Synthesis of Novel 1‐(5‐(Benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea Derivatives and Evaluation of Their Antimicrobial Activities

A new series of 1‐(5‐(benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea derivatives ( 1a – j ) were designed and synthesized. For the first time, (i) a new process was developed for N‐methylation of 1,3,4‐thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′‐tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds ( 1a – j ) were investigated for their antimicrobial activities. The tested compounds ( 1a – j ) were exhibited moderate to excellent antibacterial activities against both Gram‐positive and Gram‐negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b , 1d , 1h , and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4‐thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data.     

Efficient Total Synthesis of (S)‐14‐Azacamptothecin

An efficient total synthesis of (S)‐14‐azacamptothecin has been accomplished in 10 steps and 56 % overall yield from 5H‐pyrano[4,3‐d]pyrimidine 8 . A mild Hendrickson reagent‐triggered intramolecular cascade cyclization, a highly enantioselective dihydroxylation, and an efficient palladium‐catalyzed transformation of an O‐allyl into N‐allyl group are the key steps in the synthesis. This work provides a much higher overall yield than the previous achievement and shows sound flexibility for the further applications that will lead to new bioactive analogues.     

Reactions of 4,5‐Dihydro‐1,4‐Benzothiazepin‐3(2H)‐one 1,1‐Dioxide and 1,5‐Dihydro‐4,1‐Benzothiazepin‐2(3H)‐one 4,4‐Dioxide Derivatives with Vilsmeier Reagent and DMFDMA

The regioselectivity of the interaction between isomeric 4,5‐dihydro‐1,4‐benzothiazepin‐3(2H)‐one 1,1‐dioxide and 1,5‐dihydro‐4,1‐benzothiazepin‐2(3H)‐one 4,4‐dioxide derivatives with the Vilsmeier reagent and DMFDMA (N,N‐dimethylformamide dimethylacetal) has been investigated. The structures of synthesized compounds are confirmed by ¹H, ¹³C NMR, elemental analysis, and X‐ray data.     

Synthesis of poly(m‐phenylene) and poly(m‐phenylene)‐block‐ poly(3‐hexylthiophene) with low polydispersities

Well‐defined poly(m‐phenylene) (PMP), which is poly(1,3‐dibutoxy‐m‐phenylene), was successfully synthesized via Grignard metathesis polymerization. PMP with a reasonably high number‐average molecular weight (M_n) of 25,900 and a very low polydispersity index of 1.07 was obtained. The polymerization of a Grignard reagent monomer, 1‐bromo‐2,4‐dibutoxy‐5‐chloromagnesiobenzene, proceeded in a chain‐growth manner, probably due to the meta‐substituted design producing a short distance between the MgCl and Br groups and thereby making a smooth nickel species (? C? Ni? C? ) transfer to the intramolecular chain end (? C? Ni? Br) over a benzene ring. PMP showed a good solubility in the common organic solvents, such as tetrahydrofuran, CH₂Cl₂, and CHCl₃. Furthermore, a new block copolymer comprised of PMP and poly(3‐hexylthiophene) was also prepared. The tapping mode atomic force microscopy image of the surface of the block copolymer thin film on a mica substrate showed a nanofibril morphology with a clear contrast. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011.     

A Convenient Oxidation of 5‐Substituted Pyrazol‐3(2H)‐Ones Into Methyl 2‐Alkynoates Using Poly[4‐(Diacetoxyiodo)Styrene]

An operationally simple oxidation of 5‐substituted pyrazol‐3(2H)‐ones to the corresponding methyl‐2‐alkynoates in good yields with a mediated poly[4‐(diacetoxyiodo)styrene] system in methanol and acetonitrile at room temperature was carried out. The polymeric reagent can be regenerated and reused as an environmentally benign reagent.     

