Kseniya V. Belyaeva

A General Synthetic Strategy for the Design of New BODIPY Fluorophores Based on Pyrroles with Polycondensed Aromatic and Metallocene Substituents

BODIPYrrole: A general strategy for the design of novel BODIPY fluorophores based on pyrroles with polycondensed aromatic and metallocene substituents has been developed. The strategy involves the acylation of the condensed substituent and treatment of the acylated derivative (as oxime) with acetylene in MOH/DMSO (M = alkali metal) to give pyrroles that were then used for assembly of the BODIPY fluorophores (see scheme).

Stereoselective C(2)-Vinylation of 1-Substituted Imidazoles with 3-Phenyl-2-propynenitrile

First examples of direct vinylation of 1-substituted imidazoles at the 2-position of the imidazole nucleus are described. 1-Substituted imidazoles 1a-e are C(2)-vinylated with 3-phenyl-2-propynenitrile (2) at room temperature without catalyst and solvent to afford 3-(1-organyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitriles 3a-e, mainly (c.a. 95%) as (Z)-isomers, in 56-88% yield. The reaction is likely to involve the zwitterionic intermediates, which prototropically isomerizes to imidazole carbene and eventually undergoes the selective 3,2-shift of the functionalized vinyl substituent.

Stereoselective tandem ring opening of imidazoles with electron-deficient acetylenes and water: synthesis of functionalized (Z,Z)-1,4-diaza-2,5-dienes.

1-Substituted imidazoles undergo exceptionally facile stereoselective ring opening under the influence of electron-deficient acetylenes and water (equimolar ratio of the reactants) in MeCN at 45-60 °C without any catalysts to afford functionalized (Z,Z)-1,4-diaza-2,5-dienes, (Z,Z)-propenylaminoethenylformamides, in up to 80% yields. The reaction is rationalized to proceed in a tandem manner via zwitterionic vinyl carbanions formed by nucleophilic addition of imidazole to the triple bond. The carbanionic center is then quenched with water followed by the rearrangement of the intermediate 2-hydroxy-3-alkenylimidazolines.

New methodology for functionalization of the imidazole ring by alkynes

A new methodology for functionalization of the imidazole ring via the zwitterionic intermediates and their carbene tautomers generated by nucleophilic addition of 1-substituted imidazoles to electron-deficient acetylenes followed by reactions with the appropriate electrophiles is discussed.

Stereoselective Synthesis of N -[( Z )-2-Cyano-1-Phenylethenyl]Benzimidazole-2-Carbothioamides by a Three-Component Reaction of 1-Substituted Benzimidazoles, Phenylcyanoacetylene, and Isothiocyanates

A new method has been developed for the synthesis of benzimidazole carbothioamides, which have potential pharmacological activity, by a three-component reaction of 1-substituted benzimidazoles, phenylcyanoacetylene, and methyl, allyl, or phenyl isothiocyanates. The reaction of these components proceeds under mild conditions in acetonitrile at 50-55°C for 12-20 h and stereoselectively leads to N-[(Z)-2-cyano-1-phenylethenyl]benzimidazole-2-carbothioamides in 43-82% yield.

Opening of the pyridine ring in the system 1,1,1-trifluoro-4-phenylbut-3-yn-2-one–water. Stereoselective synthesis of 5-{[(1Z)-4,4,4-trifluoro-3-oxo-1-phenylbut-1-en-1-yl]amino}penta-2,4-dienal

We have recently discovered facile opening of the pyridine ring by the action of acyl(phenyl)acetylenes in the presence of a small amount of water (room temperature, solvent-free conditions, KOH or not), which leads to the formation of (Z)-(2-acyl-1-phenylethenyl)-5-aminopenta-2,4-dienals with high selectivity and up to 92% yield [1, 2]. Aminopentadienals (Zincke aldehydes) [3] are valuable building blocks for total syntheses of natural products, in particular of manzamine alkaloids [4–8] and alkaloid gelsemine [9], as well as of complex polycyclic structures via cascade reactions [9, 10]. However, the scope of application of these synthetic intermediates is limited due to their insufficient structural diversity [11].

