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A method for the synthesis of iodomethyl-substituted five-membered sultams has been developed. The sultams were synthesized by intramolecular iodoamination of alkenyl sulfamides. The method allows synthesis of N- and C-substituted sultams. NH-Sultams were prepared by acidic cleavage of the corresponding tert-butyl sultams that are readily available. Varying the length of alkenyl substituent at sulfamide it was shown that only five- and six-membered sultams could be prepared by this method. Neither four- nor seven-membered sultams were detected. The simple practical procedure and available starting materials make the variously substituted sultams readily available.

Diverse trifluoromethyl-substituted compounds were synthesized by deoxofluorination of cinnamic and (hetero)aromatic carboxylic acids with sulfur tetrafluoride. The obtained products were used as starting materials in the preparation of novel fluorinated amino acids, anilines, and aliphatic amines - valuable building blocks for medicinal chemistry and agrochemistry.

Facile synthesis of 5-fluoropyrazoles by direct fluorination of pyrazoles with N-fluorobenzenesulfonimide (NFSI) was elaborated. This approach was used to prepare the unsubstituted 5-fluoro-1 H-pyrazole, the known fungicide Penflufen, and many functionalized 5-fluoropyrazoles: building blocks for medicinal chemistry and agrochemistry.

The reaction of cyclic thioimidates with active methylene compounds in the presence of acetic acid anhydride was studied. In case of six- and seven-membered derivatives the reaction proceeded via substitution of thiomethoxy group affording cyclic enamines. In case of five-membered derivatives the reaction proceeded via opening of the thioimidate ring affording functionalized aminopropane derivatives.

The synthesis of multifunctional spirocycles was achieved from common cyclic carboxylic acids (cyclobutane carboxylate, cyclopentane carboxylate, l-proline, etc.). The whole sequence included only two chemical steps-synthesis of azetidinones, and reduction into azetidines. The obtained spirocyclic amino acids were incorporated into a structure of the known anesthetic drug Bupivacaine. The obtained analogues were more active and less toxic than the original drug. We believe that this discovery will lead to a wide use of spirocyclic building blocks in drug discovery in the near future.

A set of novel SO2-containing azabicyclo[3.n.1]alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO2-containing building blocks for drug discovery.

Starting from readily accessible cyclic enaminoesters, arylisothiocyanates and α-haloketones, a facile method for the synthesis of ω-aminoalkylthiophene hydrobromides was developed. It was shown that in the first step cyclic enaminoesters react with arylisothiocyanates exclusively at the enamine position. Upon treatment with base, free 5-aminopentylthiophenes were prepared. In the case of shorter alkyl substituents (4-aminobutyl and 3-aminopropyl) the free ω-aminoalkylthiophenes undergo intramolecular condensation of the amino and ketone groups affording novel fused heterocycles—thieno[2,3-c]azepine and thieno[2,3-c]azocine.

Electron-rich N-substituted pyrazoles smoothly reacted with trifluoroacetic anhydride in pyridine to form the corresponding trifluoromethyl ketones in good yields.

A two-step synthetic strategy toward difluoromethyl ethers via a CuI-catalyzed reaction of the alcohols, bearing additional protected functionalities, with FSO2CF2CO2H has been developed. The high potential of the developed protocol has been shown by preparing novel OCF2H-analogues of GABA and l-proline. The described transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage preparation of complex OCF2H-containing organic compounds as well as building blocks for drug discovery.

The reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with N-unsubstituted 5-aminopyrazoles was investigated. The reaction proceeds with high regioselectivity and is considered as an effective­ method for the preparation of new pyrazolo[1,5-a]pyrimidines bearing an ester function in the 7-position. The obtained drug-like compounds have a great potential for medicinal chemistry as they closely resemble the structure of several marketed pharmaceuticals.

The synthesis of 1-deazapurines and isosteres bearing the exocyclic nitrogen atom at position-1 was developed basing on the formal [3+3]-cyclization reaction of nitro-malonaldehyde with the set of electron-excessive aminoheterocycles. Through the functionalization of the purine-like scaffolds synthesized the diversity of compounds furnished in the possition-1 with aryl, alkinyl, and vinyl rests, were obtained.

