T. S. Khlebnikova

Heterocyclic Analogs of Prostaglandins: I. Synthesis of 3-Alkyl(Aralkyl)-2,5-dihydrofuran-2-ones as Synthons for 11-Deoxy-10-oxaprostanoids

Abstract3-Acyl(arylmethyleneacyl)tetronic acids were synthesized. Selective hydrogenation of the carbonyl group in the acyl fragment and reduction of the conjugated double bond afforded in high yield the corresponding 3-alkyl(aralkyl) derivatives possessing either natural or modified prostaglandin α-chain. Reduction of the conjugated double bond in vinylogous 3-alkyl(aralkyl)tetronic acid amides with sodium cyanotrihydridoborate gave a mixture of stereoisomeric β-amino lactones which underwent retro-Michael elimination of the amine residue, leading to 3-alkyl(aralkyl)-2,5-dihydrofuran-2-ones. The latter can be regarded as synthons for 11-deoxy-10-oxaprostanoids.

Regioselective synthesis of polyfluoroalkyl-substituted 7-(1H-1,2,3-triazol-1-yl)-6,7-dihydro-1H-indazol-4(5H)-ones

Abstract3-Polyfluoroalkyl-6,6-dimethyl-7-(1H-1,2,3-triazol-1-yl)-6,7-dihydro-1H-indazol-4(5H)-ones were synthesized with high regioselectivity by 1,3-dipolar cycloaddition of terminal alkynes (phenylacetylene, hex- 1-yne, hept-1-yne, and but-3-yn-1-ol) to 7-azido-6,6-dimethyl-3-polyfluoroalkyl-6,7-dihydro-1H-indazol-4(5H)-ones which were prepared by bromination of 6,6-dimethyl-3-polyfluoroalkyl-6,7-dihydro-1H-indazol- 4(5H)-ones with N-bromosuccinimide in anhydrous carbon tetrachloride, followed by treatment of the corresponding 7-bromo derivatives with sodium azide.

Reaction of 2-Perfluoroalkanoylcyclohexane-1,3-diones and 3-Chloro-2-perfluoroalkanoylcyclohex-2-ene-1-ones with Amines

Reactions of 2-perfluoroalkanoylcyclohexane-1,3-diones with primary and secondary amines involved acid cleavage of the substrate with formation of the corresponding 3-aminocyclohex-2-en-1-ones. Vinylogous nucleophilic substitution in 3-chloro-2-perfluoroalkanoylcyclohex-2-ene-1-ones with amines led to the formation of 3-amino-2-perfluoroalkanoylcyclohex-2-ene-1-ones.

Synthesis of perfluoroalkyl-substituted 4,5-dihydro-3H-pyrazolo[4,3-a]phenazines and tetrahydroimidazo[4,5-e]indazoles

Oxidation of 1-aryl-3-perfluoroalkyl-6,7-dihydro-1H-indazol-4(5H)-ones with selenium dioxide in the presence of sulfuric acid in glacial acetic acid, followed by treatment of 6,7-dihydro-1H-indazole-4,5-diones thus obtained with an equimolar amount of o-phenylenediamine in ethanol or with a mixture of 4-fluorobenzaldehyde and ammonium acetate in acetic acid, gave 3-aryl-1-perfluoroalkyl-4,5-dihydro-3H-pyrazolo-[4,3-a]phenazines and 6-aryl-2-(4-fluorophenyl)-8-perfluoroalkyl-1(3),4,5,6-tetrahydroimidazo[4,5-e]indazoles, respectively.

