Radical deoxygenation of 3-azatricyclo[2.2.1.0]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.     

Oxidative nucleophilic substitution of hydrogen versus ring-opening in the reaction of 4-R-2-nitrothiophenes with amines. The crucial effect of 4-alkyl groups

4-Alkyl-2-nitrothiophenes [10: R = CH3, CH(OH)CH3, CH(OCH3)CH3] react with secondary aliphatic amines, in the presence of AgNO3, to give 3-alkyl-2-amino-5-nitrothiophenes (12) through an oxidative nucleophilic substitution of hydrogen (ONSH) of synthetic interest. This behavior is in striking contrast with that of the parent 2-nitrothiophene (6), which was found to undergo ring-opening in analogous reaction conditions. A possible rationale for the crucial effect of alkyl groups is suggested, grounded also on a study of the corresponding Meisenheimer-like adducts.     

Dienone-phenol transformations in the reaction of 4, 6-di-tert-butylspiro [2.5]-3, 6-octadien-5-one with organomagnesium compounds

Conclusions 4, 6-Di-tert-butylspiro[2.5]-3,6-octadien-5-one when reacted with Grignard reagents opens the three-membered ring, with the formation of either the 4-alkyl-2,6-di-tert-butylphenol or the 4-(-haloethyl)-2,6 -di-tert-butylphenol.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1155–1157, May, 1967.     

Cyclopentanoids from phenol—9 : 3-Alkyl- and 3-alkenyl-5-hydroxycyclopent-2-enones

An efficient and versatile synthesis of 3-alkyl- and 3-alkenyl-5-hydroxycyclopent-2-enones is described. The key intermediate, 4-(t-butyldimethylsilyloxy)-3-methoxycyclopent-2-enone (5), is prepared in five steps from phenol. 1,2-Addition of various organolithium and Grignard reagents yields tertiary alcohol intermediates which afford the title compounds after solvolysis and desilylation.     

Use of quinolinium salts in parallel synthesis for the preparation of 4-amino-2-alkyl-1,2,3,4-tetrahydroquinoline

Compounds of pharmacological interest containing a 4-amino-2-alkyl-1,2,3,4-tetrahydroquinoline core structure were prepared starting from 4-chloroquinoline. This has been executed both in solution with a 1-benzyl-4-chloroquinolinium salt and on a solid support with a 1-(4-benzyloxybenzyl-PS)-4-chloroquinolinium resin as key intermediates. Diversification of such intermediates was accomplished through N-arylation of position 4 and subsequent nucleophilic addition of Grignard reagents of position 2 to deliver the expected 4-amino-2-alkyl-1,2,3,4-tetrahydroquinolines in 20-60% yields. The methods described within clearly demonstrate that the quinolinium salts are very efficient intermediates for parallel synthesis.     

Recyclization of ethyl 1-alkyl-5-benzoyl-6-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carboxylates into Bicyclic <Emphasis Type="Italic">N</Emphasis>-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives by the action of nitrogen-containing 1,4- and 1,5-binucleophiles

Reactions of ethyl 1-alkyl-5-benzoyl-6-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carboxylates with nitrogen-containing 1,4- and 1,5-binucleophiles (o-phenylenediamine, o-aminobenzenethiol, ethane-1,2-diamine, and propane-1,3-diamine) involved recyclization, leading to the formation of fused N-alkyl-5-benzoyl- 2-oxo-1,2-dihydropyridine-3-carboxamides, diethyl 6,6′-oxybis(1-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxylates), and diethyl 6,6′-[ethane-1,2-diyl(or propane-1,3-diyl)diimino]bis(1-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxylates), depending on the reactant ratio. The sequence of formation of intermediate recyclization products was determined.     