Starting from readily accessible cyclic enaminoesters, arylisothiocyanates and α-haloketones, a facile method for the synthesis of ω-aminoalkylthiophene hydrobromides was developed. It was shown that in the first step cyclic enaminoesters react with arylisothiocyanates exclusively at the enamine position. Upon treatment with base, free 5-aminopentylthiophenes were prepared. In the case of shorter alkyl substituents (4-aminobutyl and 3-aminopropyl) the free ω-aminoalkylthiophenes undergo intramolecular condensation of the amino and ketone groups affording novel fused heterocycles—thieno[2,3-c]azepine and thieno[2,3-c]azocine.

A two-step synthetic strategy toward difluoromethyl ethers via a CuI-catalyzed reaction of the alcohols, bearing additional protected functionalities, with FSO2CF2CO2H has been developed. The high potential of the developed protocol has been shown by preparing novel OCF2H-analogues of GABA and l-proline. The described transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage preparation of complex OCF2H-containing organic compounds as well as building blocks for drug discovery.

In the presence of acetic acid anhydride (III), cyclic thioimidates with five-membered ring [e.g. (II)] react with compounds containing activated methylene group [e.g. (I)] to give aminopropanes [e.g. (IV)] as the major products.

A new strategy for the synthesis of poly- cyclic imidazole-containing N-heterocycles, based on the two general synthetic ways, namely the Pd(II)- catalyzed intramolecular arylation via CH/CHal and CH/CH coupling reactions, was developed. The method proposed here enables the synthesis of many fused N-heterocycles containing purine, 1-deazapur- ines and benzimidazole structural units.

An efficient method has been developed for the synthesis of 4,6-dimethylpyridine-2,3-dicarbonitrile. A study was carried out on the reaction of this compound with N-acylhydrazines to give two structural isomers, namely, N′-(7-amino-2,4-dimethyl-5H-pyrrolo[3,4-b]pyridin-5-ylidene)carbohydrazides and N′-(5-amino-2,4-dimethyl-7H-pyrrolo[3,4-b]pyridin-7-ylidene)carbohydrazides as well as disubstituted N′,N″-(2,4-dimethyl-5H-pyrrolo[3,4-b]pyridine-5,7-diylidene)dicarbohydrazides.

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.

The first synthesis of 3-(dichloroacetyl)chromone from 3-(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one and dichlo- roacetyl chloride is described. The reaction of electron-rich amino- heterocycles with 3-(dichloroacetyl)chromone provides a set of diverse fused pyridines bearing the CHCl2-substituent at the a-posi- tion of the pyridine core. Subsequent hydrolysis leads to the forma- tion of annulated a-(formyl)pyridines.

The reaction of 5-amino-1H-imidazoles with 3-methox- alylchromone provided a set of imidazo(4,5-b)pyridines (1-des- azapurines) bearing the CO2Me substituent at the a-position of the pyridine core. The corresponding acids were synthesized by subse- quent hydrolysis of the ester function. Being typical purine isos- teres, 1-desazapurines are considered to be potent pharmacophores, and are widely used in drug design and medicinal chemistry.

The reaction of 2-(cyanomethyl)benzoic acid with amines RNH2 (R = Ar, Het, CH2Ar, CH2Het) leads to the formation of the corresponding 3-NHR-isoquinolin-1(2H)-ones. When R = CH2Ar and CH2Het, there is a side reaction involving hydrolysis of the hydrolytically-unstable intermediates, derivatives of 2-(2-amino-2-iminoethyl)benzoic acid, leading to 2-R-isoquinoline-1,3(2H,4H)-diones.

The reaction of 3-nitro-4 H-chromen-4-onewith in situ generated 1-substituted 5-amino-1 H-imidazolesaffords a set of 1-substituted 6-nitro-3 H-imidazo[4,5- B]pyridines which represent potentialadenosine deaminase (ADA) inhibitors. Reduction of the nitro groupresults in the formation of the corresponding 6-amino-3 H-imidazo[4,5- B]pyridines.

The reaction of electron-rich aminoheterocycles with 1,3-CCC -dielectrophiles, such as 3-formylchromones,acylpyruvates, and chalcone, provided diversely fused pyridines.Starting from 5-amino-1-(2,3- O-isopropylidene-β- D-ribofuranosyl)-1 H-pyrazole,nucleosides containing a pyrazolo[3,4- B]pyridinefragment were obtained, which can be considered as adenosine deaminase(ADA) inhibitors.

