Synthesis and aminolysis of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N-(oxiran-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide

A new N-(oxiran-2-ylmethyl) (glycidyl) derivative has been obtained by reaction of N-(bicyclo-[2.2.1]hept-5-en-endo-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide with epichlorohydrin. Its epoxidation and aminolysis have been studied, and the regioselectivity of these transformations has been determined by IR and ¹H NMR spectroscopy and mass spectrometry.     

Synthesis,structure, and transformations of <Emphasis Type="Italic">N</Emphasis>-(alkyl-, benzyl-, arylsulfonyl)-<Emphasis Type="Italic">N</Emphasis>-(oxiran-2-ylmethyl)bicyclo[2.2.1]hept-5-en-<Emphasis Type="Italic">exo</Emphasis>-2-ylmethanamines

Reactions of N-(alkyl-, benzyl-, arylsulfonyl)bicyclo[2.2.1]hept-5-en-exo-2-ylmethanamines with 2-(chloromethyl)oxirane in the presence of tetramethylammonium iodide gave a number of cage-like N-(oxiran-2-ylmethyl)sulfonamides, as well as N-(exo-5,6-epoxybicyclo[2.2.1]heptan-exo-2-ylmethyl)-4-nitro-N-(oxiran-2-ylmethyl)benzenesulfonamide. The latter was also synthesized by oxidation of oxiran-2-ylmethyl norbornene derivative with peroxy acids. Opening of the epoxide ring in N-(oxiran-2-ylmethyl) sulfonamides in reaction with benzylamine followed the Krasuskii rule, and the aminolysis of N-(exo-5,6-epoxybicyclo[2.2.1]-heptan-exo-2-ylmethyl)-4-nitro-N-(oxiran-2-ylmethyl)benzenesulfonamide chemoselectively occurred at the side-chain epoxy group.     

Epoxidation and Heterocyclization of Arenesulfonamides of the Norbornene Series

Reactions of previously known and newly synthesized N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)arenesulfonamides with monoperoxyphthalic acid generated in situ from phthalic anhydride and 30% hydrogen peroxide lead mostly to the corresponding N-arylsulfonyl-exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes (azabrendanes). In some cases, N-(exo-5,6-epoxybicyclo[2.2.1]hept-5-en-exo-2-ylmethyl)arenesulfonamides were isolated as the only products or mixtures of alternative oxidation products were obtained. The presence of electron-acceptor nitro groups in the benzene ring and bulky substituents, primarily in the ortho position, is considered to be a structural factor preventing the primary oxidation products (epoxy derivatives) from undergoing heterocyclization.     

Synthesis and Dehydration of endo-2-(3-R-Isoxazol-5-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-exo-2-ols

endo-2-Ethynyl-1,7,7-trimethylbicyclo[2.2.1]heptan-exo-2-ol reacts with nitrile oxides, yielding endo-2-(3-R-isoxazol-5-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-exo-2-ols. Treatment of the latter with methanesulfonyl chloride in pyridine leads to dehydration and formation of mixtures of the corresponding 1-(3-R-isoxazol-5-yl)-3,3-dimethyl-2-methylenebicyclo[2.2.1]heptanes and 2-(3-R-isoxazol-5-yl)-1,7,7-trimethylbicyclo[2.2.1]hept-2-enes at a ratio of 2:1.     

Reaction of <Emphasis Type="Italic">N</Emphasis>-(2,3-epoxypropyl)arenesulfonamides with (bicyclo[2.2.1]hept-5-en-<Emphasis Type="Italic">endo</Emphasis>-2-yl)methanamine

Reactions of bicyclo[2.2.1]hept-5-en-endo-2-ylmethanamine with N-(2,3-epoxypropyl)arenesulfonamides gave amino alcohols having a norbornene fragment and sulfonamide group. The major products were formed via opening of the oxirane ring according to the Krasuskii rule. The product structure was determined by ¹H and ¹³C NMR spectroscopy using DEPT and two-dimensional COSY, NOESY, HMQC, and HMBC techniques.     

