Yulian M. Volovenko

Nucleophilic Substitution in Some 5-Chloropyrimidines. Synthesis and Properties of Condensed Pyridopyrimidines

Abstract Reaction of hetarylacetonitriles 1 with 5-chloro-2-(methylsulfonyl)-4-pyrimidinecarbonyl chloride affords a series of new ketonitriles 3e – h . The reactions of compounds 3 with aliphatic amines were studied. In the reaction of 3c , d , g with aliphatic amines the replacement of methylsulfonyl group took place to give products 4 . In the reaction of 3a with aliphatic amines 3-NR 1 R 2 -5-oxo-5 H -pyrimido-[4,5-c]quinolizin-6-yl cyanides 5a – d were formed. Compounds 3 cyclized into fused pyridopyrimidines 6 – 10 in the presence of Et 3 N and the displacement of methylsulfonyl group in 6 , 7 , 9 by amines was investigated.

High Throughput Synthesis of Extended Pyrazolo[3,4-d]dihydropyrimidines

Thirteen 5-hetarylaminopyrazoles were synthesized in 62-93% yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles with electrophilic hetarylhalides under optimized conditions. Condensation of 5-hetarylaminopyrazoles with carbonyl compounds facilitated by AcOH or Me(3)SiCl furnished 23 pyrazolo[3,4-d]dihydropyrimidines in 69-86% yield. The target compounds were isolated through simple crystallization. The scope and limitation of the method are discussed.

Asymmetric synthesis and biological evaluation of natural or bioinspired cytotoxic C2-symmetrical lipids with two terminal chiral alkynylcarbinol pharmacophores.

Bidirectional syntheses of C2-symmetrical lipids embedding two terminal alkynylcarbinol pharmacophores are reported. Naturally occurring chiral alkenylalkynylcarbinol units were generated using Pus procedure for enantioselective addition of terminal alkynes to aldehydes, allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol pharmacophore were secured using Carreiras procedure adapted to ynal substrates. The dramatic effect of the carbinol configuration on cytotoxicity was confirmed with submicromolar IC50 values against HCT116 cells.

Synthesis of a series of tetraminic acid sulfone analogs

We have introduced a strategy for the construction of spirocycloalkane 1λ6-isothiazolidine-1,1,4-triones through the mesylation of 1-aminocyclopentane-, 1-aminocyclohexane-, and 1-aminocycloheptanecarboxylic acid esters with methanesulfonylchloride followed by alkylation with methyl iodide and consequent cyclization in the presence of potassium tert-butoxide in N,N-dimethylformamide. The spirocycloalkane 4-amino-2,3-dihydro-1H-1λ6-isothiazole-1,1-diones were prepared via mesylation of N-methylated 1-aminocyclopentyl-, 1-aminocyclohexyl-, and 1-aminocycloheptyl carbonitriles followed by treatment of obtained N-(1-cyanocycloalkyl)-N-methylmethanesulfonamides with potassium tert-butoxide in N,N-dimethylformamide. The spiro 4-amino-2,3-dihydro-1H-1λ6-isothiazole-1,1-diones were converted into the target spiro 1λ6-isothiazolidine-1,1,4-triones by acid-catalyzed hydrolysis. The structure of a target spiro compound and its isolated key intermediate was confirmed by X-ray diffraction study. The interaction of spiro 1λ6-isothiazolidine-1,1,4-triones with N,N-dimethylformamide dimethyl acetal leads to the formation of spiro 5-[(Z)-(dimethylamino)methylidene]-1λ6-isothiazolidine-1,1,4-triones.Graphical abstract

An Interaction of 2-Thiazoleacetonitriles with N-(2-Chloroacetyl)anthranilic Acid Ester

The title ester was found to react with 2-benzothiazoleacetonitrile yielding 3-( 2-benzothiazolyl)-2,4-dihydropyrrolo[1,2-a]quinazoline-1,5-drone. At the same time 4-aryl-2-thiazoleacetonitriles gave 3,4-dihydro-β,4-dioxo-α,δ-bis(4-aryl-2-thiazolyl)-2-quinazolinepentanenitriles potassium salts under identical conditions. These results were explained in terms of different solubility of the intermediate compounds. Upon acidification the obtained salts were shown to undergo intramolecular Thorpe addition leading to the 3-amino-2,4-bis(4-aryl-2-thiazolyl)-4-[4(3H)-oxo-2-quinazolinyl]-2-cyclopenten-1-ones. Above mentioned pyrrolo[1,2-a]quinazoline derivative was treated with benzylamines and active methylene nitriles to yield β-(2-benzothiazolyl)-N-arylmethyl-3,4-dihydro-4-oxo-2-quinazolinepropanamides and 2-substituted 3-amino-4-(2-benzothiazolyl)-4-[4(3H)-oxo-2-quinazolinyl]-2-cyclopenten-1-ones, respectively.

A ring opening reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with amino acids

The ring opening reactions of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with α-, β-, γ-, ε-amino acids and alkyl esters of α-amino acids as N-nucleophiles have been investigated. New functionalized amino acid derivatives containing the heterocyclic moiety have been obtained and their reactions with electrophilic and nucleophilic agents have been studied.Graphical Abstract

Novel transformations of 1H-isothiochromen-4(3H)-one 2,2-dioxide

A convenient and simple method of formylating 1H-isothiochromen-4(3H)-one 2,2-dioxide was carried out using dimethylformamide dimethylacetal. The reactions of 3-[(dimethylamino)methylene]-1H-isothiochromen-4(3H)-one 2,2-dioxide with nitrogen-containing nucleophilic reagents were investigated.Graphical abstract.

Cyclic α-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones and their spiro derivatives

Abstractα-Aminoisobutanoic acid and some representatives of cyclic α-amino acids were converted to corresponding 1-phthalimido- and N-trifluoroacylated acid chlorides. Treatment of 2-(1H-benzimidazol-2-yl)acetonitrile with 1-phthalimidoacid chlorides in DMF unexpectedly gave 2-(1H-benzimidazol-2-yl)-3-(dimethylamino)-2-propenenitrile. On the other hand, the reaction of hetarylacetonitriles with N-trifluoroacylated acid chlorides gave the desired (3-cyano-2-oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon detrifluoroacetylation provided the target 2-amino-3-hetarylpyrrolin-4-ones. The acylation of benzoimidazolylaminopyrrolinones by benzoyl chloride leads to formation of 3-benzoyl-2,3-dihydro-5-phenyl-1H-benzo[4,5]imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-1-ones.Graphical Abstract

First Evidence of 1,3-Bis-indolylallenes: Generation by a Sequential Double Nucleophilic Process from Ynones

Abstract The first examples of 1,3-bis-indol-3-ylallenes (1,3-BIAs) are described. They have been generated by addition of a 3-lithioindole reactant to tetramethylsilane-protected mono- and di-alkynyl ketones. The one-pot preparation of 1,3-BIAs is enabled by both the double electrophilic character of the ynone substrates and the double nucleophilic character of the lithio-enamine function of the indolyl moiety, leading to a transient azafulvenium intermediate. GRAPHICAL ABSTRACT

β-Chlorocinnamonitriles in a New Synthesis of 3-Functionally Substituted 6-amino-1,2-Dihydropyridin-2-ones

Abstract β-Chlorocinnamonitriles react with methylene-active compounds containing N-substituted carboxamide group in DMSO solution in the presence of potassium hydroxide, forming 3-functionally substituted 1,2-dihydropyridin-2-ones.