Stereoisomeric N-(p-Nitrobenzoyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes. Synthesis,Epoxidation, 1H and 13C NMR Spectra

Preparation is described of stereoisomeric (p-nitrobenzoyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes and their epoxidation by peracetic acid. By an example of one of amides was demonstrated a possibility of selective reduction of separated fragments in the polyfunctional compound using sulfur in alkaline medium, hydrazine hydrate in the presence of a nickel catalyst, and lithium aluminum hydride. By reaction with electrophilic reagents from the amines synthesized, (p-aminobenzoyl)-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene and (p-aminobenzoyl)-endo-2-aminomethylbicyclo[2.2.1]hept-2-ene, were obtained new bicyclic compounds containing alongside the amide group also sulfonamide, carboxamide, urea, and thiourea moieties. The structure of compounds obtained was confirmed by ^1Hand ^13C NMR spectroscopy, by two-dimensional spectra measured along COSY and NOESY procedures.     

New N-(Arylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes. Synthesis, 1H and 13C NMR Spectra,and Chemical Reactions

A synthesis of new N-(arylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes obtained by reaction of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-enes with arylsulfonyl chlorides is described. With the use of the data of ¹H and ¹³C NMR spectra, including those of two-dimensional spectra recorded in COSY and NOESY mode, the contribution of stereochemical features of sulfonamides into the spectra structure of endo- and exo-isomers was evaluated. Applying various methods of the phase-transfer catalysis alkylation and acylation of the stereoisomeric arylsulfonamides containing a norbornene fragment was carried out. The reactions of alkylated stereoisomeric sulfonamides, N-(benzyl)-N-(3,4-dichlorophenylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes, with peroxyphthalic acid provide epoxides; the orientation of substituents in the cage norbornene fragment does not affect the direction of the process. The structure of the products obtained by sulfonamides transformations was confirmed by IR, ¹H and ¹³C NMR spectra.     

Synthesis and Epoxidation of 5-(2-Aminoethyl)bicyclo[2.2.1]hept-2-ene Derivatives

A number of derivatives of 5-(2-aminoethyl)bicyclo[2.2.1]hept-2-ene (85-90% of the endo isomer) were synthesized by reactions with p-nitrobenzenesulfonyl chloride, p-toluenesulfonyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, benzyl isocyanate, m-tolyl isocyanate, phenyl isothiocyanate, and endic anhydride. By reactions of the resulting sulfon- and carboxamides with peroxyphthalic acid generated in situ from phthalic anhydride and 40-45% hydrogen peroxide the corresponding epoxy derivatives were obtained. These reactions were not accompanied by heterocyclization into azabrendane derivatives, which is typical of homologous N-(p-nitrophenylsulfonyl)-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene.     

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.     

Derivatives of exo-5-Aminomethyl-endo-5-methylbicyclo[2.2.1]hept-2-ene and exo-5-Aminomethyl-endo-5-methyl-exo-2,3-epoxybicyclo[2.2.1]heptane

exo-5-Aminomethyl-endo-5-methylbicyclo[2.2.1]hept-2-ene and its 2,3-epoxy derivative were synthesized, and their geometric parameters and conformational properties, in particular the barriers to rotation of the aminomethyl fragment about the exocyclic C⁵ÄC bond, were studied by the molecular-mechanics method (MMX) and compared with those found for structurally related exo-5-aminomethylbicyclo[2.2.1]hept-2-ene. The title compounds were brought into reactions with electrophilic reagents: arenesulfonyl chlorides, isocyanates, and isothiocyanates.     

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.     

1H-NMR Spectra of Cyclohexa-1,4-dienes and Cyclohexenes Annellated to Bicyclo[2.2.1]hept-2-enes. The Inter-Ring Homoallylic H,H Coupling Constants as Stereochemical Probes

The 360-MHz-¹H-NMR spectra of cyclohexa-1,4-dienes and cyclohexenes annellated to bicyclo[2.2.1]hept-2-enes and 7-oxabicyclo[2.2.1]hept-2-enes show inter-ring homoallylic coupling constants between the bridgehead protons of the bicyclo[2.2.1]heptenes and the exo-protons of the allylic methylene groups (0.8 ± 0.15 Hz for bicyclo[2.2.1]hept-2-enes; 0.8–1.4 Hz for 7-oxabicyclo[2.2.1]hept-2-enes). Contrastingly, the corresponding coupling between the bridgehead protons and the endo-protons is absent. The observed values are compared with those calculated by the INDO and CNDO/2 methods and discussed in the light of the bicyclo[2.2.1]hept-2-ene bond π-anisotropy. Vicinal as well as intra-ring homoallylic coupling constants are consistent with a small puckering of the cyclohexa-1,4-diene rings toward the endo-face. The allylic exo-methylene protons are more deshielded than the endo-protons independent of the nature of the substituents, the nature of the bridges, and the degree of unsaturation of the annellated systems. These results constitute a probe for the configuration of cyclohexa-1,4-dienes and cyclohexenes annellated to these bicyclic skeletons.     