Acylation of pyrrolidin-2-ylidenemalononitrile with benzoyl chloride leads to the formation of 2-(1-benzoylpyrrolidin-2-ylidene)malononitrile. The obtained product was used as starting material in the synthesis of γ-aminopropylpyrazoles and pyrimidines.

A preparative approach towards 1-desazapurines, start- ing from 4(5)-aminoimidazoles and polyfluoroalkyl-containing 1,3- CCC-biselectrophiles was developed. As a result, a set of fluorinat- ed 1-desazapurines was synthesized. Additionally, a synthetic route to 1-desazapurines bearing a sugar-mimicking group is proposed.

Starting from 5-amino-1-(2,3-O-isopropylidene-b-D-ri- bofuranosyl)-1H-pyrazole, fluorine-containing 1,3-CCC-, 1,3-CNC- dielectrophiles and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine, a set of fluorinated pyrazolo(3,4-b)pyridine and pyrazolo(3,4-d)pyrimi- dine nucleosides was obtained. Synthetic access to stable 4-(poly- fluoroalkyl)-4,7-dihydro-1H-pyrazolo(3,4-b)pyridin-4-ole was elaborated, which can be considered to be mimetics of the putative transition state involved in adenosine deaminase activity.

Isothiocyanatophosphonium salts bearing an aroxy group at the phosphorus atom have been obtained for the first time. As found, these compounds undergo an intramolecular heterocyclization to give hitherto unknown benzoxazaphosphininethiones or cyanoiminophosphoranes, according to the nature of the substituents on the aryl ring. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:667–670, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20491

The reaction of 2-aminothiazol-4(5H)-iminium salts with various 1,3-CCC-dielectrophiles was investigated. As a result, a set of diverse thiazolo[4,5-d]pyridines were obtained. The scope and limitation of the approach is described.

A new method based on the reaction of 4-bromo-1,3-diphenyl-2-buten-1-one with imidazoles and benzimidazoles was proposed to obtain imidazo[1,2-a]pyridinium and pyrido[2,1-b]benzimidazolium salts.

It was shown that 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed when 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one is heated with the chlorides and anhydrides of carboxylic acids in the presence of bases (pyridine, NaOAc) while 5-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed in the presence of NaH. In the presence of NaH 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones form the products from acylation and alkylation at position 5. The action of heat on 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one in oxalyl chloride leads to 7H,8H-2a,7a-diazacyclopenta[fg]naphthacene-1,2,8-trione.

In situ generated benzofuran-2-amine reacts with 1,3-CCC-dielectrophiles, such as CF 3 -containing β-diketones, 3-formylchromone, methyl-2,4-dioxopentanoate and pentafluoro-benzaldehyde, and the reaction leads to the formation of benzofuro[2,3- B]pyridine ring system. By using a similar approach 4-trifluoromethyl-α-carbolines were synthesized starting from indole-2-amine.

Phosphorylation of N-trimethylsilyl- and N-dimethyl-tert-butylsilylpyrroles with phosphorus tribromide in pyridine proceeds selectively at position 3 of the pyrrole ring. Removal of the trialkylsilyl protecting group has furnished the first representatives of N-unsubstituted 3-phosphorylated pyrroles. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:93–96, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20416

The reaction of 2-(dialkylamino)-1,3-thiazol-4-amines and 1,2-dimethyl-1 H-imidazol-5-amine with aryl isocyanates, α-chloroalkyl isocyanates, N-(alkoxycarbonyl)imidoyl chlorides and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine leads to thiapurines and purines containing trifluoromethyl groups in the 2- and 6-positions of the pyrimidine ring.

New convenient conditions for the Friedlander synthesis of quinolines are described. Polysubstituted quinolines were readily prepared using chlorotrimethylsilane as a promoter and water-acceptor agent.

A new method is proposed for obtaining 3,4-polymethylene-1,2,4-benzothiadiazine 1,1-dioxides by reacting o-halobenzenesulfonamides with lactim ethers. Attempts were undertaken to synthesize quaternary salts of the heterocycles obtained.

