Synthesis of 1<Emphasis Type="Italic">H</Emphasis>-1,3-benzimidazoles,benzothiazoles and 3<Emphasis Type="Italic">H</Emphasis>-imidazo[4,5-c]pyridine using DMF in the presence of HMDS as a reagent under the transition-metal-free condition

An operationally simple method for synthesis of benzimidazole and 3H-imidazo[4,5-c]pyridine from o-phenylenediamine or pyridine-3, 4-diamine and N,N-dimethylformamide (DMF) in the presence of hexamethyldisilazane (HMDS) as a reagent is described. To evaluate the scope of application of this reagent, it was also used to prepare benzothiazole, 1H-perimidine, and benzoxazole, which was successful for benzothiazole and 1H-perimidine but benzoxazole was not formed. This reaction complies with the principles of green chemistry as it does not use toxic solvents, transition metals, or strong acids. The products are obtained in moderate to excellent yields.     

Prototropic equilibrium in 1(11)<Emphasis Type="Italic">H</Emphasis>-2, 3, 4, 5-tetrahydro[1, 3]diazepino[1, 2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole,synthesis and pharmacological properties of its <Emphasis Type="Italic">N</Emphasis>-substituted derivatives

Based on the X-ray crystallography and ¹H NMR spectroscopy data and quantum chemical studies, it was found that 1(11)H-2, 3, 4, 5-tetrahydro[1, 3]diazepino[1, 2-a]benzimidazole (1) exists almost exclusively in the 1H-prototropic form. To prepare the fixed 11H-diazepinobenzimidazole forms of 1, 1-R-2-(4-chlorobutylamino)benzimidazoles (R = Me, N=CHAr) were synthesized, which underwent thermal cyclization with the formation of a mixture of 11-Rsubstituted diazepine 1 and 1-R-2-(pyrrolidin-1-yl)benzimidazole. Alkylation of diazepine 1 in a neutral medium regioselectively gave 11-R-diazepinobenzimidazoles in high yield. Their 1-substituted isomers were obtained by carrying out this reaction in the system NaH—THF. The N(11)-derivatives of diazepinobenzimidazole 1 were found to inhibit dipeptidyl peptidase 4 (DPP-4), but less actively than a comparator drug sitagliptin. The compounds under study did not exhibit antiglycation action in vitro and virtually did not affect activity of α-glucosidase and glycogen phosphorylase. However, they are characterized by a strong antiaggregant effect, making these derivatives promising for further studies.     

Structure and Reactivity of Bicyclo[2.2.1]hept-2-ene-<Emphasis Type="Italic">endo</Emphasis>-5,<Emphasis Type="Italic">endo</Emphasis>-6-dicarboxylic (endic) Acid Hydrazide

Establishing of the structure of hydrazinolysis product obtained from bicyclo[2.2.1]hept-2-ene-endo-5, endo-6-dicarboxylic (endic) acid was performed by preparation of the compound under alternative conditions followed by comparison of the characteristics and spectral parameters of the resulting substances, and also by quantum-chemical calculations by the density functional method of the chemical shifts in ¹H and ¹³C NMR spectra of different reaction products. The X-ray diffraction analysis of the hydrazide was also carried out. The compound obtained was assigned a structure of N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide. The products were prepared by its reactions with arylsulfonyl chlorides, benzoyl chlorides, m-tolyl and p-toluene-sulfonyl isocyanates, phenyl isothiocyanate, with o-nitrobenzaldehyde, and oxiranes (1,2-epoxycyclohexane and 2,3-epoxypropylcarbazole). The aromatic sulfonamides, carboxamides, and ureas were epoxidized by performic acid obtained in situ from the formic acid and hydrogen peroxide. Products of [3+2]-cycloaddition of aryl azides to the strained double bond in the N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide and its derivatives. The structures of compounds obtained were confirmed by their IR, 1H and 13C NMR spectra.     

Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazo-[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-pyridin-2-one.     

