A Double Mannich -type Reaction in the 1,4,5,6-Tetrahydropyridine-2-thiolate Series: A Convenient Approach to Functionalized 3,7-Diazabicyclo[3.3.1]nonane Derivatives

The reaction of N-methylmorpholinium 5-alkoxy-carbonyl-4-aryl-3-cyano-2-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with primary amines and formaldehyde under mild conditions afforded 7-substituted alkyl 9-aryl-5-cyano-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1-carboxylates in fair to good yields (52–74%).     

A Double <Emphasis Type="Italic">Mannich</Emphasis>-type Reaction in the 1,4,5,6-Tetrahydropyridine-2-thiolate Series: A Convenient Approach to Functionalized 3,7-Diazabicyclo[3.3.1]nonane Derivatives

Summary. The reaction of N-methylmorpholinium 5-alkoxy-carbonyl-4-aryl-3-cyano-2-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with primary amines and formaldehyde under mild conditions afforded 7-substituted alkyl 9-aryl-5-cyano-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1-carboxylates in fair to good yields (52–74%). Third author was Deceased on February 26, 2007     

Synthesis,structural and conformational study of some amides derived from 3,7-dimethyl-9-amino-3,7-diazabicyclo[3.3.1]nonane-9-carboxamide

A series of 3,7-dimethyl-9-amino-3,7-diazabicyclo[3.3.1]nonane-9-carbonitrile and 3,7-dimethyl-9-amino-3,7-diazabicyclo[3.3.1]nonane-9-carboxamide N-substituted have been synthesized and studied by ¹ H and ¹³C nmr spectroscopy and the crystal structure of 3,7-dimethyl-9-benzylamino-3,7-diazabicyclo[3.3.1]nonane-9-carboxamide dihydrochloride ( IVb· 2HCl) has been determined by X-ray diffraction. The compounds studied display in deuteriochloroform, dimethyl sulfoxide-d₆ and methanol-d₄ the same preferred flattened chair-chair conformation with the methyl groups in equatorial position. The carboxamido group lies in a plane nearly perpendicular to the bispidine skeleton. The conformation and protonation sites of IVb· 2HCl in the crystal state and in deuterium oxide solution are discussed.     

Synthesis of new functionalized 3,7-diazabicyclo[3.3.1]nonanes by aminomethylation of the Guareschi imides

The aminomethylation of 4,4-dialkyl-2,6-dioxopiperidine-3,5-dicarbonitriles (Guareschi imides) was studied for the first time. When the Guareschi imides were treated with primary aliphatic amines and an excess of formaldehyde, 2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitriles were obtained in varying yields (15–67%). The structure of 9,9-dimethyl-7-(2-methylpropyl)-2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile was studied by X-ray diffraction analysis.     

Synthesis and study on 2,4,6,8-tetraaryl- 3,7-diazabicyclo[3.3.1]nonanes and their derivatives

1-Carbethoxy-2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1] nonan-9-ones (1, 2) were synthesized and their 1H and 13C NMR data are reported. Chemical shifts and spectral assignments for 2,4,6,8-tetrakis(4-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (3), 2,4,6,8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (4) and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonanes (5-7) are also included.     

Synthesis and transformations of polyhedral compounds. Synthesis of 2-[quinolin-3(2)-yl]-1,3-diazaadamantanes

A number of new 1,3-diazaadamantane derivatives containing quinoline fragments on C² have been synthesized by condensation of 1,5-dialkyl-3,7-diazabicyclo[3.3.1]nonan-9-one, 1,5-dimethyl-3,7-diazabicyclo-[3.3.1]nonan-9-ol, and 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane with 2-oxo-1,2-dihydroquinoline-3-carbaldehyde, 2-chloro- and 2-iodoquinoline-3-carbaldehyde, and quinoline-2-carbaldehyde.     

Mass spectra of azabicyclospirohydantoins

The mass spectra of some N-substituted nortropane and granataninespirohydantoins are compared with those of N-substituted 3-azabicyclo[3.2.1]octane-8-spiro-, 3-azabicyclo[3.3.1]nonane-9-spiro-, 8-azabicyclo-[4.3.1]decane-10-spiro- and 3,7-diazabicyclo[3.3.1]nonane-9-spiro-5′-hydantoins. Mass spectra data of monothio- and dithio-tropanespirohydantoins are also included. Mass fragmentation and structure relationships of these molecules have been established.     

Trinuclear {M1}CN{M2}2 complexes (M1 = Cr(III), Fe(III), Co(III); M2 = Cu(II), Ni(II), Mn(II)). Are single molecule magnets predictable?