(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.     

Synthesis and Reactivity of Amines Containing Several Cage-like Fragments

By reaction of bicyclo[2.2.1]hept-5-en-exo- and endo-2-ylmethylamine, exo-5,6-epoxybicyclo[2.2.1]hept-exo-2-ylmethylamine and benzylamine with 1-adamantanecarbonyl chloride, 1,3-adamantanedicarbonyl dichloride, and 1,3-adamantanediacetyl dichloride amides were obtained with one, two, and three cage-like fragments that were reduced to amines by lithium aluminum hydride. The reactivity of the amines was evaluated with the use of semiempirical quantum-chemical method PM3. Derivatives of the amines were prepared by reactions with arene-sulfonyl chlorides, p-nitrobenzoyl chloride, succinic and endic anhydrides, p-toluenesulfonyl and m-tolyl isocyanates, phenyl isothiocyanate, and p-nitrophenyloxirane. The structure of the new compounds was supported by analysis of their IR and ¹H NMR spectra. The dependence of some reaction conditions was observed on the number and remoteness of the cage-like fragments from the reaction centers of the amines.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 695–705.Original Russian Text Copyright © 2005 by L. Kas’yan, Karpenko, A. Kas’yan, Isaev.     

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.     

Synthesis of methanethial s-oxide (sulfine) and alkanethial s,s-dioxides by fluorodesilylation. Stereochemistry of their cyclopentadiene diels-alder adducts

Fluorodesilylation of trimethylsilylmethanesulfinyl chloride 4 in the presence of cyclopentadiene gives 2-thiabicyclo[2.2.1]hept-5-ene endo-2-oxide,5; in a like manner 1-trimethylsilylalkanesulfonic anhydrides afford endo- and exo-3-alkyl-2-thiabicyclo[2.2.1]hept-5-ene 2,2-dioxides, with the endo isomer predominating. Sulfine and alkyl sulfenes are invoked.     

Mass spectrometry in stereochemical problems. 6 — The case of mono and di-substituted norbornanes

The mass spectrometric behaviour of pairs of stereoisomeric mono- and di-substituted norbornanes, namely bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylic acid, methyl bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylate, 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamidobicyclo[2.2.1]heptane-2-exo-carboxylic acid and methyl 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamido-bicyclo[2.2.1]heptane-2-exo-carboxylate was studied in detail with particular emphasis on characterization of the stereoisomers. The fragmentation patterns, studied with the aid of mass-analysed ion kinetic energy spectrometry, were supported by semi-empirical MO–SFC calculations, performed using the AM1 method included in the AMPAC program.     

Unusual pathway of the tantalum-catalyzed carboalumination reaction of alkenes with triethylaluminum

Carboalumination of 1-alkenes (1-hexene, 1-octene, 1-decene) with Et₃Al in the presence of catalytic amounts of TaCl₅ results in a mixture of 2-(R-substituted)- and 3-(R-substituted)-n-butylaluminums (1:1 ratio) in total yields of 75–85%. The TaCl₅-catalyzed reaction of bicyclo[2.2.1]hept-2-ene, endo-tricyclo[5.2.1.0^2,6]deca-3,8-diene, and (exo/endo)-5-methylbicyclo[2.1.1]hept-2-ene with Et₃Al leads to the formation of diethyl[2-exo-(2′-norbornylethyl)]aluminums in high yields. DFT calculations confirm the thermodynamic preference of the final exo product. The multistep reaction mechanisms for the formation of the resultant organoaluminums through tantalacyclopentanes as key intermediates are also discussed.     

Reactions of Bicyclo[2.2.1]hept-5-ene-2,3-dicarboximides with Aromatic Azides

Reactions of N-substituted bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximides with o- and p-nitrophenyl azides, as well as with p-nitrophenylsulfonyl azide and p-toluenesulfonyl azide, afforded the corresponding substituted dihydrotriazole (from aryl azides) and arylsulfonylaziridine derivatives (from sulfonyl azides). The exo orientation of the nitrogen-containing cyclic fragments (in keeping with the Alder rule) and endo orientation of the imide ring were confirmed by analysis of the IR and ¹H and ¹³C NMR spectra. The molecular structure of one of the products was examined by X-ray analysis.     

Azabrendanes V. Synthesis and reactions of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-ene-based ureas

A number of stereoisomeric ureas (N-[aryl(benzyl, or cycloalkyl)carbamoyl]-exo(endo)-5-aminomethylbicyclo[2.2.1]hept-2-enes) have been synthesized from bicyclo[2.2.1]hept-2-en-exo(endo)-5-carbonitrile by reduction with lithium aluminum hydride and subsequent reaction of the resulting amines with aryl (benzyl, or cycloalkyl) isocyanates. Regioselective alkylation of stereoisomeric ureas has been performed with benzyl chloride under liquid/solid phase-transfer catalysis. The outcome of the reactions of ureas with peroxy acids is dependent upon the orientation of substituents in the bicyclic fragment. Exo-isomeric ureas are transformed into corresponding epoxy-derivatives, while reactions of the endo-isomers are accompanied by intramolecular cyclization, resulting in the formation of azatricyclononane derivatives. Quantum-chemical calculations have established a decisive role for additional hydrogen bonding in the stabilization of transition states in these heterocyclization reactions of ureas. The structures and stereochemical homogeneity of the products have been confirmed by the analysis of ¹H and ¹³C NMR spectra and correlation spectroscopy. The mechanism of the intramolecular heterocyclization reaction of ureas and carboxamide of endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptane series has been studied at the BHandHLYP/6-31G(d) level of theory.      