Electrophilic heterocyclization of 6-alken(yn)ylsulfanyl-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(5<Emphasis Type="Italic">H</Emphasis>)-ones

6-Allylsulfanyl-1-arylpyrazolo[3,4-d]pyrimidin-4(5H)-ones react with iodine and sulfuric acid to give angular pyrazolothiazolopyrimidine derivatives. The reaction of 6-(prop-2-yn-1-ylsulfanyl)-1-(4-tolyl)-pyrazolo[3,4-d]pyrimidin-4(5H)-one with sulfuric acid gives angularly fused pyrazolo[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-4-one, whereas in the reaction with sodium methoxide linearly fused pyrazolo[3,4-d][1,3]-thiazolo[3,2-a]pyrimidin-4-one was formed. Linearly fused pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazole derivatives were also obtained by reaction of 1-aryl-6-(3-phenylprop-2-en-1-ylsulfanyl)pyrazolo[3,4-d]pyrimidin-4(5H)-ones with sulfuric acid.     

Stereochemistry of dihydroxylation of <Emphasis Type="Italic">N</Emphasis>-arylbicyclo[2.2.1]-hept-5-ene-<Emphasis Type="Italic">endo</Emphasis>- and -<Emphasis Type="Italic">exo</Emphasis>-2,3-dicarboximides

Stereochemistry of the oxidation of N-arylbicyclo[2.2.1]hept-5-ene-endo-and-exo-2,3-dicarboximides at the double bond with peroxyacetic acid generated in situ in the presence of sulfuric acid and with an anhydrous dioxane solution of peroxyacetic acid was studied. In both cases, the reaction was stereospecific, regardless of the substituent in the N-aryl group and configuration of the imide ring, but the reaction direction depended on the presence of water in the system. In the first case, the corresponding trans-5,6-dihydroxy derivatives were formed, while in the second, exo-5,6-epoxy derivatives. The oxidation of N-arylbicyclo[2.2.1]-hept-5-ene-endo-and-exo-2,3-dicarboximides with a solution of potassium permanganate in aqueous acetone gave the corresponding N-aryl-cis-5,6-dihydroxybicyclo[2.2.1]heptane-endo-and-exo-2,3-dicarboximides. The exo,cis,exo and exo,cis,endo configurations of the synthesized compounds were determined by ¹H NMR spectroscopy.     

Graphene oxide promoted synthesis of <Emphasis Type="Italic">p</Emphasis>-phenylenediamine antioxidants

Three p-phenylenediamine antioxidants (p-phenylenediamine-N,N,N′,N′-tetrapropionic acid tetramethyl ester, p-phenylenediamine-N,N,N′-tripropionic acid trimethyl ester, and p-phenylenediamine-N, N′-dipropionic acid dimethyl ester) were successfully synthesized via atom-economic aza-Michael addition of pphenylenediamine to methyl acrylate p-romoted by graphene oxide in water. The synthesized compounds were characterized by NMR, ESI-MS spectra, and elemental analyses. The effects of the solvent and graphene oxide on the reaction were investigated.     

Synthesis and reactions of 3-(3-ethoxycarbonyl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)propenic acid

The reaction of ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carboxylate with the malonic acid led to the formation (2E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-4-yl)propenic acid. In reactions of this acid chloride with 4-amino-5-aryl(hetaryl)-4H-1,2,4-triazole-3-thiols were obtained ethyl 4-[(E)-2-{3-aryl(hetaryl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl}ethenyl]-1-phenyl-1H-pyrazoe-3-carboxylates, with 5-aryltetrazoles, ethyl 4-[(E)-2-(5-aryl-1,3,4-oxadiazol-2-yl)-ethenyl]-1-phenyl-1H-pyrazole-3-carboxylates, with 1-(2-hydroxy-3,5-dimethylphenyl) followed by the Baker-Venkataraman rearrangement and the cyclization, ethyl 4-[(E)-2-(6,8-dimethyl-4-oxo-4Hchromen-2-yl)ethenyl]-1-phenyl-1H-pyrazole-3-carboxylate.     

1,3-dipolar cycloaddition of diazomethane to quinoid derivatives of pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole

Reactions of diazomethane with quinone mono(di)imines and methylidene quinone imines of pyrido[1,2-a]benzimidazole series occurs by the route of 1,3-dipolar cycloaddition and leads to the formation of quinoid compounds, in particular, previously unknown heterocyclic structures of indazolo[7',6':4,5]imidazo-[2,1-j]quinoline, indazolo[7',6':4,5]imidazo[2,1-e]acridine, indazolo[4',5':4,5]imidazo[2,1-j]quinoline, and indazolo[4',5':4,5]imidazo[2,1-e]acridine.     

