The Synthesis of (4E)‐N‐(4‐chlorophenyl)‐5‐substituted‐2‐diazo‐3‐oxopent‐4‐enoic Acid Amides

The (4E)‐N‐(4‐chlorophenyl)‐5‐(3‐chlorophenyl)‐2‐diazo‐3‐oxopent‐4‐enoic acid amides 5a˜j were synthesized with N‐(4‐chlorophenyl)‐2‐diazo‐3‐oxobutyramide 4 from p‐chloroaniline and various arylaldehydes. The yielded products 5a˜j were investigated with NMR, MS, IR, and X‐ray crystallographic techniques.     

A Convenient Synthesis of 1‐Alkoxy‐2‐alkyl‐1,2‐dihydroisoquinoline‐3,4‐diones Utilizing the Reaction of 2‐(Dialkoxymethyl)phenyllithiums with Dimethyl Oxalate

A new and convenient method for the preparation of 1,2‐dihydroisoquinoline‐3,4‐diones with alkoxy and alkyl groups at the 4‐ and 3‐positions, respectively, using an easily operated three‐step sequence starting from 2‐(dialkoxymethyl)phenyl bromides has been developed. Thus, the starting materials are treated with BuLi to generate 2‐(dialkoxymethyl)phenyllithiums, which are allowed to react with (COOMe)₂ to give methyl 2‐(dialkoxymethyl)phenyl‐2‐oxoacetates. These are then transformed into the corresponding secondary amides by the reaction with primary amines. Treatment of these keto amides with a catalytic amount of TsOH?H₂O affords the desired products. In order to demonstrate the synthetic utility of these products, transformation of one of them into the corresponding isoquinoline‐1,3,4(2H)‐trione derivative by the oxidation with PCC was achieved.     

Synthesis of 1‐Acyl‐3,4‐dihydroquinazoline‐2(1H)‐thiones by Cyclization of N‐[2‐(Isothiocyanatomethyl)phenyl] Amides Generated in situ from N‐[2‐(Azidomethyl)phenyl] Amides

An efficient method for the preparation of 1‐acyl‐3,4‐dihydroquinazoline‐2(1H)‐thiones 5 has been developed. The reaction of N‐[2‐(azidomethyl)phenyl] amides 3 , easily prepared by a three‐step sequence starting with (2‐aminophenyl)methanols, with Ph₃P, followed by CS₂, allowed generation of N‐[2‐(isothiocyanatomethyl)phenyl]‐amide intermediates 4 , which underwent cyclization on treatment with NaH to furnish the corresponding desired products in generally good yields.     

One‐Pot Synthesis of 4‐(Alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐ dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones via a Multicomponent Reaction

An effective route to novel 4‐(alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones 10 is described (Scheme 2). This involves the reaction of an enamine, derived from the addition of a primary amine 5 to 1,4‐diphenylbut‐2‐yne‐1,4‐dione, with an arenesulfonyl isocyanate 7 . Some of these pyrrolones 10 exhibit a dynamic NMR behavior in solution because of restricted rotation around the C? N bond resulting from conjugation of the side‐chain N‐atom with the adjacent α,β‐unsaturated ketone group, and two rotamers are in equilibrium with each other in solution ( 10 ? 11 ; Scheme 3). The structures of the highly functionalized compounds 10 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS), by elemental analyses, and, in the case of 10a , by X‐ray crystallography. A plausible mechanism for the reaction is proposed (Scheme 4).     

Synthesis of Nitrogen‐Containing Derivatives of (18α,19β)‐19‐Hydroxy‐2,3‐secooleanane‐2,3,28‐trioic Acid 28,19‐Lactone

The object of this study is the interaction of the cyclic anhydride 2 of (18α,19β)‐19‐hydroxy‐2,3‐secooleanane‐2,3,28‐trioic acid 28,19‐lactone ( 1 ) with primary and secondary amines. It was shown that the products of steric control (the corresponding 2‐amino‐2‐oxo‐3‐oic acids=2‐amides) were formed solely upon the opening of the anhydride cycle by secondary amines (Scheme 2), whereas the interaction with primary amines yielded a mixture of isomeric amides (Scheme 10). In the latter case, the solvent provided a noticeable effect on the reaction selectivity, which was demonstrated in the case of 4‐methoxybenzylamine. The interaction between the resulting 3‐amides and oxalyl chloride yielded the corresponding cyclic imides, whereas under these conditions, 2‐amides formed spiropyrrolidinetriones (Scheme 4).     