2-perfluoroalkanoylcyclopentane-1,3-diones. Synthesis and some transformations

Abstract2-Perfluoroalkanoylcyclopentane-1,3-diones were synthesized for the first time by acylation of cyclopentane-1,3-dione with perfluorocarboxylic acids in the presence of 1,1′-carbonyldiimidazole or with perfluorocarboxylic anhydrides in the presence of imidazole. 2-Perfluoroalkanoylcyclopentane-1,3-diones were selectively reduced to 2-(1-hydroxyperfluoroalkyl)cyclopentane-1,3-diones by the action of triethylsilane in trifluoroacetic acid in the presence of a catalytic amount of lithium perchlorate. Treatment of the title compounds with oxalyl chloride and subsequent reaction with 2 equiv of primary amine (4-fluoroaniline, 4-fluorobenzylamine, 3,4-difluoroaniline, 3-trifluoromethylbenzylamine) gave the corresponding 3-arylamino-2-perfluoroalkanoylcyclopent-2-en-1-ones.

Synthesis and transformations of perfluoroalkyl-containing 6,7-dihydro-1H-indazol-4(5H)-ones oximes

Refluxing 3-perfluoroalkyl-6,7-dihydro-1H-indazol-4(5H)-ones with 4-fold excess of hydroxylamine hydrochloride in pyridine afforded their (E)-oximes. The obtained oximes were alkylated with ethyl iodide and acylated with carboxylic acids chlorides to obtain (E)-O-alkyl- and (E)-O-acyloximes respectively. Heating oximes in PPA at 120°C results in their aromatization by Semmler-Wolff reaction, hydrolysis of perfluoroalkyl groups, and generation of 4-amino-1-aryl-5,6-dimethyl-1H-indazole-3-carboxylic acids from of 3-tri-fluoromethylindazolone oximes and 1-(4-amino-1-aryl-5,6-dimethyl-1H-indazol-3-yl)-fluoroalkan-1-ones from of 3-perfluoroethyl- and 3-perfluoropropylindazolone oximes.

Regioselective reduction of 2-perfluoroalkanoylcyclohexane-1,3-diones and their enamino derivatives

Ionic hydrogenation of 2-perfluoroalkanoylcyclohexane-1,3-diones and their endocyclic enamino derivatives containing a secondary amino group by the action of triethylsilane in trifluoroacetic acid in the presence of a catalytic amount of lithium perchlorate involved regioselective reduction of the side-chain carbonyl group to hydroxy with formation of the corresponding hydroxy diketones and hydroxy amino ketones, respectively. Under analogous conditions endocyclic enamino derivatives possessing a tertiary amino group underwent deacylation to give enamino ketones.

Reaction of 2-perfluoroalkanoylcyclohexane-1,3-diones with diazomethane

Treatment of 2-perfluoroalkanoyl-5.5-dimethylcyclohexane-1,3-diones with a solution of diazomethane in diethyl ether led to the formation of the corresponding enol ethers and 3-hydroxy-6,6-dimethyl-3-perfluoroalkyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones. The latter underwent dehydration on heating in boiling benzene in the presence of a catalytic amount of p-toluenesulfonic acid to give 6,6-dimethyl-3-perfluoroalkyl-6,7-dihydrobenzofuran-4(5H)-ones.

Synthesis of New Betulonic Acid Conjugates with 2-Perfluoroacylcycloalkane-1,3-Diones Using Polymethylenediamine Linkers

New betulonic acid conjugates were synthesized in high yields by reacting 2-perfluoroacyl-3-chloro-2-cycloalken-1-ones, which were prepared by treating F-containing cyclic β-triketones with oxalylchloride, with equivalent amounts of betulonic acid amides of aminoalkyl hydrochlorides in the presence of Et3N in CHCl3.

Synthesis of fluorine-containing betulin esters

28-O-Fluoroacylbetulins were synthesized via acylation of betulin by fluorocarboxylic (perfluorobutyric, perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides in CHCl3 in the presence of Py. 3,28-Di-O-fluoroacylbetulins were prepared by treatment of betulin with fluorocarboxylic (trifluoroacetic, pentafluoropropionic) acid anhydrides in Py in the presence of 4-dimethylaminopyridine. 3,28-Di-O- (3-fluorobenzoyl)betulin was obtained from acylation of betulin by 3-fluorobenzoic acid in CH2Cl2 in the presence of N,N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine whereas acylation by perfluorobutyric acid under the same conditions gave 28-O-perfluorobutanoylbetulin.