Alexander Yu. Rulev

Fragmentation of Trifluoromethylated Alkenes and Acetylenes by N,N-Binucleophiles. Synthesis of Imidazolines or Imidazolidines (Oxazolidines) Controlled by Substituent

The reaction of beta-halogeno-beta-polyfluoromethylstyrenes with N,N- or N,O-binucleophiles leads to unexpected fragmentation products (imidazolines) or to heterocyclization giving CF(3)-substituted imidazolidines (N,N-) and oxazolidines (N,O-) depending on aryl substituent. The scope and the reaction mechanism are discussed.

GIAO, DFT, AIM and NBO analysis of the NH···O intramolecular hydrogen‐bond influence on the 1J(N,H) coupling constant in push–pull diaminoenones

In the series of diaminoenones, large high‐frequency shifts of the 1H NMR of the NH group in the cis‐position relative to the carbonyl group suggests strong NH···O intramolecular hydrogen bonding comprising a six‐membered chelate ring. The NH···O hydrogen bond causes an increase of the 1J(N,H) coupling constant by 2–4 Hz and high‐frequency shift of the 15N signal by 9–10 ppm despite of the lengthening of the relevant NH bond. These experimental trends are substantiated by gauge‐independent atomic orbital and density functional theory calculations of the shielding and coupling constants in the 3,3‐bis(isopropylamino)‐1‐(aryl)prop‐2‐en‐1‐one (12) for conformations with the Z‐ and E‐orientations of the carbonyl group relative to the NH group. The effects of the NH···O hydrogen‐bond on the NMR parameters are analyzed with the atoms‐in‐molecules (AIM) and natural bond orbital (NBO) methods. The AIM method indicates a weakening of the NH···O hydrogen bond as compared with that of 1,1‐di(pyrrol‐2‐yl)‐2‐formylethene (13) where NH···O hydrogen bridge establishes a seven‐membered chelate ring, and the corresponding 1J(N,H) coupling constant decreases. The NBO method reveals that the LP(O) →σ*NH hyperconjugative interaction is weakened on going from the six‐membered chelate ring to the seven‐membered one due to a more bent hydrogen bond in the former case. A dominating effect of the NH bond rehybridization, owing to an electrostatic term in the hydrogen bonding, seems to provide an increase of the 1J(N,H) value as a consequence of the NH···O hydrogen bonding in the studied diaminoenones. Copyright

High pressure promoted aza-Michael addition of primary and secondary amines to α-substituted acrylates

The α-dialkoxymethyl α,β-unsaturated ester 1 can be easily converted, under high pressure and at ambient temperature, into the corresponding aza-Michael adducts 2 and/or push–pull α-aminomethyl-β-methoxy-α,β-unsaturated esters 3 by treatment with primary or secondary amines. The ratio between these two types of products is shown to depend on the nature of the nitrogen nucleophile.

Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines

A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.

N,N-Disubstituted α-Amino-α,β-unsaturated Aldehydes and their Derivatives:1H and13C NMR Study

1H and 13C NMR spectra of N,N‐disubstituted α‐amino‐α,β‐unsaturated aldehydes and their azomethines and enammonium salts were studied. The spectra reflect the degree of p–π conjugation between the nitrogen lone pair and the π‐electrons of the carbon–carbon double bond. In this respect, the title 2‐aminoenals are shown to be in an intermediate position between α‐unsubstituted aminoalkenes and α,β‐unsaturated aldehydes. The degree of conjugation depends on the nature of the amine moiety and the activating group.

Theoretical and experimental (15)N NMR study of enamine-imine tautomerism of 4-trifluoromethyl[b]benzo-1,4-diazepine system.

The tautomeric structure of 4‐trifluoromethyl[b]benzo‐1,4‐diazepine system in solution has been evaluated by means of the calculation of 15N NMR chemical shifts of individual tautomers in comparison with the averaged experimental shifts to show that the enamine–imine equilibrium is entirely shifted toward the imine form. The adequacy of the theoretical level used for the computation of 15N NMR chemical shifts in this case has been verified based on the benchmark calculations in the series of the push–pull and captodative enamines together with related azomethynes, which demonstrated a good to excellent agreement with experiment. Copyright

Alkyl-and arylsulfanyl-substituted unsaturated carbonyl compounds

ABSTRACT A method for the synthesis of captodative sulfanyl enals, enones and enoates via nucleophilic vinylic substitution of corresponding halogen-bearing derivatives has been developed. The one-pot treatment of the haloenoates, haloenones or haloenals with thiols in the presence of organic base leads either to vicinal dithiosubstituted carbonyl-bearing compound or captodative systems with good to excellent yield. The major reaction direction strongly depends on the type of base used. GRAPHICAL ABSTRACT

Regiospecific Addition of Bis(Trimethylsilyl)-Hypophosphite to 2-Halogen-2-Alkenals

Abstract 2-Halogen-2-alkenals react regiospecifically with one equivalent of bis(trimethylsilyl)hypophosphite in 1,2-addition mode.

Design of Multi-Component Reactions

Multi-component reactions (MCRs) have now been well established as a powerful synthetic tool for creating molecular complexity and diversity and are undoubtedly well suited for the drug discovery program. Another potential that has probably received less attention among synthetic chemists is the opportunity offered by MCRs for the development of new fundamentally important transformations (reactions). Indeed, although an MCR is composed of a series of known bimolecular reactions, the overall transformation could be novel. Consequently, it provides chemists the opportunities to uncover transformations that were otherwise difficult to realize. In this talk, we will present our recent work in this field, including: (1) the oxidative homologation of aldehydes to amides, (2) the oxidative coupling of aldehydes and isocyanides to α-ketoamides, (3) oxidative isocyanide-based MCRs, and (4) the enantioselective Passerini reaction.