Azabrendanes IV. Synthesis and characterization of N-(alkyl- and benzylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.0]nonanes

exo- and endo-5-Aminomethylbicyclo[2.2.1]hept-2-enes have been obtained from stereoisomeric exo- and endo-5-cyanobicyclo[2.2.1]hept-2-enes and the corresponding sulfonamides were obtained through reaction of amines with methyl-, n-propyl-, n-butyl-, benzyl-, and cyclohexylsulfonyl chlorides. From the stereoisomeric sulfonamides with peroxy acids, various products were obtained: exo-sulfonamides were transformed into epoxy derivatives, and, in contrast, most of the endo-stereoisomers underwent heterocyclization resulting in substituted exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes. The type of the products obtained did not depend on the type of peroxy acid used (peroxyacetic, peroxyphthalic, and m-chloroperoxybenzoic one). In contrast to other endo-sulfonamides, N-(cyclohexylsulfonyl)-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene in reaction with peroxyacetic acid did not undergo heterocyclization, probably, due to steric factors. The structure and stereochemical homogeneity of the sulfonamides and the structure of the products of their oxidation with peroxy acids were confirmed by spectroscopic methods. The molecular structure of N-(cyclohexylsulfonyl)-endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptane was determined by X-ray diffraction analysis. The mechanism of the intramolecular heterocyclization reaction of N-substituted endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptanes was studied at the BHandHLYP/6-31G(d) level of theory.     

5,5,6-Trimethylbicyclo[2.2.1]heptan-2-one in the Synthesis of Carbocyclic Analogs of Prostaglandin Endoperoxides

1,3-Dipolar cycloaddition of nitrile oxides to 5,5,6-trimethyl-exo-2-ethynylbicyclo[2.2.1]heptan-endo-2-ol yields the corresponding 2-(isoxazol-5-yl) derivatives. Opening of the isoxazole ring in the latter gives rise to prostanoid precursors with partially built up or completed side chain. 5,5,6-Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one reacts with nitromethane in the presence of tetramethylguanidine to afford 5,5,6-trimethyl-exo-3-(2-nitroethyl)bicyclo[2.2.1]heptan-2-one which can be converted into the corresponding nitrile oxide by the action of phenyl isocyanate in benzene in the presence of triethylamine as catalyst. 1,3-Dipolar cycloaddition of the nitrile oxide to ethyl 4-pentynoate yields 3-exo-[5-(2-ethoxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one. Treatment of the latter with hydroxyl amine leads to formation of the corresponding Z-oxime whose reaction with n-hexyl bromide results in transalkylation of the ester group to afford 3-exo-[5-(2-hexyloxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one oxime.     

Cage-like amines in the synthesis and oxidation of camphor-10-sulfonic acid amides

Reactions of bicyclo[2.2.1]hept-5-en-exo- and -endo-2-ylmethanamines, exo-5,6-epoxybicyclo-[2.2.1]hept-exo-2-ylmethanamine, 1-(bicyclo[2.2.1]hept-2-yl)ethanamine, and 1-(1-adamantyl)ethanamine with camphor-10-sulfonyl chloride in chloroform in the presence of triethylamine gave the corresponding sulfonamides having two cage-like fragments. Stereoisomeric N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)camphor-10-sulfonamides were oxidized with peroxyphthalic acid generated in situ from phthalic anhydride and 50% hydrogen peroxide. The exo stereoisomer was thus converted into the corresponding 5,6-epoxy derivative, while the endo isomer gave rise to 4-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl)-4-azatricyclo[4.2.1.0^3,7]-nonan-exo-2-ol (substituted azabrendane). The structure of the synthesized camphor-10-sulfonamides was confirmed by IR and ¹H and ¹³C NMR spectra with the use of homo- (COSY) and heteronuclear ¹H-¹³C correlation techniques (HMQC, HMBC). Heterocyclization of sulfonamides of the norbornene series was also simulated by quantum-chemical calculations at the PM3 and BHandHLYP/6-31G(d) levels of theory.     

Structural analysis of three methyl N-phosphorylated 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylates

Both exo and endo isomers of (±)-methyl N-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate and (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate were dihydroxylated with OsO₄. The unexpected formation of (±)-methyl 5,6-dihydroxy-N-diphenylphosphoryl-2-azabicyclo[2.2.1]heptane-3-endo-carboxylate from (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-endo-carboxylate is discussed based on NMR analyses and experimental observations. The two N-diphenylphosphoryl dihydroxybicycles are analyzed in terms of their crystalline structure by X-ray crystallography.     