Copper(II) bromide,nitrate and perchlorate complexes with sterically demanding N‐(6‐methylpyridin‐2‐yl)acetamide ligands

Functionalized acid amides are widely used in biology, medicine, environmental chemistry and many other areas. Among them, pyridine‐substituted amides, in particular N‐(pyridin‐2‐yl)acetamide and its derivatives, play an important role due to their excellent chelating properties. The donor properties of these ligands can be effectively modified by introducing electron‐donating substituents (e.g. alkyl groups) into the heterocycle. On the other hand, substituents in the α‐position of the pyridine ring can create steric hindrance, which significantly influences the coordination number and geometry. To achieve a better understanding of these effects, copper(II) complexes with sterically demanding N‐(6‐methylpyridin‐2‐yl)acetamide ligands (L ) and monoanions of different size, shape and coordination ability have been chosen as model compounds. The crystal structures of three new compounds, bromidobis[N‐(6‐methylpyridin‐2‐yl‐κN )acetamide‐κO ]copper(II) bromide, [CuBr(C₈H₁₀N₂O)]Br, (I), aquabis[N‐(6‐methylpyridin‐2‐yl‐κN )acetamide‐κO ]copper(II) dinitrate, [Cu(C₈H₁₀N₂O)(H₂O)](NO₃)₂, (II), and aquabis[N‐(6‐methylpyridin‐2‐yl‐κN )acetamide‐κO ]copper(II) bis(perchlorate), [Cu(C₈H₁₀N₂O)(H₂O)](ClO₄)₂, (III), have been determined by single‐crystal X‐ray diffraction analysis. It has been shown that the presence of the 6‐methyl group results in either a distorted square‐pyramidal or a distorted trigonal–bipyramidal coordination geometry around the Cu^II centres instead of the typical octahedral geometry observed when the methyl substituent is absent or occupies any other position on the pyridine ring. Moreover, due to the steric hindrance provided by the L ligands, only the bromide ligand, the smallest of the series, enters into the first coordination sphere of the Cu^II ion in (I). In (II) and (III), the vacant coordination site of the Cu^II ion is occupied by a water molecule, while the nitrate and perchlorate anions are not involved in coordination to the metal centre. The structures of (I)–(III) are characterized by the presence of one‐dimensional infinite chains formed by hydrogen bonds of the types N—H…Br [in (I)], N—H…O and O—H…O [in (II) and (III)] between the amide groups of the L ligands, the coordinated water molecules and the uncoordinated anions. The hydrogen‐bonded chains are further interconnected through π–π stacking interactions between the pyridine rings of the L ligands, with approximate interplanar separations of 3.5–3.6 Å.     

Design,Synthesis, and Evaluation of 3‐((4‐(t‐Butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones as Neuraminidase Inhibitors

A series of novel 3‐((4‐(t‐butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones ( 7a – 7z ) were designed, synthesized and evaluated for their ability of inhibiting neuraminidase (NA) of in?uenza H1N1 virus. Some compounds displayed moderate influenza NA inhibitory activity. Compound 7l with the scaffold of 2‐(2‐(2‐methoxybenzylidene)hydrazinyl)thiazole was the best one, exhibiting moderate NA inhibitory activity with IC₅₀ of 44.66 µmol/L. Structure‐activity relationship showed that compounds with methoxy or hydroxy groups at the ortho position, fluorine and nitro groups at the meta position and chlorine and bromine groups at the para position of phenyl ring were more active. Docking study indicated that compound 7l has important interactions with some key residues (including Asp151, Glu119, Arg292, Tyr406, and Asn347) and binds to 430‐cavity adjacent to NA active site.     

Synthesis and properties of phosphorus containing polyester‐amides derived from 1,4‐bis(3‐aminobenzoyloxy)‐2‐(6‐oxido‐6H‐dibenz〈c,e〉〈1,2〉oxaphosphorin‐6‐yl) phenylene

A series of polyester‐amides that contain phosphorus were synthesized by low temperature solution condensation of 1,4‐bis(3‐aminobenzoyloxy)‐2‐(6‐oxido‐6H‐dibenz〈c,e〉〈1,2〉oxaphosphorin‐6‐yl) phenylene (III) with various aromatic acid chlorides in N‐methyl pyrrolidone (NMP). All polyester‐amides are amorphous and readily soluble in many organic solvents such as dimethylacetamide (DMAc), NMP, dimethylsulfoxide, and dimethylformamide at room temperature or on heating. Light yellow and flexible films of these polyester‐amides could be cast from the DMAc solutions. The polymers with an inherent viscosity of 0.26–0.72 dL/g were obtained in quantitative yields. These polyester‐amides have good mechanical properties (G′ of ∼ 10⁹ Pa up to 200°C) and good thermal and flame retardant properties. The glass transition temperatures of these polyester‐amides ranged from 250 to 273°C. The degradation temperatures (T_d 5%) in nitrogen ranged from 466 to 478°C and the char yields at 800°C were 59.6–65.2%. The limiting oxygen indexes of these polyester‐amides ranged from 35 to 43. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 891–899, 1999     