Reactions of ethyl 6,6-dialkyl-8,9-dioxo-5,6,8,9-tetrahydrobenzo[<Emphasis Type="Italic">f</Emphasis>]pyrrolo[2,1-<Emphasis Type="Italic">a</Emphasis>]isoquinoline-10-carboxylates with <Emphasis Type="Italic">N</Emphasis>-nucleophiles

Reaction of enaminoesters, derivatives of 2,2-dialkyl-1,2,3,4-tetrahydrobenzo[f]isoquinoline, with oxalyl chloride leads to the formation of ethyl 6,6-dialkyl-8,9-dioxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-a]-isoquinoline-10-carboxylates. At reaction of the latter with ammonia and cyclic amines opening of pyrroledione cycle occurs and the formation of enaminoketoamides, and the reaction with o-phenylenediamine furnishes a fragment of benzimidazole. Hydroxylamine behaves as binucleophile and attacks not only lactam, but also the ester group, affording heterocyclic system of isoxazine-3,4,6-trione.     

Specific Features of <Emphasis Type="Italic">N</Emphasis>-Morpholinoethyl Methacrylate Synthesis

Methods for synthesis of N-morpholinoethyl methacrylate were compared. It was shown that the monomer produced by acylation of N-morpholinoethanol with methacrylic acid anhydride or methacryloyl chloride spontaneously polymerizes in storage. The possible reasons for the spontaneous polymerization of N-morpholinoethyl methacrylate produced by the acylation method were considered. The conditions in which a stable-in-storage monomer can be obtained in 86–88% yield by the method of re-esterification of methyl methacrylate with N-morpholinoethanol were determined.     

Synthesis and crystal structure of two Cu(II) complexes with benzimidazole ligands

Two new copper(II) complexes (I, II) with benzimidazole ligands have been synthesized and characterized by elemental analysis and X-ray single-crystal diffraction. Compound I is triclinic, P \(\bar 1\), a = 11.4205(6), b = 13.0956(7), c = 18.2305(9) Å, α = 85.960(1)°, β = 80.388(0)°, γ = 77.517(1)°, V = 2623.0(2) ų, Z = 2; compound II is monoclinic, C2/c, a = 24.2684(11), b = 17.5247(8), c = 19.3149(15) Å, β = 122.710(1)°, V = 6911.9(7) ų, Z = 4. In both compounds, Cu(II) atoms are coordinated by four benzimidazole nitrogen atoms in a slightly distorted tetrahedral fashion.     

Synthesis and piezoelectric properties of <Emphasis Type="Italic">N</Emphasis>-phthaloylglutamic acid derivatives

The (S,S)- and (R,R)-enantiomers of dimethyl 2,4-diphthalimidoglutarate were synthesized by nucleophilic substitution of bromine in dimethyl (2S,4RS)-4-bromo-N-phthaloyl-glutamate upon treatment with potassium phthalimide, followed by separation. The crystal structure of the obtained compounds was studied by X-ray diffraction. Crystals of enantiomerically pure dimethyl 4-hydroxy- and 4-phthalimido-N-phthaloylglutamates were found to possess a noticeable piezoelectric activity.     

Reaction of anthranilic acid 2-<Emphasis Type="Italic">N</Emphasis>-phenylhydrazide with cyclic anhydrides

In the reaction with cyclic anhydrides the anthranilic acid 2-N-phenylhydrazide depending on conditions yielded either anthranilic acid 2-N-acyl-2-N′-phenylhydrazides, 2-R-3-anilinoquinazolin-4(3H)-ones, or derivatives of 1-phenylpyridazino[3,2-b]quinazoline-2,10-dione.     

New general synthesis of benzo[4,5]imidazo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidine and benzo[4,5]imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>]quinazoline derivatives

The reactions of benzene-1,2-diamine with 5-substituted 2-(alkylsulfanyl)-4-methylpyrimidin-6(1H)-ones and 2-(propylsulfanyl)- and 5-iodo-2-(propylsulfanyl)-3,4-dihydroquinazolines at 175–185°C under solvent-free conditions unexpectedly afforded benzo[4,5]imidazo[1,2-a]pyrimidine, benzo[4,5]imidazo[2,1-b]-quinazoline, and 2,2′-(benzene-1,2-diyldiimino)bis[pyrimidin-4(3H)-ones]. The described reaction is the first example of synthesis of these heterocyclic systems by fusion of benzimidazole to pyrimidine or quinazoline and is likely to follow ANRORC mechanism.     