The reaction of the hexacyanometalates K3[M(1)(CN)6] (M(1) = Cr(III), Fe(III), Co(III)) with the bispidine complexes [M(2)(L(1))(X)](n+) and [M(2)(L(2))(X)](n+) (M(2) = Mn(II), Ni(II), Cu(II); L(1) = 3-methyl-9-oxo-2,4-di-(2-pyridyl)-7-(2-pyridylmethyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylic acid dimethyl ester; L(2) = 3-methyl-9-oxo-7-(2-pyridylmethyl)-2,4-di-(2-quinolyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylic acid dimethyl ester; X = anion or solvent) in water-methanol mixtures affords trinuclear complexes with cis- or trans-arrangement of the bispidine-capped divalent metal centers around the hexacyanometalate. X-ray structural analyses of five members of this family of complexes (cis-Fe[CuL(2)]2, trans-Fe[CuL(1)]2, cis-Co[CuL(2)]2, trans-Cr[MnL(1)]2, trans-Fe[MnL(1)]2) and the magnetic data of the entire series are reported. The magnetic data of the cyanide bridged, ferromagnetically coupled cis- and trans-Fe[ML]2 compounds (M = Ni(II), Cu(II)) with S = 3/2 (Cu(II)) and S = 5/2 (Ni(II)) ground states are analyzed with an extended Heisenberg Hamiltonian which accounts for anisotropy and zero-field splitting, and the data of the Cu(II) systems, for which structures are available, are thoroughly analyzed in terms of an orbital-dependent Heisenberg Hamiltonian, in which both spin-orbit coupling and low-symmetry ligand fields are taken into account. It is shown that the absence of single-molecule magnetic behavior in all spin clusters reported here is due to a large angular distortion of the [Fe(CN)6](3-) center and the concomitant quenching of orbital angular momentum of the Fe(III) ((2)T2g) ground state.     

Novel Complexes of 3-[3-(1H-Imidazol-1-yl)propyl]-3,7-diaza-bispidines and β-Cyclodextrin as Coatings to Protect and Stimulate Sprouting Wheat Seeds

We report the syntheses and characterization of novel 3,7-bicycl[3.3.1]bispidines possessing an imidazolpropyl group attached to N-3, and at N-7 a Boc group, as well as a benzoylated-oximated group at C-9. These compounds were complexed with β-cyclodextrin [β-CD] and evaluated as seed protectors of selected wheat seedlings. Using strong acid, condensations of N-substituted piperidones with the appropriate imidazolpropyl groups at N-3 and N-7 led to bispidinones 6 and 7. These intermediates were reduced to the corresponding 3,7-diazabicyclo[3.3.1]nonane targets. The oxime at C-9 was benzoylated to yield 13. Heating these 3,7-diazabicyclo[3.3.1]nonanes in ethanol with β-CD generated the complexes required. We investigated the ability of such complexes as coatings on seedlings to protect and stimulate growth of three varieties of wheat, namely Kazakhstanskaya-10, Severyanka, and Miras. The complex of 3-[3-(1H-imidazol-1-yl)propyl]-7-(3-methoxypropyl)-3,7-diazabicyclo[3.3.1]nonane (2) promoted growth in the root systems of all three wheat varieties by more than 30% in Kazakhstanskaya-10, 30% in Severyanka and 8.5% in Miras. A complex of 3-Boc-7-[3-(1H-imidazol-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (9) increased both shoot and root length in only the Severyanka variety. The complex of 3-(3-butoxypropyl)-7-[3-(1H-imidazol-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (11) stimulated both shoot growth (0.8%, 12.3%, 13.5%) and root growth (12.3%, 9.4%, 21.7%) in all three varieties of wheat, respectively. The nature of substituents on the bispidine affect the activity. Solid complexes (1:1) were generated as powders which melted above 240 °C (dec) and were characterized via elemental analyses as 1:1 complexes.     

Synthesis,structural, and biochemical study of a series of methyl 2,6-diaryl-1-methyl-4-oxopiperidine-3,5-dicarboxylates and a series of methyl 2,4-diaryl-3,7-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylates

A series of methyl-2,6-diaryl-1-methyl-4-oxopiperidine-3,5-dicarboxylates Ia-c and 2,4-diaryl-3,7-dimethyl-1,5-dimethoxycarbonyl-9-bispidinones IIa-c have been synthesized and studied by ir, ¹H and ¹³C nmr spectroscopy and the crystal structure of methyl 2,4-diphenyl-3,7-dimethyl-9-oxo-3,7-diazabicyclo[3,3.1]nonane-1,5-dicarboxylate (IIa) has been determined by X-ray diffraction. The enolic form of compound Ia (I'a) was also studied.     

Synthesis and conversions of polyhedral compounds. 25. Synthesis and convepsions of certain oxindole derivatives of 1,3-diazaadamantane and 3,7-diazabicyclo[3.3.1]nonane

By the reaction of 1,5-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane with isatin and a number of its derivatives, spiro(1,3-diazaadamantane-2,3′-oxindoles) have been synthesized. In the case of 5-bromoisatin, either 3-(3-hydroxyoxindolyl)-3,7-diazabicyclo[3.3.1]nonane or the corresponding spirane is obtained, depending on the temperature. The interaction of these products with acetic anhydride has been studied. For communication 24, see [1]. A. L. Mndzhoyan Institute of Fine Organic Chemistry, Academy of Sciences of the Republic of Armenia, Erevan 375014. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1490–1493, November, 1997.     

