Lina P. Nikitina

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.

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.

First example of noncatalytic C2–H functionalization of imidazole ring with an alkoxy enone system

Functionalized imidazoles are well known due to their pharmaceutical importance. It is not occasional that many popular medications such as metronidazole (antibiotic) [1], dacarbazine (antitumor drug) [2], cimetidine (histamine H2 receptor antagonist) [3], as well as best sold losartan and olmesartan (anti-hypertensive agents) and ondanserton (anti-vomiting drug), are imidazole derivatives [4]. Therefore, search for new methods for functionalization of imidazole ring remains one of the priority problems of modern organic synthesis. It is related to the general problem of C–H functionalization, which now attracts increasing attention of synthetic chemists [5]. In most cases such functionalization is achieved by reactions catalyzed by transition metal compounds which often have fairly complicated structure. For example, aryl substituents are introduced into the 2-position of imidazole ring via cross-coupling reactions catalyzed by palladium and copper complexes [6–9]. 1-Methylimidazole was converted into 2-{1-[diethyl(methyl)silyloxy]methyl}1-methylimidazoles in 32–92% yield in the presence of Ir4(CO)12, carbonyl compounds, and diethyl(methyl)silane [10]. However, even traces of transition metals (sometimes very toxic) in substances for pharmaceutical purposes are strongly undesirable [11]. In this communication we report the first example of noncatalytic regioselective C–H functionalization of imidazole ring with an alkoxy enone system via three-component condensation of 1-methylimidazole (1) with 1,3-diphenylprop-2-yn-1-one (2) and isobutyraldehyde (3). The product of this reaction was 3-[2-methyl-1-(1-methyl-1H-imidazol-2-yl)propoxy]1,3-diphenylprop-2-en-1-one (4) which was isolated in 69% yield as a 3 : 2 mixture of E and Z isomers (Scheme 1). The reaction was complete in 10 days at room temperature under solvent-free conditions. The progress of the reaction was monitored by IR spectroscopy, following the disappearance of the C≡C stretching band at 2198 cm. Raising the temperature to 55– 60°C shortened the reaction time to 21 h, but the yield of 4 decreased to 32%, and the isomer ratio essentially changed in favor of the E isomer (E/Z 9 : 1). It may be presumed that the Z isomer is the kinetically controlled product which is converted into more thermodynamically stable E isomer at elevated temperature. Thus, the reaction time may be shortened by more than an order of magnitude, and the E isomer can be obtained with high selectivity at the expense of the yield. The structure of 4 was proved by IR and H, C, and N NMR spectra. The H NMR spectrum of 4 ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 4, pp. 602–604.