Synthesis and Cytotoxicity of 6‐Pyrrolidinyl‐2‐(2‐Substituted Phenyl)‐4‐Quinazolinones

In our continuing search for potential anticancer candidates, 2‐(3‐methoxyphenyl)‐6‐pyrrolidinyl‐4‐quinazolinone ( JJC‐1 ) was selected as the lead compound. Starting 5‐pyrrolidinyl‐2‐aminobenzamide was prepared using standard methodology from 5‐chloro‐2‐nitrobenzoic acid by reaction with SOCl₂, NH₃, pyrrolidine, and H₂. The starting benzamide then was reacted with 2‐substituted benzaldehyde or benzoyl chloride in N,N‐dimethylacetamide (DMAC) in the presence of NaHSO₃ at 150 °C. Thermal cyclodehydration/dehydrogenation gave the target 6‐pyrrolidinyl‐2‐(2‐substituted phenyl)‐4‐quinazolinones ( 15–22 ). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI‐3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI‐3 cells, with EC₅₀ values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.     

Copper‐Catalyzed Bis(methoxycarbonyl)carbene Reactions of α,β‐Unsaturated Carboxamides

The [Cu(acac)₂]‐catalyzed reactions of α,β‐unsaturated carboxamides with dimethyl diazomalonate yielded dihydrofuran derivatives by a 1,5‐electrocyclic reaction at C(β), and butadiene derivatives by carbene addition reaction at C(α) (Schemes 4 and 5; Table). Phenyl substituents at the N‐atom of the amides seem to be effective on the reaction pathways (Table).     

Preparation,Structural Characterization,and Antifungal Activities of Complexes of Group 12 Metals with 2‐Acetylpyridine‐ and 2‐Acetylpyridine‐N‐oxide‐4N‐phenylthiosemicarbazones

Reaction of group 12 metal dihalides in ethanolic media with 2‐acetylpyridine ⁴N‐phenylthiosemicarbazone ( H4PL ) and 2‐acetylpyridine‐N‐oxide ⁴N‐phenylthiosemicarbazone ( H4PLO ) afforded the compounds [M(H4PL)X₂] (X = Cl, Br, M = Zn, Cd, Hg; X = I, M = Zn, Cd) ( 1–8 ), [Hg(4PL)I]₂ ( 9 ) and [M(H4PLO)X₂] (X = Cl, Br, I, M = Zn, Cd, Hg) ( 10–18 ). H4PL , H4PLO and their complexes were characterized by elemental analysis and by IR and ¹H and ¹³C NMR spectroscopy (and the cadmium complexes by ¹¹³Cd NMR spectroscopy), and H4PL , H4PLO , ( 5 · DMSO) and ( 9 ) were additionally studied by X‐ray diffraction. H4PL is N,N,S‐tridentate in all its complexes, including 9 , in which it is deprotonated, and H4PLO is in all cases O,N,S‐tridentate. In all the complexes, the metal atoms are pentacoordinate and the coordination polyhedra are redistorted tetragonal pyramids. In assays of antifungal activity against Aspergillus niger and Paecilomyces variotii, the only compound to show any activity was [Hg(H4PLO)I₂] ( 18 ).     

Poly(methacrylamide‐co‐2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) hydrogels: Investigation of pH‐ and temperature‐dependent swelling characteristics and their characterization

Novel poly(methacrylamide‐co‐2‐acrylamido‐2‐methyl‐ 1‐propanesulfonic acid) (poly(MAAm‐co‐AMPS)) hydrogels were synthesized by free radical polymerization of methacrylamide (MAAm) and 2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid (AMPS) in deionized water at 60 °C by using ammonium peroxydisulfate (APS), N,N′‐methylenebisacrylamide (MBAAm) and N,N,N′,N′‐tetramethylethylenediamine (TEMED) as initiator, crosslinker, and activator, respectively. To investigate the effects of feed content on the pH‐ and temperature‐dependent swelling behavior of poly(MAAm‐co‐AMPS), molar ratio of MAAm to AMPS in feed was varied from 90/10 to 10/90. Structural characterization of gels was performed by Fourier transform infrared (FTIR) spectroscopy using attenuated total reflectance (ATR) technique. Thermal and morphological characterizations of gels were performed by thermogravimetric analysis (TGA) and scanning electron microscopy (SEM), respectively. Although an apparent pH‐sensitivity was not observed for the poly(MAAm‐co‐AMPS) gels during the swelling in different buffer solutions, their temperature‐sensitivity became more evident with the increase in AMPS content of copolymer. Thermal stability of poly(MAAm‐co‐AMPS) gels increased with MAAm content. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2010     