Transformation of schiff bases derived from alpha‐naphthaldehyde. Synthesis,spectral data and biological activity of new‐3‐aryl‐2‐(α‐naphtyl)‐4‐thiazolidinones and N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines

New N‐aryl substituted 2‐(α‐naphthyl)‐4‐thiazolidinones were prepared by the cyclocondensation of α‐mercaptoacetic acid and corresponding N‐(α‐naphthyliden)anilines. The same starting materials were utilized to obtain a new series of N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines, which was synthesized through an addition of the Grignard reagent (allylmagnesium bromide) to the double bond C?N of the aldimines. The antichagasic and trichomonacidal in vitro activity, as well as, the antifungal and cytotoxic properties of some of these compounds were evaluated.     

Novel immonium type peptide coupling reagent: 5‐(1H‐benzotriazol‐1‐yloxy)‐3,4‐dihydro‐1‐methyl 2H‐pyrrolium hexachloroantimonate (BDMP® )

A novel immonium type coupling reagent, 5‐(1H‐benzotriazol‐1‐yloxy)‐3,4‐dihydro‐1‐methyl 2H‐pyrrolium hexachloroantimonate (BDMP) has been designed, synthesized and utilized to synthesize oligopeptides and biologically active peptide both in solution and solid phase with satisfactory yield, low racemization and fast reaction rate. The estimation of racemization and the influence of several reaction parameters were studied by HPLC method using the model reaction: Z‐Gly‐Phe‐OH + Val‐OMe·HCl·Z‐Gly‐D/L‐Phe‐Val‐OMe. It was shown that the reactivity of BDMP was much higher and the racemization was much lower than those of HOBt‐based ‘onium’ reagents, even though its analogues BOMI. To further verified me effectiveness of BDMP, Leu‐enkephalin was synthesized both in solution and solid phase using BDMP as coupling reagent. The proposed mechanism was also speculated.     

On the Reactions of Furan‐2,3‐diones with Oxindole (=1,3‐Dihydro‐2H‐indol‐2‐one) and Lawesson Reagent. Synthesis of New 1,3‐Dihydro‐2H‐indol‐2‐ones,Bis‐furanones,and Bis‐pyrrolones

Lactone analogues of 3‐substituted oxindoles (=1,3‐dihydro‐2H‐indol‐2‐ones) and nonbenzoid oxa‐analogous isoindigoid or nonbenzoid isoindigoid dyes were prepared by the reactions of furan‐2,3‐diones with oxindole and Lawesson reagent (Schemes 1 and 3), respectively. So, new derivatives of 2‐oxobutanoic acid, bis‐furanone, and bis‐pyrrolone, which are potentially biologically active compounds, were synthesized for the first time.     

Two 17‐hydroxy‐9(10→5)‐abeo‐estr‐4‐ene‐3,10‐diones

(5S,9S,17S)‐17‐Hydroxy‐9(10→5)‐abeo‐estr‐4‐ene‐3,10‐dione, C₁₈H₂₆O₃, (II), and (5R,9R,17S)‐17‐hydroxy‐9(10→5)‐abeo‐estr‐4‐ene‐3,10‐dione, C₁₈H₂₆O₃, (III), are equimolecular products of the Fe^II‐induced transposition of 10β‐hydro­peroxy‐17β‐hydroxyestr‐4‐en‐3‐one, (I). With respect to reagent mol­ecules, the configuration at C9 is retained for (II) while it is inverted in (III). The conformations of the five‐ and six‐membered rings are compared.     

Kinetic Resolution of Racemic Secondary Benzylic Alcohols by the Enantioselective Esterification Using Pyridine‐3‐carboxylic Anhydride (3‐PCA) with Chiral Acyl‐Transfer Catalysts

Pyridine‐3‐carboxylic anhydride (3‐PCA) was found to function as an efficient coupling reagent for the preparation of carboxylic esters from various carboxylic acids with alcohols under mild conditions by a simple experimental procedure. This novel condensation reagent 3‐PCA was applicable not only for the synthesis of achiral carboxylic esters catalyzed by 4‐(dimethylamino)pyridine (DMAP) but also for the production of chiral carboxylic esters by the combination of chiral nucleophilic catalyst, such as tetramisole (=2,3,5,6‐tetrahydro‐6‐phenylimidazo[2,1‐b][1,3]thiazole) derivatives. An efficient kinetic resolution of racemic benzylic alcohols with achiral carboxylic acids was achieved by using 3‐PCA in the presence of (R)‐benzotetramisole ((R)‐BTM), and a variety of optically active carboxylic esters were produced with high enantiomeric excesses by this new chiral induction system without using a tertiary amine.     