Complex formation of copper(II) and palladium(II) with L,L-3,7-bis[2-(4-hydroxyphenyl)-1-(methoxycarbonyl)ethyl]-1,5-di(ethoxycarbonyl)-3,7-diazabicyclo[3.3.1]nonan-9-one

Complexation of copper(II) chloride, copper(II) triflate, and palladium(II) chloride with optically active L,L-3,7-bis[2-(4-hydroxyphenyl)-1-(methoxycarbonyl)ethyl]-1,5-di(ethoxycarbonyl)-3,7-diazabicyclo[3.3.1]nonan-9-one was studied.     

Reaction of 1,3-thiazolidine-4-carboxylic and 1,4-tetrahydro-thiazine-3-carboxylic acid esters with isocyanates and isothiocyanates and structures of the reaction products

7-Thia-1,3-diazabicyclo[3.3.0]octane-2,4-diones and 7-thia-1,3-diazabicyclo[4.3.0]-nonane-2, 4-diones, as well as their thio analogs, were obtained by the reaction of (S)-1,3-thiazolidine-4-carboxylic and 1,4-tetrahydrothiazine-3-carboxylic acid esters with isocyanates and isothiocyanates. Intermediate reaction products, viz., heterocyclic derivatives of urea, were isolated. The three-dimensional structures of the 3-methyl-4-oxo-7-thia-1,3-diazabicyclo[3.3.0]octane-2-thione and 3-methyl-4-oxo-7-thia-1, 3-diazabicyclo[4.3.0]nonane-2-thione molecules were determined by x-ray diffraction analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1327–1332, October, 1985.     

Photochemistry of 3,7-Bis(arylmethylene)bicyclo[3.3.1]nonane Derivatives

UV irradiation of trans-trans-3,7-bis(arylmethylene)bicyclo[3.3.1]nonane-2,6-diones leads to their complete or partial transformation into the corresponding cis-cis isomers. Irradiation of trans-trans-3,7-bis(arylmethylene)bicyclo[3.3.1]nonane-2,6-diol in ether in the presence of CuCl results in intramolecular cyclization involving the exocyclic double bonds and one benzene ring to give exo-7endo-10-dihydroxy-2-phenyl-3,4-benzotetracyclo[4.3.3.18,11.01,6]tridecane.     

Heteroadamantanes and their derivatives. 9. Synthesis of 1,5-dinitro-3,7-diazabicyclo[3.3.1]nonane and derived 2,2-disubstituted 5,7-dinitro-1,3-diazaadamantanes

Heating 1,5-dinitro-3,7-di(tert-butyl)-3,7-diazabicyclo[3.3.1]-nonane with concentrated hydrobromic acid gives 1,5-dinitro-3,7-diazabicyclo[3.3.1]nonane. Cyclization of the latter with various aldehydes and ketones gave a series of 2,2-disubstituted 5,7-dinitro-1,3-diazaadamantanes. The behavior of the synthesized compounds under electron impact has been studied.For Communication 8 see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 538–542, April, 1990.     

The Mannich-type interaction of sulfur-containing CH acids with formaldehyde and primary amines

One-pot reactions of dimethyl sulfonyldiacetate and N-methyl-2r,6c-di(methoxycarbonyl)-3t,5t-diphenyltetrahydro-1,4-thiazine 1,1-dioxide with formaldehyde and primary amines lead to derivatives of 9-thia-3,7-diazabicyclo[3.3.1]nonane 9,9-dioxide resulted from decarboxylation of the ester groups at the positions 1 and 5. The effects of the reaction conditions and structure of the starting reagents on the yields of 9-thia-3,7-diazabicyclo[3.3.1]nonane 9,9-dioxides were studied.     

New stereoselective intramolecular redox reaction in the system of 3,7-diazabicyclo[3.3.1]nonan-9-one

The ring opening in the 1-benzyl-5,7-dimethyl-6-oxo-1-azonia-3-azaadamantane chloride under the treatment with excess aqueous alkali led to a stereoselective formation of anti-1,5-dimethyl-7-benzyl-3-formyl-3,7-diazabicyclo[3.3.1]nonan-9-ol whose structure was established by means of X-ray diffraction analysis and NMR spectroscopy. A reaction mechanism was suggested involving an intramolecular redox hydride transfer.     

Synthesis and Reactions of Polyhedral Compounds. 27. Development of a Synthetic Route for 2- Spiro-substituted 6-Hydroxy-5,7-dimethyl-1,3-diazaadamantanes

Alternative methods for the synthesis of 2-spiro-substituted 6-hydroxy-5,7-dimethyl-1,3-diazaadamantanes have been developed. These are the reduction of the ketone group to hydroxyl in the corresponding 6-oxo-1,3-diazaadamantanes and the condensation of 9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane (obtained by different routes from 5,7-dimethyl-6-oxo-1,3-diazaadamantane) in reaction with cyclic ketones.     

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C₂- or C₃-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C₂- or a methylene group at the C₃-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge     

Synthesis,crystal and molecular structure of 3,7-ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonane

3,7-Ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonane has been found to adopt a chair–chair conformation in the crystalline state in contrast to 3,7-ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one, which had been previously found to exist in a chair-boat conformation.