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.     

Zur Bildung polycyclischer Ketone bei der Umsetzung von 5, 6-Dimethyliden-bicyclo[2.2.1]hept-2-en mit Dieisen-enneacarbonyl

On the Formation of Polycyclic Ketones in the Reaction of 5, 6-Dimethylidene-bicyclo[2.2.1]hept-2-ene with Diiron-enneacarbonyl 5,6-Dimethylidene-bicyclo[2.2.1]hept-2-ene (4) , in the presence of diiron-ennea-carbonyl in boiling hexane, produces the endo-and exo-tricarbonyl-iron complex of 4 (endo- and exo- 5 ). A mixture of numerous tricarbonyl-iron complexes with ligands derived from coupling and carbonylation reactions of 4 are also formed. The endo- and exo- 5 compounds as well as two tricarbonyl-iron complexes ( 7 and 8 ) of penta-cyclic ketones could be isolated and characterized. After oxidative removal of the tricarbonyl-iron groups in the reaction mixture the three pentacyclic ketones 9 , 10 and 11 were separated. Structure and configuration of these ketones were deduced from spectroscopic analyses, especially from their ¹H- and ¹³C-NMR. spectra (see tables 1–4). Whereas the symmetric pentacyclic ketone 11 is of a known type (cf. [1]) the two spiroketone 9 and 10 represent compounds of a new type. Their structure and configuration shows that in ironcarbonyl induced thermal cyclopentanone formations, an exocyclic double bond can also take part.     

Amino Alcohols with Bicyclic Carbon Skeleton. Alternative Functionalization of Nucleophilic Reaction Centers

Electron density distribution in the molecules of stereoisomeric N-[2-(4-nitrophenyl)-2-hydroxyethyl](bicyclo[2.2.1]hept-2-en-5-ylmethyl)amines was studied by quantum-chemical methods, and their chemical transformations were examined. According to the results of PM3 semiempirical calculations, the nitrogen atom in the amino alcohols possesses greater proton affinity, as compared to the oxygen atom. Chemoselective functionalization of the amino alcohols at the nitrogen and oxygen nucleophilic centers was effected using 4-nitrobenzoyl chloride, 4-toluenesulfonyl isocyanate, and hexamethyldisilazane in the presence of chlorotrimethylsilane. N,O-Bis-acylated amino alcohols were synthesized, one of which was subjected to oxidation with peroxyphthalic acid. The oxidation was not accompanied by heterocyclization, and it led to formation of the corresponding exo-epoxynorbornane derivative with the endo-oriented substituent at the bicyclic framework. The structure of the products was confirmed by the IR and ¹H NMR spectra.     

Reaction of bicyclo[2.2.1]hepta-2,5-diene with the arenesulfenamide—phosphorus(v) oxohalide system: chemo-, regio-, and steroselectivity

The chemo-, regio- and stereoselectivities of electrophilic sulfenylation of bicyclo[2.2.1]hepta-2,5-diene with arenesulfenamides activated by phosphorus(v) oxohalides were studied. The ratio of the products of endo- to exo-attack of the diene by the electrophilic species depends on the solvent nature. The proportions of the products formed upon addition to one double bond and upon homoallylic participation of the second double bond depend on solvent polarity, the nature of the halogen, the substituents in the sulfenamide benzene ring, and on the reaction time. In addition, the formation of mixed adducts was proven for the reaction carried out in acetonitrile and the formation of disulfenylation products was found in the reaction with excess sulfenylating reagent. Isomerization of exo-3-arylthio-endo-2-halobicyclo[2.2.1]hept-5-enes to the products formed with homoallylic participation of the second double bond, exo-5-arylthio-endo-3-halotricyclo[2.2.1.0^2,6]heptanes, was shown to be possible.     

Reaction of Endic Anhydride with Hydrazines and Acylhydrazines

Reaction products of bicyclo[2.2.1]hept-2-ene-endo,endo-5,6-dicarboxylic (endic) acid with hydrazines and acylhydrazines were prepared. The features distinguishing of these reactions from those with amines were revealed. The compounds obtained were characterized by ¹H, ¹³C NMR, and IR spectra. The assignment of the signals in NMR spectra was done with the use of quantum-chemical calculations of chemical shifts performed by the density functional method. The structure of one among compounds synthesized, N-(m-hydroxybenzoylamino)-bicyclo[2.2.1]hept-2-ene-endo,endo-5,6-dicarboxamide, was proved by X-ray diffraction analysis.