The synthesis,characterization and polycondensation of metal‐containing diols: crystal structure of [(η5‐C5H5)(CO)2Fe(CH2)3O‐{2,6‐(CH2OH)2‐4‐CH3?C6H2}]

The synthesis of two new transition‐metal‐containing polyesters is described. The precursors are bifunctional organometallic monomers that were synthesized using 2,6‐bis(hydroxymethyl)‐p‐cresol as the key reagent. This was achieved by simple coupling reactions between the appropriate organometallic alkyl halide and the cresol reagent. Polycondensation reactions were carried out with terephthaloyl chloride using ambient temperature solution techniques. The new low molecular weight oligomeric polyesters were characterized using Fourier transform infrared and ¹HNMR spectroscopy, differential scanning calorimetry, thermogravimetric analysis and size‐exclusion chromatography analyses. Copyright © 2002 John Wiley & Sons, Ltd.     

Thionation of N‐(ω‐Halogenoalkyl)‐Substituted Amides with Lawesson's Reagent: Facile Synthesis of 4,5‐Dihydro‐1,3‐thiazoles and 5,6‐Dihydro‐4H‐1,3‐thiazines

The thionation and cyclization of N‐(ω‐halogenoalkyl)‐substituted amides (and related compounds) with Lawesson's reagent (LR=2,4‐bis(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphosphetane 2,4‐disulfide) has been investigated. Treatment of the amides 1 with LR gave the corresponding thioamides 2 in moderate to good yields (Table). The latter, upon treatment with base, afforded, either in a separate step or in a one‐pot procedure, the cyclized title compounds, i.e., the 4,5‐dihydro‐1,3‐thiazoles 3 or the corresponding 5‐6‐dihydro‐4H‐thiazines 4 via dehydrohalogenation.     

Polymeric [dihydrobis(pyrazol‐1‐yl)borato]potassium(I) and three dihydrobis(pyrazol‐1‐yl)borate–magnesium(I) compounds obtained by disproportionation of the Grignard reagent

Reaction of the Grignard reagent with polydentate nitrogen‐donor ligands yields new species with rare magnesium coordination and possible catalytic activity. In the first of the title compounds, poly[[μ₄‐dihydrobis(pyrazol‐1‐yl)borato‐κ²N,N′]potassium(I)], [K(C₆H₈BN₄)]_n, (I), polymeric chains form a two‐dimensional network in the [100] plane. Each potassium ion is coordinated by four N atoms of pyrazolyl ligands, while weak (μ‐BH)...K⁺ interactions additionally stabilize the structure. The K and B atoms both lie on a mirror plane. In three new structures obtained by disproportionation of the Grignard reagent, each Mg atom is bound to a κ²N,N′‐type ligand, forming the basal plane, and tetrahydrofuran molecules occupy the axial positions. Di‐μ‐chlorido‐bis[dihydridobis(pyrazol‐1‐yl)borato]tris(tetrahydrofuran)dimagnesium(II), [Mg₂(C₆H₈BN₄)₂Cl₂(C₄H₈O)₃], (II), adopts a dimeric structure with μ‐Cl—Mg interactions. One of the Mg atoms has an octahedral coordination, while the other has a distorted square‐pyramidal environment. However, in the bis‐chelate compounds bis[dihydridobis(pyrazol‐1‐yl)borato‐κ²N,N′](tetrahydrofuran‐κO)magnesium(II), [Mg(C₆H₈BN₄)₂(C₄H₈O)], (III), and bis[dihydridobis(pyrazol‐1‐yl)borato‐κ²N,N′]bis(tetrahydrofuran‐κO)magnesium(II), [Mg(C₆H₈BN₄)₂(C₄H₈O)₂], (IV), the Mg atoms have square‐pyramidal and octahedral environments, respectively. The Mg atom in (IV) lies on an inversion centre.     

