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.     

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.     

Structure and Reactivity of Bicyclo[2.2.1]hept-2-ene-<Emphasis Type="Italic">endo</Emphasis>-5,<Emphasis Type="Italic">endo</Emphasis>-6-dicarboxylic (endic) Acid Hydrazide

Establishing of the structure of hydrazinolysis product obtained from bicyclo[2.2.1]hept-2-ene-endo-5, endo-6-dicarboxylic (endic) acid was performed by preparation of the compound under alternative conditions followed by comparison of the characteristics and spectral parameters of the resulting substances, and also by quantum-chemical calculations by the density functional method of the chemical shifts in ¹H and ¹³C NMR spectra of different reaction products. The X-ray diffraction analysis of the hydrazide was also carried out. The compound obtained was assigned a structure of N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide. The products were prepared by its reactions with arylsulfonyl chlorides, benzoyl chlorides, m-tolyl and p-toluene-sulfonyl isocyanates, phenyl isothiocyanate, with o-nitrobenzaldehyde, and oxiranes (1,2-epoxycyclohexane and 2,3-epoxypropylcarbazole). The aromatic sulfonamides, carboxamides, and ureas were epoxidized by performic acid obtained in situ from the formic acid and hydrogen peroxide. Products of [3+2]-cycloaddition of aryl azides to the strained double bond in the N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide and its derivatives. The structures of compounds obtained were confirmed by their IR, 1H and 13C NMR spectra.     

Synthesis of cyclic sulfonamides by reaction of <Emphasis Type="Italic">N</Emphasis>-sulfinyl-3-(trifluoromethyl)aniline with norbornenes

N-Sulfinyl-3-(trifluoromethyl)aniline reacted with bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]-hepta-2,5-diene to give the corresponding Diels?Alder adducts which were oxidized to 8-trifluoromethyl-2,3,4,4a,6,10b-hexahydro-5λ⁶-1,4-methanodibenzo[c,e][1,2]thiazine-5,5(1H)-diones. The cycloaddition occurred predominantly with participation of the S=N–C¹=C⁶ fragment of N-sulfinyl-3-(trifluoromethyl)aniline and exclusively at the endo side of bicyclo[2.2.1]heptenes.     

Stereochemistry of dihydroxylation of <Emphasis Type="Italic">N</Emphasis>-arylbicyclo[2.2.1]-hept-5-ene-<Emphasis Type="Italic">endo</Emphasis>- and -<Emphasis Type="Italic">exo</Emphasis>-2,3-dicarboximides

Stereochemistry of the oxidation of N-arylbicyclo[2.2.1]hept-5-ene-endo-and-exo-2,3-dicarboximides at the double bond with peroxyacetic acid generated in situ in the presence of sulfuric acid and with an anhydrous dioxane solution of peroxyacetic acid was studied. In both cases, the reaction was stereospecific, regardless of the substituent in the N-aryl group and configuration of the imide ring, but the reaction direction depended on the presence of water in the system. In the first case, the corresponding trans-5,6-dihydroxy derivatives were formed, while in the second, exo-5,6-epoxy derivatives. The oxidation of N-arylbicyclo[2.2.1]-hept-5-ene-endo-and-exo-2,3-dicarboximides with a solution of potassium permanganate in aqueous acetone gave the corresponding N-aryl-cis-5,6-dihydroxybicyclo[2.2.1]heptane-endo-and-exo-2,3-dicarboximides. The exo,cis,exo and exo,cis,endo configurations of the synthesized compounds were determined by ¹H NMR spectroscopy.     

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.     

Synthesis of <Emphasis Type="Italic">para</Emphasis>-substituted bicyclo[2.2.1]hept-5-en-2-ylmethyl benzoates

para-Substituted bicyclo[2.2.1]hept-5-en-2-ylmethyl benzoates were synthesized by the Diels-Alder reaction of cyclopentadiene with the corresponding para-substituted allyl benzoates, and optimal reaction conditions were found. The product structure was confirmed by independent synthesis and IR and ¹H NMR spectroscopy.     

Synthesis, structure, and transformations of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N-[(oxiran-2-yl) methyl]-arenesulfonamides

Reaction of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)arenesulfonamides with epichlorohydrin in the presence of tetramethylammonium iodide afforded a group of framework N-[(oxiran-2-yl)methyl]sulfonamides and also a series of new dioxiranes, N-(oxiran-2-yl)methyl-N-(exo-5,6-epoxybicyclo[2.2.1]heptan-endo-2-ylmethyl)arenesulfonamides. The aminolysis of N-(oxiran-2-yl)methyl]arenesulfonamides with benzylamine and benzylpiperazine led to the chemo- and regioselective opening of the epoxy ring according to Krasusky rule. The structure of compounds was established by spectral methods and the XRD analysis.     

Reactivity of 5-<Emphasis Type="Italic">endo</Emphasis>-hydroxy-4-azatricyclo[5.2.1.0<Superscript>2,6</Superscript>]dec-8-en-3-ones and their isomerization initiated by acids and bases

Study of isomerization of 5-endo-hydroxy-4-azatricyclo[5.2.1.0^2,6]dec-8-en-3-ones under the action of Lewis acids (MgBr₂, AlCl₃), CF₃COOH, and NaH showed that the optimum catalyst of the process was trifluoroacetic acid. In reaction of 4-benzyl-5-endo-hydroxy-4-azatricyclo-[5.2.1.0^2,6]dec-8-en-3-one with anhydrous AlCl₃ in benzene was unexpectedly isolated N-benzyl-3-(diphenylmethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide. A convenient method was developed for the preparation of 5-exo-alkoxy-4-alkyl(aryl)-4-azatricyclo[5.2.1.0^2,6]dec- 8-en-3-ones.     