Syntheses on the basis of diethyl (2-morpholinoethyl)malonate

New functionally substituted butan-4-olides were synthesized by reactions of diethyl (2-morpholinoethyl) malonate with 2-(allyloxymethyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, N-ethyl-N-(oxiran-2-ylmethyl)aniline, and 1-chloro-2,3-epoxypropane. 5-[2-(Morpholino)ethyl]barbituric and -thiobarbituric acids were also synthesized.     

Synthesis of new imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]thiazole derivatives from 2-amino-4-(2,2-dichlorovinyl)-1,3-thiazole and <Emphasis Type="Italic">N</Emphasis>-(2,2-dichloro-2-phenylethylidene)arenesulfonamides

2-Amino-4-(2,2-dichlorovinyl)-1,3-thiazole reacted with highly electrophilic N-(2,2-dichloro-2-phenylethylidene)- and N-(2,2,2-trichloroethylidene)arenesulfonamides through the exocyclic amino group to give products of nucleophilic addition to the azomethine bond, N-[2,2-di(or 2,2,2-tri)chloro-1-(1,3-thiazol-2-ylamino)ethyl]arenesulfonamides in good yields. Intramolecular heterocyclization of the latter afforded N-[3-(2,2-dichloroethyl)-6-phenylimidazo[2,1-b][1,3]thiazol-5-yl]arenesulfonamides.     

The Homoconjugated Electron-Releasing Carbonyl Group of 1-Methylbicyclo[2.2.1]hept-5-en-2-one. Regioselective syntheses of 5-chloro- and 6-chloro-1-methylbicyclo[2.2.1]hept-5-en-2-one

Syntheses of (±)-2-exo-cyano-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate ( 1 ) and of (±)-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 2 ) are reported. The additon of PhSeCl to 1 afforded (±)-5-endo-chloro-2-exo-cyano-1-methyl-6-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate ( 6 ), whereas 2 added to PhSeCl with the opposite regioselectivity giving (±)-6-endo-chloro-1-methyl-5-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]heptan-2-one ( 7 ). These adducts were converted into 5-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 9 ) and 6-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 10 ), respectively.     

Reactions of Bi-, Tri-, and tetracyclic amines with succinic anhydride

Succinic anhydride reacted with cage-like amines {bicyclo[2.2.1]hept-5-en-exo-and-endo-2-yl-methanamines, 2-(bicyclo[2.2.1]hept-5-en-endo-2-yl)ethanamine, exo-5,6-epoxybicyclo[2.2.1]heptan-exo-2-yl-methanamine, tetracyclo[6.2.1.1^3,6.0^2,7]dodec-9-en-endo-4-ylmethanamine, 1-(bicyclo[2.2.1]heptan-2-yl)ethanamine, and 4-azatricyclo[5.2.1.0^2,6]dec-8-ene} to give the corresponding amido acids having a cage-like fragment. The latter were converted into carboximides by the action of hexamethyldisilazane in boiling benzene in the presence of zinc(II) chloride and then into epoxy derivatives. The structure of the newly synthesized compounds was confirmed by IR and NMR spectroscopy.     

2-Amino-4-(aminomethyl)thiazole-based derivatives as potential antitumor agents: design,synthesis, cytotoxicity and apoptosis inducing activities

Novel 2-amino-4-(aminomethyl)thiazole derivatives were designed and synthesized by a facile method including the Hantzsch construction of thiazole core followed by amidation and nucleophilic substitution steps. Bioassay results showed that 4-(tert-butyl)-N-[4-(piperazin-1-ylmethyl)thiazol-2-yl]-benzamide and 4-(tert-butyl)-N-{4-[(4-piperidinopiperidin-1-yl)methyl]thiazol-2-yl}benzamide possessed similar activities compared with 5-fluorouracil. The 4-piperidino-piperidin-1-yl-containing derivative also suppressed proliferation of cultured tumor cells by inducing apoptosis.     

Microwave-assisted synthesis of methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-2-carboxylate through unexpected stereoselective substitution reaction

Methyl (1S,2R,4S,5R)-7-aza-5-bromo-bicyclo[2.2.1]heptane-2-carboxylate was synthesized in high yield in short time from methyl (1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanecarboxylate through intramolecular cycloamination under microwave-assisted conditions. The following substitution reaction by trifluoro-acetate anion also took place in microwave-assisted conditions to afford methyl (1S,2R,4S,5S)-7-aza-5-hydroxy-bicyclo[2.2.1]heptane-2-carboxylate. In the acyloxylation reaction, unusual endo-selectivity was observed owing to 7-azabicyclo[2.2.1]heptane skeleton.     