Synthesis of 4-alkyl-3-pyridinols from 3-benzyloxypyridine

The addition of Grignard reagents to the 1-phenoxycarbonyl salt of 3-benzyloxypyridine and a catalytic amount of cuprous iodide afforded 4-alkyl-3-benzyloxy-1-phenoxycarbonyl-1,4-dihydropyridines in good yield. The crude dihydropyridines were aromatized with o-chloranil to give 4-alkyl-3-benzyloxypyridines, which were debenzylated with hydrogen and 10% palladium on carbon to provide 4-alkyl-3-pyridinols.     

5-nitro-2-thienylvinylation. Nucleophilic substitution on 2-(2-bromovinyl)-5-nitrothiophene,new one-step method for preparation of new biologically active ethylenic derivatives of 5-nitro--2-thiophene

A facile method for preparing 2-(2-X-vinyl)-5-nitrothiophene has been established by the reaction of (Z)-2-(2-bromovinyl)-5-nitrothiophene with O, S and N nucleophiles.     

Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

Two 2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4-chloropyridines. In addition, a number of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2c-h were obtained from 2-(4-pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1-alkylhydroxyisoindolones 6a-f which, in two cases 6a,b , were dehydrated and subjected to three separate reductions to give targets 2c,d . In three cases, the intermediate hydroxyisoindolones 6c-e were reduced in one step to the target compounds 2c-g with lithium aluminum hydride-aluminum chloride. When 6f , the product of the addition of phenyl Grignard to 5 , was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane-trifluoroacetic acid. The lithium aluminum hydride-aluminum chloride conditions were successfully applied to the synthesis of a 1-benzyl-4-piperidine derivative 21.     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Functional derivatives of thiophene. I. Synthesis and 1H-NMR spectra in the 2-aminothiophene series

The preparation of 2-amino-5-nitrothiophene, 2-formamido-5-nitrothiophene, 2-acetamido-5-nitrothiophene and 2-t-butyloxycarbonylamino-5-nitrothiophene are described. Abnormal values of the coupling constants J_3.4 had been observed in the ¹H-nmr spectra of compounds obtained.     

Regioselective synthesis of 1-alkyl-5-(indol-3-yl- and -2-yl)pyrrolidin-2-ones from available reagents

The reaction under mild conditions of 1-alkyl-5-hydroxypyrrolidin-2-ones with different indoles having a free 3 position leads exclusively to 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones but if position 3 is occupied to 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones.     

Synthesis and synthetic utility of 1-acyl-2-alkyl-4-trimethylstannyl-1,2-dihydropyridines

1-Acyl-2-alkyl-1,2-dihydropyridines were prepared from 4-trimethylstannylpyridine and Grignard reagents. This methodology was utilized in the synthesis of N-methyl-2-azatricyclo[5.3.1.0]undecane.     

Reactivity of 2-fluoro-5-nitrothiophene towards sodium thiophenoxide and piperidine. Comparison with other 2-halogeno-5-nitrothiophenes

2-Fluoro-5-nitrothiophene reacts with sodium thiophenoxide and piperidine much faster than other 2-halogeno-5-nitrothiophenes. In methanol the reactions with both nucleophiles follow overall second order kinetics, while in benzene the observed second order rate constants of the reaction with piperidine show a linear dependence by the piperidine concentration. Such a dependence, which is mild for the chloro, bromo and iodo derivative, becomes strong for the fluoro compound. Moreover, the reaction of 2-fluoro-5-nitrothiophene with [1-²H]piperidine shows the absence of a primary isotope effect. The results are interpreted within the framework of the two-stage, intermediate-complex mechanism, the first stage (attack of the nucleophile on the substrate) being rate determing for the reactions of 2-fluoro-, -chloro-, -bromo- and -iodo-5-nitrothiophene with thiophenoxide in methanol and of 2-chloro-, -bromo- and -iodo-5-nitrothiophene with piperidine in benzene. In the case of the reaction of 2-fluoro-5-nitrothiophene with piperidine in benzene the data are in agreement with a mechanism in which the rate determining step is the decomposition of the tetrahedral intermediate into products. The intervention of a second amine molecule in the transition state of the rate determining step can be rationalized in terms of bifunctional catalysis. A comparison of reactivity of thiophenoxide and piperidine towards 2-halogeno-5-nitrothiophenes (Hal = F, Cl, Br, I) indicates a greater sensitivity of the reaction with piperidine than that with thiophenoxide to the change of the leaving group.     