A Novel and Facile Synthesis of 2‐(Benzofuran‐2‐yl)benzo[h]quinoline‐3‐carboxylic Acid Derivatives

A simple and concise approach for the synthesis of a series of new heterocyclic systems of 2‐(benzofuran‐2‐yl)benzo[h]quinoline‐3‐carboxylic acid derivatives ( 3a–3g ) is described. The synthetic strategy features the one‐pot reaction of ethyl 2‐(chloromethyl)benzo[h]quinoline‐3‐carboxylate ( 2 ) with various substituted salicylaldehydes as well as 2‐hydroxy‐1‐naphthaldehyde as a key step. The substrate 2 was prepared in good yield by a mild, efficient and direct reaction of 1‐naphthylamine ( 1 ) with Vilsmeier‐Haack reagent. The structures of all the new compounds were identified by spectral data and elemental analysis.     

Synthesis of New Heterocyclic Compounds Using 2‐(3,3‐dimethyl‐1H‐pyrroloisoquinolin‐2(3H)‐ylidene)malonaldehydes

Isoquinolin‐5‐ylhydrazinium chloride 13 and 5‐bromoisoquinolin‐8‐ylhydrazinium chloride 14 were converted via Fischer syntheses with 3‐methylbutan‐2‐one into indolenines, 2,3,3‐trimethyl‐3H‐pyrrolo[2,3‐f]isoquinoline 15 and 5‐bromo‐2,3,3‐trimethyl‐3H‐pyrrolo[3,2‐h]isoquinoline 16 , respectively. Exposure of the indolenines to the Vilsmeier reagent produced diformyl compounds 17 and 18 , which reacted with arylhydrazines to give the corresponding pyrazoles 19a , 19b , 19c , 19d , 19e , 19f , 19g , 19h , 19i and 20a , 20b , 20c , 20d , 20e , 20f , 20g . Reaction of 17 with thiourea gave a pyrimidine‐2(1H)‐thione 23 or with hydroxylamine hydrochloride, an isoxazole 24 .     

Enantiospecific Synthesis of (R)‐3‐Amino‐4‐(2,4,5‐trifluorophenyl)butanoic Acid Using (S)‐Serine as a Chiral Pool

Starting from (S)‐serine, a new method was developed for the synthesis of the β‐amino acid part of sitagliptin in ten steps and with an overall yield of 30%. The crucial step of the synthesis was the ring opening of N‐ and O‐protected (R)‐aziridin‐2‐methanol with (2,4,5‐trifluorophenyl)magnesium bromide to give N‐ and O‐protected (R)‐2‐amino‐3‐(2,4,5‐trifluorophenyl)propan‐1‐ol.     

Synthesis of New Chiral Derivatives of N,N′‐Dimethylpropyleneurea (DMPU) and Examination of Their Influence on the Regio‐ and Enantioselectivity of Addition of 2‐(1,3‐Dithianyl)lithium to Cyclohex‐2‐en‐1‐one

The preparation of three new chiral derivatives of DMPU (N,N′‐dimethylpropyleneurea) is described (Schemes 2–4); one type of derivative carries 1‐phenylethyl or 1‐cyclohexylethyl groups at the N‐atoms of the tetrahydropyrimidin‐2(1H)‐one ring ( 2 and 4 ), another type of derivative is substituted at C(4) and C(6) of the heterocyclic ring ( 7 ). The potential of these chiral Lewis bases as promoters in the regio‐ and/or enantioselective addition of 2‐(1,3‐dithianyl)lithium to cyclohex‐2‐en‐1‐one was explored; they are all unable to effect enantioselective addition; the derivatives with branched substituents at the N‐atoms do not shift the addition mode from 1,2 to 1,4, while the 3,4,5,6‐tetrahydro‐1,3,4,6‐tetramethylpyrimidin‐2(1H)‐one does (Scheme 5). The results provide useful information regarding the nature of the nucleophilic organolithium reagent: obviously, the steric hindrance to Li complexation on the CO O‐atom of the tetrahydropyrimidin‐2(1H)‐one by branched substituents at N‐atoms (cf. X‐ray crystal structure of 2 in the Fig.) prevents solvent‐separated‐ion‐pair (SSIP) formation; this was confirmed by PM3 and B3LYP/3‐21‐G(d)//PM3 calculations (Scheme 6).     

