different resonance structures.     

Synthesis and Characterization of 11‐Amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one Derivatives

A series of 2‐amino‐7‐methoxy‐4‐aryl‐4H‐chromene‐3‐carbonitrile compounds 2 were obtained by condensation of 3‐methoxyphenol with β‐dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesuflonic acid (TsOH) as catalyst. The title compounds 11‐amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one 4 were synthesized by cyclization of the intermediate enamines 3 in THF with K₂CO₃ /Cu₂Cl₂ as catalyst. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal structure of compound 4i was determined by single‐crystal X‐ray diffraction analysis.     

An Exceedingly Mild,Green Synthesis of Substituted N‐3‐diaryl‐1,8‐naphthyridin‐2‐amine Derivatives and Their Antimicrobial Activity

An exceedingly and highly efficient procedure has been described for the synthesis of substituted N‐3‐diaryl‐1,8‐naphthyridin‐2‐amines by the reaction of 2‐chloro‐3‐aryl‐1,8‐naphthyridines with various anilines in the presence of N‐methyl‐2‐pyrrolidone and K₂CO₃ under thermal green solvent‐free conditions. The significant features of this green reaction include very good yields in purity, simple experimental, short reaction time, easy workability, and avoidance of toxic solvents. All synthesized compounds have been evaluated for their antibacterial activity.     

Ligand‐free CuTC‐catalyzed N‐arylation of amides,anilines and 4‐aminoantipyrine: synthesis of N‐arylacrylamides, 4‐amido‐N‐phenylbenzamides and 4‐amino(N‐phenyl)antipyrenes

N‐Arylation of amides and anilines with aryl iodides was efficiently catalyzed by copper thiophenecarboxylate under ligand‐free conditions with good to excellent yields. A variety of substituted aryl iodides, amides, anilines and 4‐aminoantipyrine were found to be applicable to the simple catalytic system. Furthermore, some practical, unique secondary amides, such as N‐arylacrylamides and 4‐amido‐N‐phenylbenzamides, and 4‐amino(N‐phenyl)antipyrenes, which are difficult to obtain by the classical methods, were prepared. Copyright © 2013 John Wiley & Sons, Ltd.     

1‐Methyl‐3‐phenyl‐3‐thiocyanato‐1H,3H‐quinoline‐2,4‐dione: A novel thiocyanating agent

Under mild reaction conditions, the thiocyanato group is selectively transferred from 1‐methyl‐3‐phenyl‐3‐thiocyanato‐1H,3H‐quinoline‐2,4‐dione ( 3 ) to some nucleophiles. Aliphatic primary and secondary amines are converted to S‐cyanothiohydroxylamines, anilines afford p‐thiocyanatoanilines, Wittig reagent is thiocyanated in α‐position, and thiols are oxidized to disulfides.     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.     

Synthesis of 2‐[4‐(Imidazolin‐2‐Ylideneamino)Benzyl]‐Indan‐1‐Ones as Novel Potent Prostacyclin Antagonists

Prostacyclin is involved in many pathological conditions, such as sensitization of inflammation induced pain and isovolumetic distention. Therefore, antagonism of prostacyclin action may be useful in the alleviation of these conditions. In this study, novel potent prostacyclin antagonists, 2‐[4‐(imidazolin‐2‐ylideneamino)benzyl]‐indan‐1‐ones were synthesized from their respective substituted indanones in three steps. The construction of the amino‐imidazole moiety of these derivatives is achieved by using in situ generation of chloro‐imidazole and reaction with their respective anilines. Thus, these N‐substituted 2‐imidazolines can be prepared safely and efficiently. Moreover, these compounds show potent prostacyclin antagonistic activity by inhibition of prostacyclin agonist induced ERK_1/2 phosphorylation in human erythroleukemia cells. Moreover, we observed an increase in activity with the increase in electro‐donating property of the substitution on the indanone aromatic ring. Prostacyclin antagonists with increased potency may be designed based on these findings. These compounds may also be invaluable tools for the study of the physiological functions of prostacyclin.     

Pseudopolymorphs of 2,6‐diaminopyrimidin‐4‐one and 2‐amino‐6‐methylpyrimidin‐4‐one: one or two tautomers present in the same crystal

