Alkenyl derivatives of 5-nitro-2-pyridone: Synthesis and halocyclization

Alkylation of 5-nitro-2-pyridone by alkenyl halides in acetone in the presence of K₂СО₃ proceeds with generation of a mixture of N- and О-derivatives with N-isomer prevailing. 1-Allyl- and 1-methylallyl-5-nitro-2-pyridone react with halogens with the formation of 2-halomethyl-6-nitro-2,3-dihydrooxazolo[3,2-a]-pyridinium halides. 1-Prenyl-5-nitro-2-pyridone reacts with bromine with the formation of 3-bromine-2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium bromide, and with iodine giving 2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium triiodide.     

Alkylation of 4(5)-nitro-1,2,3-triazole with alcohols in strongly acidic media

Alkylation of 4(5)-nitro-1,2,3-triazole with alcohols in concentrated H₂SO₄ occurs at all three endocyclic N atoms, giving a mixture of isomeric N(1)-, N(2)-, and N(3)-alkyl-4-nitro-1,2,3-triazoles (alkyl is isopropyl, sec-butyl, and cyclohexyl). The selectivity of the alkylation depends on the alcohol used. The most selective alkylation is provided at the N(2) atom when isopropyl (81%) and sec-butyl alcohols are used (67%). With an increase in the reaction time, also in the order isopropyl-, sec-butyl-, and cyclohexyl-4-nitro-1,2,3-triazoles, the N(2)-isomers undergo isomerization into N(1)-alkyl-4-nitro-1,2,3-triazoles. In all the cases, the fraction of the N(3)-substitution products in the mixtures is 6–30%.     

Synthesis of (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone and (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone as colchicine mimetics

Colchicine mimetic (±)-4S,5R-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene (1) was epoxidized to afford a mixture of epoxides. The epoxides were separately converted in two steps, with high stereoselectivity, to two regioisomeric α-methoxyketones. One regioisomer, (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone (17), proved to be about 12-fold more potent than synthetic precursor 1 against HCT-116 tumor cells while the other regioisomer, (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone (16), and the synthetic intermediates tested showed no improvement in potency.     

Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes

A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of phenols. The reaction always provided C2 substitution in the phenol ring, dictated by hydrogen bond interactions between the phenolic hydroxyl group and the nitro group in 3-nitro-4H-chromenes. Reduction of the nitro group with concomitant hydrolysis of the enamine in 4-(2-hydroxyaryl)-3-nitro-4H-chromenes with Zn, Ac₂O in AcOH furnished hybrid amino-acid lactone incorporating ortho-tyrosine and phenyl alanine moieties.     

Synthesis and reactions of 5-tributylstannyl-4-fluoro-1H-pyrazole

The palladium-catalyzed cross-coupling reactions of 5-tributylstannyl-4-fluoro-1H-pyrazole with aryl iodides provided high yields of the corresponding 5-aryl-4-fluoro-1H-pyrazoles. Furthermore, these cross-coupling reactions proceeded smoothly under an atmosphere of carbon monoxide (CO) to afford the corresponding 5-acyl-4-fluoro-1H-pyrazoles as CO-insertion products.     

5-substituted 3-nitro-1-trinitromethyl-1,2,4-triazoles

A number of 5-R-substituted 3-nitro-1-trinitromethyl-1H-1,2,4-triazoles (R = Me, Cl, Br, N₃, NH₂, NO₂) were synthesized by nitration of the corresponding ω-(5-R-3-nitro-1H-1,2,4-triazol-1-yl)alkan-2-ones with mixtures of concentrated sulfuric and nitric acids.     

Darstellung von 3-Amino-4-nitro-5-methylisoxazol aus 3-Amino-5-methylisoxazol

Zusammenfassung 3-Amino-5-methylisoxazol wird mit Bernsteinsäureanhydrid in 3-Succinimido-5-methylisoxazol übergeführt, welches sich mit Oleum und rauch. HNO₃ nitrieren läßt. Die Abnahme der Schutzgruppe zu 3-Amino-4-nitro-5-methylisoxazol erfolgt mit alkohol. HCl.