A stereoselective synthesis of tri-substituted alkenes. The nickel-catalysed coupling of Grignard reagents with 6-alkyl-3,4-dihydro-2H-pyrans.

The nickel-catalysed coupling of certain Grignard reagents with 6-alkyl-3,4-dihydro-2H-pyrans is highly stereoselective and gives tri-substituted alkenes with retention of configuration. The method was applied to the synthesis of (E)-3-Acetoxy-7-methyl-6-nonene, the aggregation phermone of the square-necked grain beetle.     

2-Formyl-5-nitrothiophene as a reagent for phosphoranes

2-Formyl-5-nitrothiophene has high reactivity with respect to phosphoranes, with which it reacts quantitatively to give l-aryl-3-(5-nitro-2-thienyl)propenones. The reaction can be used for the qualitative detection of phosphoranes.     

Stereochemical effect on biological activities of new series of piperidin-4-one derivatives

New series of (2S,3R,4S,6R)-3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol were synthesised by the reduction of cis-3-alkyl-2,6-diarylpiperidin-4-one using Grignard reagent. The structural assignments and conformational studies of the synthesised compounds were established based on the IR, ¹H NMR, ¹³C NMR, NOESY and mass spectral studies. Their stereochemical effect on antibacterial, antifungal and anthelmintic activities was studied.     

Diastereoselective addition of organozinc reagents to 2-alkyl-3-(arylsulfanyl)propanals

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-alkyl moiety of high diastereomeric purity is described. Such compounds can serve as potential building blocks for the preparation of several kinds of natural products. Diastereoselective synthesis of two potential pine sawfly pheromone components, one the pure racemic threo-isomer of 3-methylpentadecan-2-ol and the other the racemic erythro-isomer of 3-methyltridecan-2-ol are described. The diastereoselective addition of R₂Zn (R=Me, Et and n-Bu) to several 2-alkyl-3-(arylsulfanyl)propanals in the presence of a Lewis acid and CH₂Cl₂ as solvent was studied. An excellent diastereomeric ratio (95/5 anti-Cram/Cram) was obtained with 2-[(phenylsulfanyl)methyl]pentanal, 2-[(phenylsulfanyl)methyl]decanal and 2-[(phenylsulfanyl)methyl]dodecanal and Me₂Zn in the presence of TiCl₄.     

Isothiazoles. part X : New 3-substituted-2-arylpropenamidines by base catalyzed ring opening of 3-amino-4-arylisothiazole 1,1-dioxides

Starting from 5-unsubstituted or 5-alkyl-, aryl-, heteroarylsubstituted 3-diethylamino-4-arylisothiazole 1,1-dioxides by base induced ring opening 3-alkoxypropenamidines were synthesized in excellent yields in a mild and efficient way. When 5-bromo-3-diethylamino-4-arylisothiazole 1,1-dioxide was used as the reagent, 3,3-dialkoxy-propenamidines, a new class of unsaturated amidines, were obtained. By using Grignard reagents 3-substituted acrylamidines can be produced.     

Highly effective stereoselective synthesis of vinyl ethers of 5-alkyl-2-(2-furyl)-5-hydroxymethyl-1,3-dioxanes

The vinylation of cis-5-alkyl-5-hydroxymethyl-2-(2-furyl)-1,3-dioxanes in the KOH–DMSO system in acetylene at atmospheric or elevated pressures (85-100°C, 3 h) takes place stereoselectively and leads to the formation of cis-5-alkyl-2-(2-furyl)-5-vinyloxymethyl-1,3-dioxanes with yields of up to 93%.