Alexey Yu. Barkov

Rational design of cyclopropane-based chiral PHOX ligands for intermolecular asymmetric Heck reaction

Summary A novel class of chiral phosphanyl-oxazoline (PHOX) ligands with a conformationally rigid cyclopropyl backbone was synthesized and tested in the intermolecular asymmetric Heck reaction. Mechanistic modelling and crystallographic studies were used to predict the optimal ligand structure and helped to design a very efficient and highly selective catalytic system. Employment of the optimized ligands in the asymmetric arylation of cyclic olefins allowed for achieving high enantioselectivities and significantly suppressing product isomerization. Factors affecting the selectivity and the rate of the isomerization were identified. It was shown that the nature of this isomerization is different from that demonstrated previously using chiral diphosphine ligands.

Stereoselective addition of ethyl 3-morpholino(piperidino)-crotonates to 2-trihalomethyl-3-nitro-2H-chromenes. Synthesis of 4-acetonyl-3-nitrochromans

Tertiary enamines of acetoacetic ester, obtained with morpholine and piperidine, add to 2-R1-3-nitro-2Н-chromenes (R1 = CF3, CCl3, Ph) via the vinylogue β-methyl group and give the respective cis,trans-2,3,4-trisubstituted chromans, the stereoconfiguration of which was established by X-ray structural analysis. Acidic hydrolysis of these compounds was accompanied by decarboxylation and produced 4-acetonyl-3-nitrochromans with retention of configuration.

Synthesis of trans,trans-2,3,4-trisubstituted chromans from 3-nitro-2Н-chromenes and enamines of acetoacetic ester and acetylacetone. A new type of configurationally stable atropisomers

Enamines of acetoacetic ester and acetylacetone added at the activated double bond of 2-R1-3-nitro-2Н-chromenes (R1 = CF3, CCl3, Ph) with their central α-С atoms, forming trans,trans-2,3,4-trisubstituted chromans. The adducts obtained from acetylacetone enamines represented mixtures of comparable amounts of configurationally stable atropisomers, the formation of which was connected with hindered rotation around the C(sp3)–C(sp2) bond. A reaction with enamines of acetoacetic ester led practically exclusively to a single anti atropisomer.

3-Nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes: synthesis and reactions with nucleophiles

A method is proposed for the synthesis of 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes by tandem condensation of salicylic aldehydes with (E)-3,3,3-trifluoro-1-nitro-2-phenylprop-1-ene in the presence of triethylamine. The example of 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromene was used to demonstrate conjugated addition reactions with enamines, nitromethane, and aniline, which are characteristic for this class of compounds. The structure of the obtained products was confirmed by X-ray structural analysis.

Regio- and stereoselective 1,3-dipolar cycloaddition reactions between arylideneacetones and stabilized azomethine ylides obtained from ninhydrin and indenoquinoxalinones

Stabilized azomethine ylides, generated in situ from proline/sarcosine and ninhydrin or indenoquinoxalinones, underwent 1,3-dipolar cycloaddition at the activated double bond of arylideneacetones, leading predominantly to endo-spiro adducts. These products formed as a result of addition between the less substituted carbon atom of azomethine ylide and the most electrophilic site of the dipolarophile.

Reactions of 3,3,3-Trihalogeno-1-nitropropenes with Arenes in the Superacid CF3SO3H: Synthesis of (Z)-3,3,3-Trihalogeno-1,2-diarylpropan-1-one Oximes and Study on the Reaction Mechanism

3,3,3-Trihalogeno-1-nitropropenes C(Hal3)CH═CH(NO2) (Hal = F, Cl, Br) in reaction with arenes in the superacid CF3SO3H (TfOH) at room temperature in 1 h afford 3,3,3-trihalogeno-1,2-diarylpropan-1-one oximes C(Hal3)CH(Ar)-C(Ar)═NOH (CHal3-oximes) in yields of 23-99%. Such CHal3-oximes having one ortho-substituent in the aryl ring exist as atropoisomers in solutions at room temperature. Several cationic intermediates of this reaction were studied by means of NMR and DFT calculations, which proves the detailed reaction mechanism of the formation of CHal3-oximes in TfOH. CHal3-oximes (for Hal = Cl, Br) with DBU in DMF at microwave or thermal activation are cyclized into 5-halogeno-3,4-diarylisoxazoles in yields of 37-59%. CHal3-oximes under the conditions of Beckmann rearrangement with PCl5 in benzene at room temperature in 24 h are turned at first into imidoyl chlorides (yields of 94-96%), which undergo transformation into the corresponding benzamides PhCONHCHPh(CHal3) on silica gel (yields of 46-47%).

Unexpected regiochemistry in [3+2] cycloaddition reaction of azomethine ylides of indenoquinoxalinone series to arylidene malononitriles

1,3-Dipolar cycloaddition of azomethine ylides generated in situ from proline and indenoquinoxalinones occurred at the double bond of arylidene malononitriles upon heating in isopropanol, leading to the respective spirocyclic adducts with cis orientation of the aryl substituent and the quinoxaline moiety. The regioselectivity of this process depended on the electron donor-acceptor properties of substituents in the aromatic ring of the dipolarophile molecule. Analogous reaction involving azomethine ylide derived from sarcosine produced adducts with a trans relationship of the most sterically demanding substituents.

3-Nitro-2-(trihalomethyl)-2H-chromenes in reactions with sodium azide: synthesis of 4-(trihalomethyl)-2,4-dihydrochromeno[3,4-d][1,2,3]triazoles

A method was developed for the synthesis of 4-(trihalomethyl)-2,4-dihydrochromeno[3,4-d][1–3]triazoles, based on the reaction of 3-nitro-2-(trifluoro(trichloro)methyl)- and 3-nitro-2-(trifluoromethyl)-2-phenyl-2H-chromenes with sodium azide in DMSO or DMF in the presence of p-toluenesulfonic acid.

One-pot synthesis of functionalized benzo[c]coumarins and their precursors via the reaction of 2-(polyfluoroalkyl)chromones with 4-alkyl-3-cyanocoumarins

2-(Polyfluoroalkyl)chromones react with 4-alkyl-3-cyanocoumarins in dichloromethane in the presence of triethylamine to give a wide variety of functionalized benzo[c]coumarin derivatives in good yields. This new annulation reaction presumably proceeds by a tandem intermolecular Michael addition and subsequent intramolecular condensation between an intermediate enolate anion and cyano group. In the case of 3-cyano-4-methylcoumarin and 2-(trifluoromethyl)chromones activated by two electron-withdrawing substituents, three acyclic intermediates were isolated and the possible mechanism of the reaction was suggested.

Products from the addition of acetoacetic ester or acetylacetone to 3-nitro-2Н-chromenes – axially chiral trans,trans-2,3,4-trisubstituted chromans and related pyrazoles

The trans,trans-2,3,4-trisubstituted chromans, previously described by us as addition products of acetoacetic ester or acetylacetone at the activated double bond of 2-substituted 3-nitro-2Н-chromenes, are axially chiral molecules due to the hindered rotation around the C(sp3)–C(sp2) bond.