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Preparation of 3-amino-4-nitro-5-methylisoxazole from 3-amino-5-methylisoxazole

3-Amino-5-methylisoxazole is converted to 3-succinimido-5-methylisoxazole with succinic anhydride. The product can be nitrated with oleum and fuming HNO₃. Removal of the protective group yielding 3-amino-4-nitro-5-methylisoxazole is effected with alcoholic HCl.

     

Reactions of polyfluorinated thietanes: Selective synthesis of 4-R-2,2-bis(trifluoromethyl)thietane-1-S-oxides and 2-substituted 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes

Oxidation of 4-substituted 2,2-bis(trifluoromethyl)thietanes by m-chloroperoxybenzoic acid results in selective formation of the corresponding S-oxides in 65-86% yield. Oxidation of 4-C₂H₅S-2,2-bis(trifluoromethyl)thietane under mild conditions led to selective formation of 4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane, which under more rigorous conditions was selectively converted into trans-4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane-1-S-oxide. Reaction of 4-substituted 2,2-bis(trifluoromethyl)thietanes with activated aluminum powder results in a highly selective ring expansion process, producing the corresponding 5-fluoro-4-(trifluoromethyl)-2,3-dihydro-2-alkoxythiophenes in 58-93% yield. These compounds were also prepared in 61-85% yield using a “one-pot” procedure, starting from sulfur, hexafluoropropene and the corresponding vinyl ether without isolation of any intermediates. Both 2-i-C₃H₇O- and 2-t-C₄H₉O- 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes were converted into 2-fluoro-3-trifluormethylthiophene by reaction with P₂O₅.     

The preparation of 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles

We report the first synthetic route to prepare 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles in high yields and exclusively as E-diastereoisomers.     

Chlorination and oxidation of 4-fluoro-5-tetrafluoroethyl-1,2-dithiole-3-thione

Chlorination of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-1,2-dithiole-3-thione with an equimolar amount of chlorine or sulfuryl chloride gives 3-chlorosulfanyl-4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-1,2-dithiolium chloride. The reaction of the title compound with excess chlorinating agent leads to 3,3,4,5-tetrachloro-4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-1,2-dithiolane. By oxidation and oxidative imination of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-1,2-dithiole-3-thione, the corresponding S-oxide and sulfimide were obtained, respectively.     

N-Alkylation of 4-nitro-1,2,3-triazole revisited. Detection and characterization of the N3-ethylation product, 1-ethyl-5-nitro-1,2,3-triazole

The products of the alkylation of sodium 4-nitro-1,2,3-triazolate with ethyl bromide were investigated using ¹H, ¹³C, and ¹⁵N NMR spectroscopy. It was found that alkylation proceeds on the triazole nitrogen atoms giving a mixture of three isomeric N-ethyl-4-nitro-1,2,3-triazoles. The molar ratio of N1, N2, and N3-alkylation products was 4:8:1. The formation of a minor N3-isomer, namely 1-ethyl-5-nitro-1,2,3-triazole was confirmed by X-ray structural analysis of single crystals of its tetranuclear copper(II) complex obtained by reaction of copper(II) chloride dihydrate with a mixture of the N2 and N3-isomers.     

Stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone

A stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate via asymmetric transfer hydrogenation catalyzed by [Ru(η⁶-arene)(S,S)-R₂NSO₂DPEN].     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.     

Reactions of 3-nitro-2-trihalomethyl-2H-chromenes with C-nucleophiles. Synthesis of 3-nitro-4-(pyrazol-4-yl)-2-trihalomethylchromanes

The nucleophilic addition of acetylacetone and ethyl acetoacetate at the double bond of 3-nitro-2-trihalomethyl-2H-chromenes in the presence of NaH affords 2,3,4-trisubstituted chromanes containing the β-dicarbonyl fragment at position 4. The trans-trans configuration and the enol structure of the reaction products were confirmed by ¹H NMR spectroscopy and X-ray diffraction. Treatment of these compounds with hydrazine gives the corresponding 3-nitro-4-(pyrazol-4-yl)-2-trihalomethylchromanes. The reactions of 3-nitro-2-trihalomethyl-2H-chromenes with nitromethane and nitroethane in the presence of K₂CO₃ produce 1,3-dinitro derivatives of the chromane series. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1945–1955, November, 2006.     