The investigation concerns the effect of a bulky substituent at the pyrrole nitrogen atom on the orientation and regioselectivity of pyrrole phosphorylation with phosphorus(III) halides. As shown, phosphorylation of N-iso-propylpyrrole with phosphorus tribromide or trichloride proceeds nonregioselectively at positions 2 and 3 but it is followed by the 2 3 migration of the dihalogenophosphine group which quantitatively yields the 3-isomer. N-tert-butylpyrrole is regioselectively phosphorylated with halogenophosphines at position 3. The tert-butyl substituent at the nitrogen atom does not preclude the binding of even two or three pyrrolyl residues to the phosphorus atom. The key compounds, 3-pyrrolyldihalogenophosphines, were isolated in a pure state, characterized and used to obtain a number of stable phosphorus(V) derivatives. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:599–604, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20158

The reactions of cyclic nitroenamines with isocyanates were investigated. It was found that two different products could be obtained: in inert media β-carbamoyl products were observed and when a strong base was used 1,6-polymethylene-6-nitromethyl-1,3,5-triazine-2,4-dione derivatives were isolated.

The reaction of β-trifluoroacetylvinyl ethers with ‘push–pull’ enamines having a methyl group at the α-position was investigated. As a result, a set of CF3-containing dialkyl anilines and their covalent hydrates were obtained. A possible reaction mechanism and the stability of the covalent hydrates obtained are discussed.

The synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles and 7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazoles from cyclic amidines is described.

New N-substituted 7-amino-1-nitro-2-heptanone derivatives have been obtained starting from readily accessible 2-(nitromethylidene)hexahydro-1H-azepine. These compounds have been further used as starting materials for the synthesis of some heterocycles with 5-aminopentyl fragment.

The reaction of ‘push–pull’ enamines—derivatives of β-aminocrotonic acid with diphenylchlorophosphine has been investigated. Structural sensitivity of the reaction was found and is discussed.

The reaction of 4,4,4-trifluoro-3-oxobutanoates with the corresponding electron-rich amino heterocycles was investigated. A simple and flexible general procedure for the regiospecific annulation of the trifluoromethylpyridine ring to electron-rich amino heterocycles was proposed. A set of CF 3 -containing fused pyridines in almost quantitative yield was obtained.

A study on the stepwise hydrolysis of hetarene- and cycloalkenecarboxamidophosphoryl dichlorides afforded the synthesis of hitherto unknown hetarene- and cycloalkene-carboxamidophosphoric acids as well as allowing the introduction of unsubstituted carbamoyl group in the molecules of pyrroles, indoles, indolizines, and some enamines.

I-Aryl-5-arylcarboxamidopyrazoles react with phosphorus(III) halides giving the new heterocyclic system: pyrazolo[4,3-c][1,5,2]oxazaphosphinine. Treatment of pyrazolo[4,3-c][1,5,2]oxazaphosphinines with nucleophilic or electrophilic reagents leads to a cleavage of the oxazaphosphinine ring yielding derivatives of (5-aminopyrazol-4-yl)phosphonic acid.

Three isomers of C-(2,2,2-trifluoroethyl)aniline were prepared on a multigram scale from readily available nitrophenylacetic acids­ in two steps. First, the carboxy groups of the latter were converted into the trifluoromethyl moieties by treatment with sulfur tetra­fluoride. The obtained 2,2,2-trifluoroethyl-substituted nitrobenzenes were reduced catalytically into the corresponding anilines.

trans-2-(Trifluoromethyl)cyclopropylamine was prepared on a multigram scale from readily accessible 4,4,4-trifluorobut-2-enoic acid in five steps. The key step was a high-yielding cyclopropane ring formation from 4,4,4-trifluorobut-2-enoic acid methoxymethyl amide under Corey-Chaykovsky reaction conditions.

A direct method for the synthesis of N -phosphanyl-heterocyclic carbenes is described. The method is based on the reaction of lithium imidazolides and benzimidazolides having a bulky alkyl group at the nitrogen atom with di( tert -butyl)chlorophosphine leading directly to the carbenes.

Electron-rich N-substituted pyrazoles smoothly reacted with trifluoroacetic anhydride in pyridine to form the corresponding trifluoromethyl ketones in good yields.