Opening of pyridine ring with benzoyl(phenyl)acetylene in the presence of water with formation of 5-aminopenta-2,4-dienal

Opening of a pyridine ring is a possible synthetic route to 5-aminopenta-2,4-dienals and their derivatives, though aromaticity of the pyridine system creates a fundamental obstacle to such transformation. Efforts have been made to solve this problem [1, 2]. As a rule, the substrates were pyridinium salts or pyridine oxide, and hydroxide ion [3–6], ozone [7], Raney nickel [8], amines [9–12], Grignard compounds or acetylide ion [13, 14], and thiophosgene [15] were used as reagents; photolytic hydrolysis of pyridine was also performed [16, 17]. However, these studies have not received further development. We have found that heating of benzoyl(phenyl)acetylene (1) in boiling pyridine (115°C) in the presence of an equimolar amount of water is accompanied by opening of the pyridine ring with formation of isomeric 5-aminopenta-2,4-dienals E,E-2a and E,Z-2b a t a ra t io of (5–6) : 1 (unopt imized y ield 7%; Scheme 1). Isomer mixture 2a/2b was isolated by alumina column chromatography. Presumably, alkyne 1 reacts with pyridine to give zwitterionic adduct A which is converted into pyridinium hydroxide B as a result of proton transfer from water molecule to the carbanionic center. A covalent form of intermediate B, hydroxypyridine C undergoes rearrangement through cleavage of the N‒C bond, and Z,Z,Z-adduct D thus formed isomerizes to 2a/2b (Scheme 2).

Signs of formation and chemical evolution of zwitterions in the reaction of 1-methylimidazole with cyanophenylacetylene and benzaldehyde

Primary monitoring of the three-component reaction of 1-methylimidazole with cyanophenylacetylene and benzaldehyde by EPR, UV, NMR, and IR spectroscopy has been carried out. Experimental evidence has been obtained for the formation of zwitterions and carbenes of the imidazole series as intermediates of a new functionalization reaction of the imidazole ring leading to 2-benzoyl-3-(1-methyl-1H-imidazol-2-yl)-3-phenylpropanenitrile.

Catalyst-free 1 : 2 annulation of quinolines with trifluoroacetylacetylenes: an access to functionalized oxazinoquinolines

Metal- and solvent-free reaction of quinolines with two molecules of aryltrifluoroacetylacetylenes afforded 3-arylethynyl-3-trifluoromethyl-1,3-oxazinoquinolines in up to 92% yields. The formation of a zwitterionic intermediate in the first step triggered a multistep domino reaction. This one-pot synthesis opens an easy access to novel quinoline derivatives bearing trifluoromethyl, acetylene and ketone functions, thus providing a powerful tool for drug design.

Reaction of 2-methylquinoline with 3-phenylprop-2-ynenitrile in the KOH—H 2 O system

The reaction of 2-methylquinoline with 3-phenylprop-2-ynenitrile in the presence of water (0—25 °C, 20 mol.% KOH, 5 equiv. H2O) is accompanied by the loss of aromaticity of the quinoline nucleus and results in double functionalization of the molecule at the nitrogen atom and the methyl group. Two 2-cyano-1-phenylethenyl groups were introduced into the molecule to form (2E,4E)-4-{1-[(Z)-2-cyano-1-phenylethenyl]quinolin-2(1H)-ylidene}-3-phenylbut-2-enenitrile in 59—67% yield. This reaction is stereoselective: the N-2-cyano-1-phenylethenyl-substituent has the Z-configuration, while the 1,3-diene moiety at the methyl group has the E,E-configuration. (2E)-3-Phenyl-4-(quinolin-2-yl)but-2-enenitrile that formed as a by-product (0—24% yields) is formally the addition product of the methyl group of the quinoline substrate at the acetylenic bond.