Derivatives of α,β-dehydroamino acids: V. Intramolecular cyclization of 2-{2-[(<Emphasis Type="Italic">Z</Emphasis>)-1-Benzamido-2-phenylvinyl]acetamidomethyl}benzimidazole

Reaction of 4-benzylidene-2-phenyl-1,3-oxazol-5(4H)-one with 2-(1H-benzimidazol-2-yl)ethaneamine led to the formation of 2-{2-[(Z)-1-benzamido-2-phenylvinyl]acetamidomethyl}benzimidazole that in a reaction with hexamethyldisilazane in DMF gave 5-benzylidene-1-(1H-benzimidazol-2-yl)-2-phenyl-3,5-dihydro-4H-imidazol-4-one. In the presence of K₂CO₃ in dioxane the reaction with hexamethyldisilazane resulted in the product of intramolecular addition, N-(4-benzyl-3-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]-benzimidazol-4-yl)benzamide     

Crystal and molecular structure of 3,5-dimethyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazolide of 3-O-acetyl ursolic acid

3,5-Dimethyl-1H-pyrazolide of 3-O-acetyl ursolic acid (II) is obtained in the course of the interaction of 3 O-acetyl ursolic acid acyl chloride (I) and 3,5-dimethyl-1H-pyrazole. The crystal structure of compound II is determined from the single crystal XRD data (150 K, Bruker X8 Apex CCD autodiffractometer, MoK _α radiation). The crystals are rhombic, the unit cell parameters are as follows: a = 10.6034(2) Å, b = 12.4096(2)Å, c = 24.5972(5)Å, P2₁2₁2₁ space group. The structure consists of discrete acentric molecules. When pyrazolide II is boiled in the alcohol alkali solution, secondary hydroxyl is deacetylated and 3,5-dimethyl-1H-pyrazolide of ursolic acid IV is formed. Compounds II and IV are studied by NMR spectroscopy.     

Fused Pyrimidine Systems: XVII. Imidazo- and Pyrimidopyrido[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(3<Emphasis Type="Italic">H</Emphasis>)-ones

2-(Allylamino)pyrido[3,2-d]pyrimidin-4(3H)-one was converted to linearly fused dihydroimidazo- [1,2-a]pyrido[3,2-d]pyrimidine on heating in polyphosphoric acid, whereas its reactions with molecular iodine and chlorosulfanylarenes afforded mainly angularly fused analogs. 2-(Cinnamylamino)pyrido[3,2-d]pyrimidin- 4(3H)-one reacted with polyphosphoric acid and chlorosulfanylarenes to give linear pyrido[3,2-d]pyrimido-[1,2-a]pyrimidinones, and its iodocyclization led to the formation of angularly fused derivative.     

Synthesis and nucleophilic substitution reaction of 1-Halo-9<Emphasis Type="Italic">H</Emphasis>-hioxanthen-9-one

Treatment of thiosalicylic acids with p-halotoluene in concentrated sulfuric acid gave 1-halo-9H-thioxanthen-one 3 and its isomer 4 in high yields. Aromatic nucleophilic substitutions of the resulted 1-halo-9H-thioxanthen-9-ones with O-, N- and Snucleophiles are studied in a comparative manner, and various new O-, N- and S-substituted 9H-thioxanthen-9-ones are obtained.     

Synthesis of novel 4<Emphasis Type="Italic">H</Emphasis>-furo[3,2-c]pyran-4-ones and 4<Emphasis Type="Italic">H</Emphasis>-furo[3,2-<Emphasis Type="Italic">c</Emphasis>]chromen-4-ones

It was found that the condensation of two equivalents of 4-hydroxy-6-methyl-2H-pyran-2-one or 4-hydroxycoumarin with arylglyoxals in boiling formic acid leads to 4H-furo[3,2-c]-pyran-4-ones or 4H-furo[3,2-c]chromen-4-ones, respectively.