G. M. Zhdankina

Regio-, stereo-, and enantioselective reactions of carbon acids catalyzed by recoverable organic catalysts bearing ionic liquid moieties

Organic compounds bearing specific ionic liquid (IL) moieties, in particular, bulky organic cations and fluorinated organic or inorganic anions, catalyze many important reactions of carbon acids involving carbanions and enols as reactive species, such as aldol, Michael, and dichlorocyclopropanation reactions. Many of these catalysts are at least comparable to traditional phase-transfer catalysts (PTCs) with halide anions or organocatalysts based on amino acid derivatives. Furthermore, they enjoy the advantage of being readily recoverable and hence are available for multiple recycling in chemical reactions.

Reactions of CH-acids with α,β-unsaturated aldehydes in ionic liquids

Metal carbonate-catalyzed reactions of CH-acids (diethyl malonate, ethyl acetoacetate, ethyl cyanoacetate, and ethyl 2-acetyl- and 2-ethoxycarbonyl-5,9-dimethyldeca-4,8-dienoates) with α,β-unsaturated aldehydes (acrolein, crotonaldehyde, citral) were studied in an ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF6], and in a 1-butyl-3-methylimidazolium bromide ([bmim][Br]) — benzene system. The reactions with acrolein and crotonaldehyde afforded Michael addition products, those with citral resulted in Knoevenagel addition products. Sonication increased the yields of the Michael adducts. The ionic liquid [bmim][PF6] can be recovered and repeatedly used in the reactions.

Synthesis of derivatives of prenylacetic acids by reactions of alkyl malonate, cyanoacetate, and acetoacetate with alkylating reagents in ionic liquids

A method for the synthesis of carboxylic acid derivatives containing one or two —CH2CHn(Me)CHn+1CH2— fragments (n = 0, 1) was developed. The method is based on the alkylation of (di)alkyl malonates, cyanoacetates, and acetoacetates with acyclic prenyl halides in ionic liquids, 1-butyl-3-methylimidazolium hexafluorophosphate and tetrafluoroborate. For the ambident ethyl acetoacetate anion, the reactions with prenyl halides devoid of a double bond in the allylic position relative to the halogen atom carried out in the ionic liquids give mixtures of C- and O-alkylation products, while in the case of allylic prenyl halides, only C-alkylation products are formed. The reactions of ethyl 2-geranylmalonate and 2-geranylacetoacetate with bromocyclohexane and 1-chloro-3-dimethylaminopropane in ionic liquids provided derivatives of pharmacologically active geranylacetic acids. The product yields are higher than those in molecular organic solvents. The ionic liquids were recovered and reused in the alkylation.

Stereoselective synthesis of analogs of natural isoprenoids based on the reaction of alkyl 4-dialkoxyphosphoryl-3-methylbut-2-enoates with aldehydes in ionic liquids and in an imidazolium salt—benzene system

Condensation of alkyl 4-dialkoxyphosphoryl-3-methylbut-2-enoates with a number of aldehydes under the Horner—Emmons reaction conditions in 1-butyl-3-methylimidazolium hexafluorophosphate and tetrafluoroborate and in 1-butyl-3-methylimidazolium bromide—benzene and 1-butyl-2,3-dimethylimidazolium hexafluorophosphate—benzene systems was studied. The E/Z-stereoisomer ratio of the olefination products for the reaction carried out in ionic liquids was 3 : 1, which corresponds to the values attained previously in the KOH—benzene—Bu4nNBr (cat.) system. Quantum-chemical calculations were used to determine the averaged radii (r0) of the [Bu4nN] and substituted imidazolium cations by means of the Gaussian 98 program package. The stereoselectivity of olefination in the KOH—PhH—phase-transfer catalyst system decreases with a decrease in the r0 value for the catalyst cation. The possibility of recovery and reuse of ionic liquids is demonstrated.

Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines

Simple enantiomerically pure C2-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2′-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (∼99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.

Synthesis of methaprogerol analogs

Novel synthetic approaches towards analogs of methaprogerol, the efficient wound healing drug, were developed. Several hitherto unknown compounds obtained exhibited in vivo activity similar to methaprogerol. 2-(3-Dimethylaminopropyl)-5-methylhex-4-enoic acid enhanced the efficacy of the treatment of diseases of various etiologies and different organ injuries by transplantation of mesenchymal stem cells (MSC) and MSC-derived cardiomyoblasts.

Simple synthesis of 2-alkenyl- and 2-aryl-substituted 1,1-dichloroethylenes from unsaturated aldehydes

ConclusionsA three-step synthesis has been proposed for the preparation of 2-alkenyl- and 2-aryl-1,1-dichloroethylenes, involving the conversion of an aldehyde to its acylal (or α-trichloromethylcarbinol), α-trichloromethylcarbinol acetate, and 2-substituted 1,1-dichloro-olefin. The best procedure for the dechloroacetoxylation by the action of zinc powder in a mixture of acetic acid and ether.

REACTION OF CITRAL WITH ACETONE CYANOHYDRIN AND DIETHYLAMINE, AND THERMOLYSIS OF THE RESULTING AMINONITRILE

The reactions of citral with acetone cyanohydrin and secondary amines (diethylamine, piperidine, morpholine, and N-methylaniline) to give 2-substituted amino-4, 8-dimethyl-3,7-nonadienoic acid nitriles have been examined. Possible path-ways for these reactions are discussed. The thermolysis of 2-diethylamino-4,8-dimethyl-3, 7-nonadienoic acid nitrile has been examined in solution, to give irreversibly 3-cyano-1-diethylamino-3,7-dimethyl-1,6-octadiene, this reaction proceeding faster in polar than in nonpolar solvents.

Catalytic hydrogenation of the adduct of citral diethyl acetal with 2-methoxy-propene, and the synthesis of 6,10-dimethylundec-3-en-2-one

Conclusions1.Catalytic hydrogenation of a mixture of isomeric 2,2,4-methoxydiethoxy-6,10-dimethylundeca-5,9-dienes over skeletal nickel in ethanol at 50°C and a hydrogen pressure of 50–80 atm gives good yields of 4-ethoxy-6,10-dimethyl-undecan-2-ol (as a mixture of stereoisomers), which is a convenient intermediate for the preparation of 6,10-dimethyl-undec-3-en-2-one.2.Depending on the catalyst and the conditions used, 2,2,4-trialkoxy-6,10-dimethyl-undeca-5,9-diene gives selectively four different products of hydrogenation and hydro-genolysis.3.Hydrogenation of citronellal over 2% Pd/C in methanol at 40°C and 40 atm of hydrogen gives 80% of 3,7-dimethyloctanal dimethyl acetal.

Synthesis of ethyl 3,7,11-trimethyldodeca-2,4-dienoate (hydroprene) from citral

Conclusions1.A method is described for the preparation of hydroprene from citral, isopropenyl methyl ether, and ethoxyacetylene by a e10+C3+C2 route.2.The Iotsich-Preobrazhenskii reaction of 6,10-dimethyl-2,3-undecen-2-one with ethoxyacetylene is an efficient route for the conversion of the C13-precursor into hydro-prene. The overall yield of hydroprene from citral is around 31% over the six stages of the synthesis.