The derivatives of pyrimidin‐4‐one can adopt either a 1H‐ or a 3H‐tautomeric form, which affects the hydrogen‐bonding interactions in cocrystals with compounds containing complementary functional groups. In order to study their tautomeric preferences, we crystallized 2,6‐diaminopyrimidin‐4‐one and 2‐amino‐6‐methylpyrimidin‐4‐one. During various crystallization attempts, four structures of 2,6‐diaminopyrimidin‐4‐one were obtained, namely solvent‐free 2,6‐diaminopyrimidin‐4‐one, C₄H₆N₄O, (I), 2,6‐diaminopyrimidin‐4‐one–dimethylformamide–water (3/4/1), C₄H₆N₄O·1.33C₃H₇NO·0.33H₂O, (Ia), 2,6‐diaminopyrimidin‐4‐one dimethylacetamide monosolvate, C₄H₆N₄O·C₄H₉NO, (Ib), and 2,6‐diaminopyrimidin‐4‐one–N‐methylpyrrolidin‐2‐one (3/2), C₄H₆N₄O·1.5C₅H₉NO, (Ic). The 2,6‐diaminopyrimidin‐4‐one molecules exist only as 3H‐tautomers. They form ribbons characterized by R²₂(8) hydrogen‐bonding interactions, which are further connected to form three‐dimensional networks. An intermolecular N—H...N interaction between amine groups is observed only in (I). This might be the reason for the pyramidalization of the amine group. Crystallization experiments on 2‐amino‐6‐methylpyrimidin‐4‐one yielded two isostructural pseudopolymorphs, namely 2‐amino‐6‐methylpyrimidin‐4(3H)‐one–2‐amino‐6‐methylpyrimidin‐4(1H)‐one–dimethylacetamide (1/1/1), C₅H₇N₃O·C₅H₇N₃O·C₄H₉NO, (IIa), and 2‐amino‐6‐methylpyrimidin‐4(3H)‐one–2‐amino‐6‐methylpyrimidin‐4(1H)‐one–N‐methylpyrrolidin‐2‐one (1/1/1), C₅H₇N₃O·C₅H₇N₃O·C₅H₉NO, (IIb). In both structures, a 1:1 mixture of 1H‐ and 3H‐tautomers is present, which are linked by three hydrogen bonds similar to a Watson–Crick C–G base pair.     

New Highlights in the Synthesis of 4‐Aryl‐1,4‐dihydropyrazines

The 4‐aryl‐1,4‐dihydropyrazines were prepared via the cyclization of N,N‐bisalkylated anilines with ammonium acetate. These reactions were aided by improvements in the synthesis of N,N‐bisalkylated anilines which were alkylated with anilines using ethyl 2‐diazo acetoacetate in a reaction catalyzed by rhodium acetate in the absence of oxygen. A possible mechanistic route is postulated on the basis of the isolation of the N‐alkylation intermediates, which were determined to be N‐aryloxamates by ¹H NMR data and X‐ray diffraction.     

Hydro­gen‐bonded chains in N‐(2‐nitrophenyl)phenylamine

Molecules of the title compound, C₁₂H₁₀N₂O₂, are markedly non‐planar. There is an intramolecular N—H?O hydrogen bond, and the mol­ecules are linked into zigzag chains by a single C—H?O hydrogen bond. Comparisons are made with the supramolecular aggregation in isomeric amino–nitro derivatives, and in some N‐methylnitro­anilines.     

Z and E isomers of butenedioic acid with 2‐amino‐1,3‐thiazole: 2‐amino‐1,3‐thiazolium hydrogen maleate and 2‐amino‐1,3‐thiazolium hydrogen fumarate

Maleic acid and fumaric acid, the Z and E isomers of butenedioic acid, form 1:1 adducts with 2‐amino‐1,3‐thiazole, namely 2‐amino‐1,3‐thiazolium hydrogen maleate (2ATHM), C₃H₅N₂S⁺·C₄H₃O₄⁻, and 2‐amino‐1,3‐thiazolium hydrogen fumarate (2ATHF), C₃H₅N₂S⁺·C₄H₃O₄⁻, respectively. In both compounds, protonation of the ring N atom of the 2‐amino‐1,3‐thiazole and deprotonation of one of the carboxyl groups are observed. The asymmetric unit of 2ATHF contains three independent ion pairs. The hydrogen maleate ion of 2ATHM shows a short intramolecular O—H...O hydrogen bond with an O...O distance of 2.4663 (19) Å. An extensive hydrogen‐bonded network is observed in both compounds, involving N—H...O and O—H...O hydrogen bonds. 2ATHM forms two‐dimensional sheets parallel to the ab plane, extending as independent parallel sheets along the c axis, whereas 2ATHF forms two‐dimensional zigzag layers parallel to the bc plane, extending as independent parallel layers along the a axis.     