Synthetic approaches to physiologically active polycyclic compounds: VII. Synthesis of 2-(7-Hydroxybicyclo-[3.3.1]non-3-ylmethyl)propane-1,3-diol

2-(endo-7-Hydroxybicyclo[3.3.1]non-exo-3-ylmethyl)propane-1,3-diol was synthesized in seven steps starting from endo-7-hydroxybicyclo[3.3.1]nonane-exo-3-carboxylic acid. The title compound attracts interest as intermediate product for the synthesis of potential tubulin ligands.     

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.     

(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 of 7-sulfonyl-substituted norpinan-6-ones and -thiones from 1-bromotricyclo[4.1.0.0<Superscript>2,7</Superscript>]heptane

1-Bromotricyclo[4.1.0.0^2,7]heptane reacted with benzene- and methanesulfonyl thiocyanates in benzene at 20°C via anti addition to the central C¹–C⁷ bicyclobutane bond with formation of 6-endo-bromo-6-exo-thiocyanato-7-syn-(R-sulfonyl)bicyclo[3.1.1]heptanes. Treatment of the benzenesulfonyl thiocyanate adduct with potassium tert-butoxide in THF at 20°C gave 7-endo-(benzenesulfonyl)norpinan-6-one, whereas the reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene in methylene chloride afforded 7-exo-(benzenesulfonyl)-norpinane-6-thione which was converted into 7-exo-(benzenesulfonyl)norpinan-6-one by alkaline hydrolysis.     

Acylation of Aminopyridines and Related Compounds with Endic Anhydride

Reactions of bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboxanhydride (endic anhydride) with 2-, 3-, and 4-aminopyridines, 3-hydroxy- and 5-iodo-2-aminopyridines, 6-aminoquinoline, and 6-aminoquinoxaline involve chemoselective transformation of the exocyclic amino group. The resulting amido acids were converted into the corresponding carboximides, and the latter were epoxidated with peroxy acids. The structure of the products was confirmed by the IR, UV, and ¹H and ¹³C NMR spectra, as well as by calculation of the ¹H and ¹³C chemical shifts using the GIAO method (B3LYP/6-31G** approximation).     

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.     

Lactonation of <Emphasis Type="Italic">N</Emphasis>-alkyl-and <Emphasis Type="Italic">N,N</Emphasis>-dialkylamido acids of norbornene series in reactions with performic acid

Reaction products were obtained from bicyclo[2.2.1]hept-5-ene-endo,endo-2,3-dicarboxylic (endic) acid anhydride and ammonia, methyl-, benzyl-, dimethyl-, methylbenzyl-, dibenzyl-, diethyl-, dipropyl-, diisopropyl-, and dipentylamines. The synthesized amido acids were subjected to epoxidation by organic peracids. The structure of compounds obtained was confirmed by IR, ¹H and ¹³C NMR spectra, and in some instances, by X-ray diffraction analysis.     

Reactions of p-Nitrophenyloxirane with Amines Containing Fragments with Bicyclic Skeleton

Reactions of p-nitrophenyloxirane with amines containing fragments with bicyclic skeleton of norbornene, norbornane, epoxynorbornane (stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-enes, N-benzyl-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene, endo-5-(2-aminoethyl)bicyclo[2.2.1]hept-2-ene, stereoisomeric exo- and endo-2-aminomethylbicyclo[2.2.1]heptanes, 2-(1-aminoethyl)bicyclo[2.2.1]heptane, exo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptane) were investigated. The aminolysis of p-nitrophenyloxirane occurred regioselectively according to Krasusky rule as was proved by ¹H and ¹³C NMR data. As shown by ¹H and ¹³C NMR spectroscopy the oxyalkylation product obtained from N-benzyl-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene was composed of two diastereomers originating from the presence of a chiral nitrogen atom in the rear part of the rigid bicyclic skeleton. New products of amino groups transformation in the molecules of hydroxyamines were obtained by reaction with p-methylbenzoyl chloride and p-nitrophenylsulfonyl chloride. Regioselectivity of the attack of electrophilic reagents on the nitrogen in the hydroxyamines was confirmed by IR and ¹H NMR spectra of the products. The data on pharmacological activity tests of N-2-hydroxyethyl(p-nitrophenyl)-5-aminomethylbicyclo[2.2.1]hept-2-ene are reported.     

Tandem molecular rearrangement in the alkylation of phenol with camphene

The alkylation of phenol with camphene in the presence of boron trifluoride in glacial acetic acid was accompanied by tandem molecular rearrangement with formation of a mixture of ortho- and para-substituted phenols having 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl and 5,5,6-trimethylbicyclo[2.2.1]hept-exo-2-yl substituents. The same products were obtained by rearrangement of 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yloxybenzene under analogous conditions. Similar reactions performed in the presence of aluminum phenoxide as catalyst resulted in predominant formation of the corresponding ortho-substituted phenols.     

Asymmetric oxidation of verbenone ethylene dithioacetal

Asymmetric oxidation of verbenone ethylene dithioacetal with m-chloroperoxybenzoic acid at different substrate-to-oxidant ratios in methylene chloride at ?10°C gave previously unknown (1S,1′S,2S,3′S,5S)-4,6,6-trimethylspiro[bicyclo[3.1.1]hept-3-ene-2,2′-[1,3]dithiolane] 1′,3′-dioxide, (1S,2S,3′S,5S)-4,6,6-trimethylspiro[bicyclo[3.1.1]hept-3-ene-2,2′-[1,3]dithiolane] 1′,1′,3′-trioxide, and (1S,5S)-4,6,6-trimethylspiro[bicyclo-[3.1.1]hept-3-ene-2,2′-[1,3]dithiolane] 1′,1′,3′,3′-tetraoxide whose structure was determined by X-ray analysis.     

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.