Synthesis of Three‐, Five‐, and Six‐Membered Heterocycles Derived from New β‐Amino‐α‐(trifluoromethyl) Alcohols

Nucleophilic trifluoromethylation of α‐imino ketones 2 , derived from arylglyoxal, with Ruppert–Prakash reagent (CF₃SiMe₃) offers a convenient access to the corresponding O‐silylated β‐imino‐α‐(trifluoromethyl) alcohols. In a ‘one‐pot’ procedure, by treatment with NaBH₄, these products smoothly undergo reduction and desilylation yielding the expected β‐amino‐α‐(trifluoromethyl) alcohols 4 . The latter were used as starting materials for the synthesis of diverse trifluoromethylated heterocycles, including aziridines 5 , 1,3‐oxazolidines 8 , 1,3‐oxazolidin‐2‐ones 9 , 1,3,2‐oxazaphospholidine 2‐oxides 10 , 1,2,3‐oxathiazolidine 2‐oxides 11 , and morpholine‐2,3‐diones 12 . An optically active 5‐(trifluoromethyl)‐substituted 1,3‐oxazolidin‐2‐one 9g was also obtained.     

A comparative study of conventional conditions versus microwave irradiation for the preparation of novel 1,2‐dihydro‐2‐imino‐7‐methyl‐1,6(6H)‐naphthyridin‐5‐ones

The synthesis of novel 1,6‐naphthyridines 6 with potential activity against tuberculosis is described using the reaction sequence 2←4←6. Depending on the ring N‐substitution of the 4‐alkylamino‐6‐methyl‐2(1H)‐pyridones 1 and 2 the electrophilic attack of the Vilsmeier reagent gives rise to the formation of the exocyclic N‐formyl derivatives 3 from 1 and the corresponding 3‐carbaldehydes 4 from 2. 1,2‐Dihydro‐2‐imino‐7‐methyl‐1,6(6H)‐naphthyridin‐5‐ones 6a‐j are prepared by the Knoevenagel reaction of 4 with CH‐acidic nitriles 5. These reactions are carried out using a comparative study of conventional conditions (room temperature or reflux) versus microwave irradiation.     

Selective Pre-concentration and Solid Phase Extraction of Mercury（Ⅱ） from Natural Water by Silica Gel-loaded （E）-N-（1-Thien-2＇-ylethylidene）-1,2-phenylenediamine Phase

Silica gel-loaded （E）-N-（1-thien-2＇-ylethylidene）-1,2-phenylenediamine （TEPDA） phase was synthesized based on physical adsorption approaches. The stability of a chemically modified TEPDA especially in concentrated hydrochloric acid that was then used as a recycling and preconcentration reagent allowed the further uses of silica gel-loaded immobilized TEPDA phase. The application of this silica gel-loaded phase to sorption of a series of metal ions was performed by using different controlling factors such as the pH of the metal ion solution and the equilibration shaking time by the static technique. This difference was interpreted on the basis of selectivity incorporated in these sulfur containing silica gel-loaded TEPDA phases. Hg（Ⅱ） was found to exhibit the highest affinity towards extraction by these silica gel-loaded TEPDA phases. The pronounced selectivity was also confirmed by the determined distribution coefficients （Kd） of all the metal ions, showing the highest value reported for mercury（Ⅱ） extraction by the silica gel immobilized TEPDA phase. The potential applications of the silica gel immobilized TEPDA phase to selective extraction of mercury（Ⅱ） from aqueous solution were successfully accomplished and preconcentration of low concentration of Hg（Ⅱ） （30 pg·mL^-1） from natural tap water with a preconcentration factor of 200 for Hg（Ⅱ） off-line analysis was conducted by cold vapor atomic absorption analysis.