Kinetic Studies on Nucleophilic Addition Reactions of 4‐X‐substituted Anilines to N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium terafluoroborate in Acetonitrile: Reaction Mechanism and Mayr's Approach

The kinetics of the coupling of N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium tetrafluoroborate 1 with a series of 4‐X‐substituted anilines 2a–f (X = OH, OMe, Me, H, Cl, and CN) have been investigated in acetonitrile at 20°C. The second‐order rate constants result in a nonlinear Brönsted‐type plot. The Hammett plot is also nonlinear, whereas the Yukawa–Tsuno plot exhibits an excellent linear correlation with ρ = –1.62 and r = 1.44. The large Brönsted (β_nuc = 1.24) and Hammett (ρ = –5.16) values suggest that the reactions proceed trough a single electron transfer mechanism. The finding of satisfactory correlation between the log k₁ of the reactions and the oxidation potentials (E°) of anilines 2a–d supports this mechanism. On the other hand, electrophilicity parameter E of benzothiadiazolium cation 1 as defined by the correlation log k_20°C = s(E + N) has been determined and compared with the electrophilic reactivities of a large variety of electrophiles.     

A series of (E)‐5‐(arylideneamino)‐1‐tert‐butyl‐1H‐pyrrole‐3‐carbonitriles and their reduction products to secondary amines: syntheses and X‐ray structural studies

An efficent access to a series of N‐(pyrrol‐2‐yl)amines, namely (E)‐1‐tert‐butyl‐5‐[(4‐chlorobenzylidene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₆ClN₃, (7a), (E)‐1‐tert‐butyl‐5‐[(2,4‐dichlorobenzylidene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₅Cl₂N₃, (7b), (E)‐1‐tert‐butyl‐5‐[(pyridin‐4‐ylmethylene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₅H₁₆N₄, (7c), 1‐tert‐butyl‐5‐[(4‐chlorobenzyl)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₈ClN₃, (8a), and 1‐tert‐butyl‐5‐[(2,4‐dichlorobenzyl)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₇Cl₂N₃, (8b), by a two‐step synthesis sequence (solvent‐free condensation and reduction) starting from 5‐amino‐1‐tert‐butyl‐1H‐pyrrole‐3‐carbonitrile is described. The syntheses proceed via isolated N‐(pyrrol‐2‐yl)imines, which are also key synthetic intermediates of other valuable compounds. The crystal structures of the reduced compounds showed a reduction in the symmetry compared with the corresponding precursors, viz. Pbcm to P from compound (7a) to (8a) and P2₁/c to P from compound (7b) to (8b), probably due to a severe change in the molecular conformations, resulting in the loss of planarity observed in the nonreduced compounds. In all of the crystals, the supramolecular assembly is controlled mainly by strong (N,C)—H…N hydrogen bonds. However, in the case of (7a)–(7c), C—H…Cl interactions are strong enough to help in the three‐dimensional architecture, as observed in Hirshfeld surface maps.     

Synthesis of 1,3‐Selenazol‐2(3H)‐imines

The reaction of N,N′‐diarylselenoureas 16 with phenacyl bromide in EtOH under reflux, followed by treatment with NH₃, gave N,3‐diaryl‐4‐phenyl‐1,3‐selenazol‐2(3H)‐imines 13 in high yields (Scheme 2). A reaction mechanism via formation of the corresponding Se‐(benzoylmethyl)isoselenoureas 18 and subsequent cyclocondensation is proposed (Scheme 3). The N,N′‐diarylselenoureas 16 were conveniently prepared by the reaction of aryl isoselenocyanates 15 with 4‐substituted anilines. The structures of 13a and 13c were established by X‐ray crystallography.     

Oxazoline chemistry part III. Synthesis and characterisation of [2‐(2′‐anilinyl)‐2‐oxazolines] and some related compounds

The syntheses and characterisation of a series of chiral and achiral 2‐(aminophenyl)‐2‐oxazolines and some related compounds is reported. All of the derivatives have been produced by a one‐step procedure involving the treatment of isatoic anhydride (i.e. [2H]‐3, 1‐benzoxazine‐[1H‐2,4‐dione: 1 ) or its 5‐chloro analogue with a slight excess of appropriate amino‐alcohols. In most cases, anhydrous ZnCl₂ is shown to be an effective Lewis acid catalyst for this reaction at reflux temperature in high boiling aromatic solvents (PhCl or PhMe). Oxazolines have been readily formed using rac‐2‐amino‐1‐butanol, (S)‐phenylglycinol, 2‐methyl‐2‐amino‐1‐propanol and (1S,2R) or (IR,2S)‐cis‐ 1 ‐amino‐2‐indanol; yields range from 85% to 22%. The use of aminoalcohols such as 2‐ethanolamine, (±)‐2‐amino‐1‐phenyl‐1‐propanol or 3‐amino‐1‐propanol (to give the corresponding 4,5‐dihydro‐1,3‐oxazine) results in poor yields. The use of other Lewis acid catalysts (silicic acid, Cd(acac)₂·2H₂O, CuCl₂·2H₂O, InCl₃) or higher temperatures did not improve the yields with these latter two substrates. Benzoxazoles and N‐substituted benzoxazoles can also be obtained in reasonable yields from 1 using 2‐aminophenol (36%) or 2‐amino‐3‐hydroxypyridine (45%).