Substituted 2-norbornyl carbenes

A series of endo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have been generated by pyrolysis of the sodium salt of the tosylhydrazone precursors. The endo-6-trimethylsilyl and endo-6-thiomethoxy substituted carbenes give 1,3-migration of these substituents to the carbene center. However groups such as methyl, CH₂SiMe₃, phenyl, and methoxy are ineffective 1,3-migrating groups. The facile 1,3-migration of trimethylsilyl and thiomethoxy has been rationalized in terms of stabilized transition states where the migrating group interacts effectively with the carbene vacant orbital. In the cases of endo-6-thiomethoxy and methoxy derivatives, the carbene also inserts effectively into the methyl group of the substituent. Heteroatom stabilization of the transition state for C-H insertion facilitates these processes. Certain exo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have also been generated. While the exo-6-thiomethoxy and carbomethoxy systems give exclusive 1,3-hydrogen migration, the exo-6-sulfonyl derivative gives, in addition to 1,3-hydrogen migration, an alkene product derived from 1,2-hydrogen migration. The lowered propensity for 1,3-hydrogen migration is attributed to the strong electron-withdrawing sulfonyl group, which decreases the hydridic 1,3-interaction with the carbene vacant orbital.     

Modification of 2-trifluoromethyl-1H-benzimidazole with hydroxyalkyl substituents

Alkylation of 2-(trifluoromethyl)-1H-benzimidazole with 4-bromobutyl acetate gave 4-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]butyl acetate which was deacylated by the action of hydrogen chloride in anhydrous ethanol. 4-[2-(Trifluoromethyl)-1H-benzimidazol-1-yl]butan-1-ol thus formed showed a moderate tuberculostatic activity. Alkylation of the title compound with chloromethyloxirane afforded a mixture of 1-chloro-3-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]-propan-2-ol and 1-(oxiran-2-ylmethyl)-2-trifluoromethyl-1H-benzimidazole. A new procedure was proposed for the synthesis of 2-[(2-trifluoromethyl-1Hbenzimidazol-1-yl)methoxy]ethyl acetate.     

Preparation of methano[1,3]oxazolo[3,2-a]quinolin-2-ones from 2-(pent-3-en-2-yl)anilines

Acid-catalyzed Claisen aromatic rearrangement of ethyl N-(pent-3-en-2-yl)-N-phenylglycinate leads to the formation of ethyl N-[2-(pent-3-en-2-yl)phenyl]glycinate. The reaction of sodium salt of N-acetyl-2-(pent-3-en-2-yl)-4-methylaniline with methyl bromoacetate afforded ethyl N-acetyl-N-[4-methyl-2-(pent-3-en-2-yl)phenyl]glycinate. The hydrolysis of synthesized esters, the conversion of the obtained acids by treating with ethyl chloroformate into munchnones, and the subsequent [3+2]-cycloaddition provided methoxazoloquinoline structures.     

Synthesis of sulfur-containing vicinal aminoalcohols on the basis of N-(oxiran-2-ylmethyl)amines

The reaction of (methanediyldibenzene-4,1-diyl)dimethanethiol, (oxydibenzene-4,1-diyl)dimethanethiol, biphenyl-4,4′-diyldimethanethiol with 1-(oxiran-2-ylmethyl)piperidine and N-(oxiran-2-ylmethyl)-N-ethylaniline afforded the corresponding sulfur-containing vicinal aminoalcohols resulting from the opening of the oxirane ring in keeping with Krasusky rule.     

(η3-allyl)palladium(II) catalysts for the addition polymerization of norbornene derivatives with functional groups

Cycloaliphatic polyolefins with functional groups were prepared by the Pd(II)-catalyzed addition polymerization of norbornene derivatives. Homo- and copolymers containing repeating units based on bicyclo[2.2.1] hept-5-en-2-ylmethyl decanoate (endo/exo-ratio = 80/20), bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (exo/endo = 80/20), bicyclo[2.2.1]hept-5-ene-2-methanol (endo/exo = 80/20), and bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (100% endo) were prepared in 49–99% yields with {(η³-allyl)Pd(BF₄)} and {(η³-allyl)Pd(SbF₆)} as catalysts. The catalyst containing the hexafluoroantimonate ion was slightly more active than the tetrafluoroborate based Pd-complex.