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By reaction of bicyclo[2.2.1]hept-5-en-exo-and endo-2-ylmethylamine, exo-5,6-epoxybicyclo[2.2.1]heptexo-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 arenesulfonyl 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 1 H 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.Amines from the norbornene and norbornane series exhibit versatile pharmacological activity. Antiviral agents were found among them [1], for example, amine Ia introduced into the medical practice as hydrochloride (deutiforin) [2]. Mecamilamine Ib is known as ganglioblocking preparation [3]. Amines exhibit styptic and topical anesthetic action, they are indicators of psychic and physical dystrophy, remove fatigue [3].Amines of the Ic group are strong analgetics; depending on the number n and character of the substituents attached to carbon and nitrogen atoms these compounds either increase or decrease the blood pressure and show bactericidal properties [4]. Derivatives of bicyclo[2.2.1]-hept-5-en-2-ylmethylamine containing piperidine, pyrrolidine and other moieties resemble by their activity the amines of the Ic group: specific inhibitors have been found among them for the pathogenic flora, tubercle bacillus, and other bacteria [5]. Up till now a single amine with two cage-like fragments was described whose derivatives (Id, R = COCH 3 , CONHAr) possessed anti-arrhythmic, hypoglycemic, and hypotensive activity [6].Taking into account the favorable effect of the bicyclic carbon cage-like structure on the pharmacological characteristics of amines we aimed this research to development of synthetic procedures and to study of reactivity of amines with norbornene and adamantane skeleton, of the dependence of their chemical behavior on the number and relative position of the cage-like fragments. The amines were prepared by reduction with lithium aluminum hydride of adamantanecarboxamides; a similar procedure had been previously used in the synthesis of alkyl-(aralkyl)norbornenylmethylamines [7]. In amides preparation 1-adamantanecarbonyl chloride (IIa), 1,3-adamantanedicarbonyl dichloride (IIb), and 1,3-adamantanediacetyl dichloride (IIc) were used.
Reactions of stereochemically pure bicyclo[2.2.1]hept-5-en-exo-and endo-2-ylmethylamines with bicyclo[2.2.1]hept-2-ene-5-carbonyl chlorides gave the corresponding carboxamides having two norbornene fragments. Their conformations and steric strains were studied by the MM2 molecular mechanics method, and electron density distribution in their molecules was determined by PM3 quantum-chemical calculations. The results of calculation of the energy of activation for epoxidation of the dienes in the gas phase and in solution (COSMO) showed that chemoselective oxidation of only one double bond therein is impossible. The corresponding diepoxy derivatives were synthesized by oxidation of the dienes with peroxyacetic acid; the oxidation of amides with endo orientation of the carbonyl group was accompanied by heterocyclization with formation of exo- 2-hydroxy-4-oxatricyclo[4.2.1.0 3,7 ]nonan-5-one. Reduction of the amides and their epoxy derivatives with lithium tetrahydridoaluminate afforded the corresponding secondary amines possessing two cage-like fragments; the reduction products were functionalized at the nitrogen atom by treatment with p-nitrobenzenesulfonyl chloride and p-toluenesulfonyl isocyanate. The structure of the prepared compounds was confirmed by the IR and 1 H and 13 C NMR spectra. IIaAmine 2.73, 2.59 5.96, 6.03 3 J 2, 3 = 6.0, 3 J 2, 1 = 2.8, 3 J 3, 4 = 2.8 1.35 1.14 2 J exo-6, endo-6 = 11.3, 3 J exo-6, 1 = 8.0 1.04 3 J endo-6, 5 = 3.6 1.14, 1.22 2.65 1.13 IIb Amine 2.81, 2.72 5.86, 6.07 3 J 2, 3 = 5.8, 3 J 2, 1 = 2.8, 3 J 3, 4 = 3.0 2.03 1.75 2 J exo-6, endo-6 = 11.4, 3 J exo-6, 5 = 9.2, 3 J exo-6, 1 = 3.9 0.42 3 J endo-6, 5 = 4.1, 4 J endo-6, syn-7 = 2.6 1.37, 1.18 2 J syn-7, anti-7 = 7.9 2.37, 2.29 2 J 8A, 8B = 12.2, 3 J 8A, 5 = 7.3, 3 J 8B, 5 = 8.2 Vc Amine 2.81 6.16, 5.96 3 J 2, 3 = 3.0, 3 J 2, 1 = 2.4, 3 J 3, 4 = 2.7 2.20 1.84 2 J exo-6, endo-6 = 12.6, 3 J exo-6, 5 = 9.0, 3 J exo-6, 1 = 3.9 0.54 3 J endo-6, 5 = 3.0, 4 J endo-6, syn-7 = 2.2 1.42, 1.27 2 J syn-7, anti-7 = 8.1 2.95, 3.03 2 J 8A,8B = 13.5, 3 J 8A, 5 = 7.2, 3 J 8B, 5 = 5.7 VIa Acid 2.88, 2.85 6.06, 6.01 3 J 2, 3 = 5.5, 3 J 2, 1 = 3.0, 3 J 3, 4 = 3.0 1.95 1.27 2 J exo-6, endo-6 = 11.1, 3 J exo-6, 5 = 8.5, 3 J exo-6, 1 = 2.5 1.88 3 J endo-6, 5 = 3.7, 4 J endo-6, syn-7 = 3.7 1.32, 1.68 2 J syn-7, anti-7 = 8.4 a 4.39, 4.34 a 5.79 VIb Acid 2.92, 3.16 6.23, 5.98 2.91 1.93 2 J exo-6, endo-6 = 12.8, 3 J exo-6, 5 = 9.4, 3 J exo-6, 1 = 3.8 1.41 3 J endo-6, 5 = 4.0, 4 J endo-6, syn-7 = 2.7 1.46, 1.29 2 J syn-7, anti-7 = 7.9 a 4.43, 4.35 a 6.02 a Benzyl CH 2 group. VIIa Amine 2.57, 2.25 3.00-3.10 1.60 1.36 2 J exo-6, endo-6 = 11.5, 3 J exo-6, 5 = 8.4, 3 J exo-6, 1 = 2.4 1.05 1.25, 0.81 2 J syn-7, anti-7 = 10.2 3.00-3.10 5.72 Acid 2.47, 2.41 3.00-3.10 2.08 1.64 2 J exo-6, endo-6 = 12.4 1.20 1.39, 1.18 2 J syn-7, anti-7 = 8.3 --VIIc Amine 2.51, 2.48 3.28, 3.09 3 J 2, 3 = 3.0 1.50 1.73 2 J exo-6, endo-6 = 12.7, 3 J exo-6, 5 = 10.7, 3 J exo-6, 1 = 4.3 0.81 3 J endo-6, 5 = 4.9, 4 J endo-6, syn-7 = 2.3 1.37, 0.76 2 J syn-7, anti-7 = 10.0 3.20-3.32 2 J 8A,...
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