Acid-Catalyzed Transformations of 2-(Phenylethynyl)isoborneol

2-(Phenylethynyl)isoborneol was synthesized by treatment of camphor with lithium phenylacetylide. Skeletal rearrangements of the title compound under the Ritter reaction conditions afforded a mixture of N-(4-phenylethynyl- and 4-benzoylmethyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)acetamides at a ratio of 8:3. The reaction of 2-(phenylethynyl)isoborneol with formic acid involved mainly Meyer-Schuster rearrangement instead of the expected Rupe rearrangement, and the major product was 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-1-phenylethanone. The minor product (∼6%) was 1-(2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2-phenylethanone. The Ritter reaction of 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-1-phenylethanone selectively yielded N-(4-benzoylmethyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)acetamide.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005, pp. 853–858.Original Russian Text Copyright © 2005 by Koval’skaya, Kozlov, Dikusar.     

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 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.     

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.     

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.     

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.     

Reaction of 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione with hexaethyltriamidophosphite in the presence of diethylammonium chloride. Synthesis and the three-dimensional structure of (1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-yloxy)tris(diethylamino)phosphonium chloride

The reaction of 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione with hexaethyltriamido-phosphite in the presence of diethylammonium chloride afforded a stable quasiphosphonium salt, viz., (1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-yloxy)tris(diethylamino)phosphonium chloride, as one diastereomer (racemate, 1R*,3S*,4S*). Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 383–385, February, 2006.     

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.     

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.     

Bis(trifluoromethyl)-containing 1-azatricycloheptanes

6-Substituted 7-halo-3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were synthesized by the addition of water, alcohols, and acetic acid to 3-halo-7,7-bis(trifluoromethyl)-1-azatricyclo[2.2.1.0^2,6]heptanes in the presence of H₂SO₄. 5,6-Disubstituted 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were prepared by oxymercuration of 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene.     

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.     

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.     

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 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.     

(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.     

Addition von organomagnesium-verbindungen an nicht aktivierte CC-doppelbindungen : IV. Benzylmagnesiumchlorid und olefine

Benzylmagnesium chloride (I) adds to ethylene and 1-alkenes, to the strained CC double bonds in bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]heptadiene and to 1,3-alkadienes if the reaction of the etherate of (I) with olefin is carried out in an apolar reaction medium between 60 and 130°. Reaction products of the mono-olefins are the 1,1-adducts; derivatives of divinylcyclohexane are formed with butadiene as 1,3-adducts. With bicyclo[2.2.1]heptadiene the addition of the magnesium compound is followed by an intramolecular MgC-addition to the second double bond forming 2-benzyltricyclo[2.2.1.0¹]hept-3-ylmagnesium chloride.     

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.     

Acid-Catalyzed Rearrangement of 3-Aza-8-oxatricyclo[3.2.1. 02,4]octan-6-one Acetals. Highly Stereoselective Total Synthesis of 3-Amino-3-deoxy-D-altrose and Derivatives

Ethyl and tert-butyl azidoformate added to 7-oxabicyclo[2.2.1]hept-5-en-2-one dimethyl ( 5 ) and dibenzyl ( 6 ) acetals to give mixtures of regioisomeric triazolines. The latter gave the corresponding aziridines (6,6-dialkoxy-3-aza-8-oxatricyclo[3.2.1.0^2,4]octane-3-carboxylates 15 , 19 , 23 , and 27 and 31 ) on UV irradiation. In the presence of protic acids, the aziridines were rearranged into protected amines ([3-endo-alkoxy-5-oxo-7-oxabicyclo[2.2.1]hept-2-exo-yl]carbamates 16 , 20 , 24 , and 28 and 33 ). Using (+)-(1R, 4R)-5,5-bis(benzyloxy)7-oxabicyclo[2.2.1]hept-2-ene((+)- 6 ) derived from furan and l-cyanovinyl (1S)-camphanate, the method was applied to prepare 2-O-benzyl-3-[(tert-butoxy)carbonyiamino]-5-O-(3-chlorobenzoyl)-3-deoxy-β-D -altrofuranurono-6,1-lactone ((?)- 37 ). This compound was converted to methyl 3-amino-3-deoxy-α-D-altropyranoside hydrochloride ( 44 ) and several derivatives.     

Azabrendanes. I. Synthesis,structure and spectral parameters of N-(arylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.03,7]nonanes

A number of N-(arylsulfonyl)bicyclo[2.2.1]hept-2-enendo-5-methylamines have been synthesized from bicyclo[2.2.1]hept-2-en-endo-5-carbonitrile via reduction of the latter by lithium aluminum hydride and subsequent reactions of the resulting amine with arylsufonyl chlorides. The structures and stereochemical homogeneity of the products have been supported by the analysis of ¹H NMR spectra and by COSY-experiments. The reactions of the sulfonamides with peroxyphthalic acid are accompanied by intramolecular cyclizations and are completed by the formation of N-(arylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes. The structures of the substituted azabrendanes have been confirmed by spectral methods. The molecular structure of N-(p-methoxy-carbonylaminophenylsulfonyl)-exo-2-hydroxy-4-azatricyclo-[4.2.1.0^3,7]nonane 8j has been determined by X-ray diffraction analysis. © 1997 John Wiley & Sons, Inc.     

2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution,absolute configuration and hydrogen-bonding properties

The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.