Kinetics of proton transfer from tetra(4-nitro-5-tert-butyl)phthalocyanine to nitrogen-containing bases in benzene

The acid-basic interaction between tetra(4-nitro-5-tert-butyl)phthalocyanine and pyridine, 2-methylpyridine, morpholine, piperidine, n-butylamine, diethylamine, and triethylamine in benzene is studied. It is found that the intermolecular transfer of protons of NH groups from tetra(4-nitro-5-tert-butyl)phthalocyanine to morpholine and diethylamine is characterized by unusually low values of the reaction constant rates. The effect of the structure of tetra(4-nitro-5-tert-butyl)phthalocyanine and tetra(3-nitro-5-tert-butyl)phthalocyanine, and of the nature of the base on the kinetic parameters of acid-base interaction is demonstrated. A structure is proposed for complexes with the transfer of displaced phthalocyanines’ protons. It is found that they undergo decomposition over time.     

Nucleophilic substitution and ring closure reactions of 4-chloro-3-nitro-2-quinolones

4-Chloro-3-nitro-2-quinolones 3 obtained from the 4-hydroxy quinolones 1 by nitration and chlorination, reacted with sodium azide to the 4-azido derivatives 4 which cyclized on thermolysis to yield the furoxanes 5 . Nucleophilic substitution reactions of 3 led to the 4-amino-, 4-fluoro- and 4-alkoxy-3-nitroquinolones 7, 8 and 9 , respectively. With thiols either 4-thio-3-nitro- 10 or 3,4-dithioquinolones 11 were obtained depending on the basic catalyst.     

N-Arylation of 4-fluoro-5-trimethylsilyl-1H-pyrazole

The 1,3-dipolar cycloaddition reaction of fluoro(trimethylsilyl)acetylene prepared in situ with an excess of diazomethane smoothly proceeded to give the corresponding 4-fluoro-5-trimethylsilyl-1H-pyrazole in 84% yield. The copper iodide-catalyzed N-arylation of the fluorinated pyrazole with a variety of aryl iodides afforded N-aryl-4-fluoropyrazoles as desilylation products in good to excellent yields.     

Study on the reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines with amines and thiols

Reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines with amines and thiols have been investigated. Pyridine catalyzes rearrangement of the title compounds into 6-phenyl-7-oxo-7H-pyrrolo[3,2-d]pyrimidine-5-oxides. Primary and secondary amines and thiols take part in a regio- and stereoselective addition reaction to the triple bond of 5-nitro-6-phenylethynylpyrimidines to form the corresponding syn-addition (in the case of secondary amines) or anti-addition (in the case of primary amines or thiols) products.     

4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides

4-Methyl- and 4-benzyl-5-aminoisoquinolin-1-ones are close analogues of the water-soluble PARP-1 inhibitor 5-AIQ. Their synthesis was approached through Pd-catalysed cyclisations of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave a mixture of 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydroisoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide similarly gave 2-benzhydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. The isomeric products are not interconvertible. A deuterium-labelling study indicated that the isomers were formed by different pathways: a π-allyl-Pd route and the classical Heck route. The corresponding secondary amides N-allyl-2-iodo-3-nitrobenzamide and N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCl, 150 °C, rapid heating). Hydrogenation of the nitro groups gave 4-methyl- and 4-benzyl-5-aminoisoquinolin-1-ones, which were potent inhibitors of PARP-1 activity.     

Synthesis,pharmacokinetics, and biological activity of a series of new pyridonecarboxylic acid antibacterial agents bearing a 5-fluoro-2-pyridyl group or a 3-fluoro-4-pyridyl group at N-1

The 1-(5-fluoro-2-pyridyl) or 1-(3-fluoro-4-pyridyl) group was introduced in the syntheses of new pyridonecarboxylic acid antibacterial agents. 1-(5-Fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxoquinolone-3-carboxylic acid 7b (DW-116) showed a moderate in vitro antibacterial activity but it was found to have very excellent pharmacokinetic profiles so that 7b (DW-116) showed dramatic increased in vivo efficacy.