Fluorine in Peptides: The Synthesis of α‐Fluoro‐β‐Amino Dipeptides by Direct Deoxofluorination/Rearrangement of N‐Seryl Dipeptides

This article describes the stereo‐ and regioselectivity of the deoxofluorination of N‐terminal dipeptides bearing a serine residue to generate, after rearrangement, α‐fluoro‐β‐amine‐terminated dipeptides. The ratio of the rearranged α‐fluorinated regioisomer is increased, relative to the non‐rearranged β‐fluoro isomer, with N‐alkylated amides. Otherwise, an intramolecular H‐bond between the free amine and the amide NH suppresses formation of the key aziridinium intermediate required for α‐fluorination. N‐Methyl and N‐allyl amides give exclusively α‐fluorination products. Subsequent deprotection of the N‐allyl amide to give a α‐fluoro‐β‐amino dipeptide product is demonstrated.     

Synthesis of 2‐Mercaptobenzaldehyde, 2‐Mercaptocyclohex‐1‐enecarboxaldehydes and 3‐Mercaptoacrylaldehydes

A novel one‐pot approach for the preparation of 2‐mercaptobenzaldehyde, 2‐mercaptocyclohex‐1‐enecarboxaldehydes and 3‐mercaptoacrylaldehydes [(Z)‐3‐mercapto‐2‐methyl‐3‐phenylacrylaldehyde, 3‐mercapto‐3‐(o‐tolyl)acrylaldehyde)] starting from ortho‐bromobenzaldehyde, 2‐chlorocyclohex‐1‐enecarbaldehydes, (Z)‐3‐chloro‐2‐methyl‐3‐phenylacrylaldehyde and 3‐chloro‐3‐(o‐tolyl)acrylaldehyde is reported. The reaction of sulfur with the Grignard reagent of the acetal for the protection of the aldehyde group affords the title compounds through hydrolysis with dilute hydrochloric acid in high yields.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Synthesis of Some New 2‐Oxo‐N‐[(10H‐phenothiazin‐10‐yl)alkyl] Derivatives of Azetidine‐1‐carboxamides

The synthesis of a new series of 4‐aryl‐3‐chloro‐2‐oxo‐N‐[3‐(10H‐phenothiazin‐10‐yl)propyl]azetidine‐1‐carboxamides, 4a – 4m , is described. Phenothiazine on reaction with Cl(CH₂)₃Br at room temperature gave 10‐(3‐chloropropyl)‐10H‐phenothiazine ( 1 ), and the latter reacted with urea to yield 1‐[3‐(10H‐phenothiazin‐10‐yl)propyl]urea ( 2 ). Further reaction of 2 with several substituted aromatic aldehydes led to N‐(arylmethylidene)‐N′‐[3‐(phenothiazin‐10‐yl)propyl]ureas 3a – 3m , which, on treatment with ClCH₂COCl in the presence of Et₃N, furnished the desired racemic trans‐2‐oxoazetidin‐1‐carboxamide derivatives 4a – 4m . The structures of all new compounds were confirmed by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, FAB mass spectrometry, and chemical methods.     

Synthesis of (4Z)‐4‐(Arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones by the Reaction of Ethyl (2Z)‐3‐Aryl‐2‐isothiocyanatoprop‐2‐enoates with Organolithium Compounds

A convenient one‐pot method for the preparation of (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones 2 and 3 from ethyl (2Z)‐3‐aryl‐2‐isothiocyanatoprop‐2‐enoates 1 , which can be easily prepared from ethyl 2‐azidoacetate and aromatic aldehydes, has been developed. Thus, these α‐isothiocyanato α,β‐unsaturated esters were treated with organolithium compounds, including lithium enolates of acetates, to provide 5‐substituted (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones, 2 , and 2‐[(4Z)‐(4‐arylmethylidene)‐5‐ethoxy‐2‐thioxo‐1,3‐oxazolidin‐5‐yl]acetates, 3 .     

Catalytic Enantioselective Synthesis of a 3‐Aryl‐3‐benzyloxindole (=3‐Aryl‐3‐benzyl‐1,3‐dihydro‐2H‐indol‐2‐one) Exhibiting Antitumor Activity

A palladium‐catalyzed intramolecular α‐arylation of an amide in the presence of a bulky chiral N‐heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)‐6‐chloro‐3‐(3‐chlorobenzyl)‐1,3‐dihydro‐3‐(3‐methoxyphenyl)‐2H‐indol‐2‐one ((R)‐ 5 ). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)‐ 5 was obtained with an overall yield of 45% and with 96% enantioselectivity.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.