Lewis acid catalyzed reactions of donor-acceptor cyclopropanes with 1- and 2-pyrazolines: formation of substituted 2-pyrazolines and 1,2-diazabicyclo[3.3.0]octanes

The reaction of 2-substituted cyclopropane-1,1-dicarboxylates with 1- and 2-pyrazolines is efficiently catalyzed by scandium or ytterbium triflates to give N-substituted 2-pyrazolines or 1,2-diazabicyclo[3.3.0]octanes. The reactions of 2-pyrazolines give diazabicyclooctanes as the major products. In contrast, the reactions starting from 1-pyrazolines predominantly give N-substituted 2-pyrazolines, which become the major compounds obtained if an equimolar amount of GaCl₃ is used. A possible reaction mechanism is suggested.     

Synthesis of N- and N,N′-coordinated derivatives of 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes and their fungicidal activity

Possibility of obtaining water-soluble N- and N,N′-coordinated adducts by reacting 3,7-dithia-1,5-diazabicyclo[3.3.0]octane with methyl iodide and Brønsted (HCl, HBr) and Lewis (AlCl₃) acids was examined. The fungicidal activity of 3,7-dithia-1,5-diazabicyclo[3.3.0]octane and its water-soluble adducts with hydrobromide and methyl iodide against a number of microscopic fungi affecting cultivated plants and various materials was studied.     

Reaction of 1-arylmethylidenepyrazolidin-1-azomethine imines with aryl ketenes

A reaction of aryl ketenes with 1-arylmethylidenepyrazolidin-1-azomethine imines, generated by the diaziridine ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes catalyzed with Et2O·BF3, leads to 1,2-bis(phenylacetyl)pyrazolidine, 2-arylacetyl-1-arylidenepyrazolidin-1-ium chlorides, or a representative of 1,5-diazabicyclo[3.3.0]octan-2-ones, viz., 4-(4-eth-oxyphenyl)-3,3-diphenyl-1,5-diazabicyclo[3.3.0]octan-2-one, depending on the reaction conditions and the structure of the starting compounds. A mechanism suggested earlier for the transformation of 1,5-diazabicyclo[3.1.0]hexanes in the reaction with ketenes was confirmed.     

Reactions of diazo esters with electron-deficient alkenes in the presence of Lewis acids

1,3-Dipolar cycloaddition reaction of diazo esters to electron-deficient dipolarophiles to yield the corresponding 1- or 2-pyrazolines was found to be significantly accelerated with Lewis acids (Yb(OTf)₃, Sc(OTf)₃, GaCl₃, EtAlCl₂). The use of GaCl₃ as the catalyst leads to the acceleration not only of the 1,3-dipolar cycloaddition reaction, but also subsequent insertion of the CHCO₂Me electrophilic fragment of methyl diazoacetate into the N-H bond of 2-pyrazolines formed. Such Lewis acids as SnCl₄, BF₃, TiCl₄, and In(OTf)₃ are not efficient in the described processes, since they rapidly decompose starting diazo compounds.     

Lewis acid-mediated reactions of donor-acceptor cyclopropanes with diazo esters

The reactions of diazo esters with 2-arylcyclopropane-1,1-dicarboxylates, the represen- tatives of donor-acceptor cyclopropanes (DACs), mediated by Sc(OTf)₃, SnCl₄, and GaCl₃ proceeded with nitrogen elimination to give the C—C coupling products. No products of the formal [3+3] cycloaddition of diazo compounds to DACs were formed but the main reaction direction was addition of diazo ester to either 1,3- or 1,2-zwitterions generated upon Lewis acid-mediated cyclopropane ring opening giving rise to new 1,4- and 1,3-zwitterionic inter- mediates. The formed intermediates underwent further fragmentations and rearrangements to give substituted cyclopropanedi-, -tri-, and -tetracarboxylates. Mechanistic aspects of the observed reactions were discussed.     

New dimerization and cascade oligomerization reactions of dimethyl 2-phenylcyclopropan-1,1-dicarboxylate catalyzed by Lewis acids

New routes to transform donor-acceptor cyclopropanes in the presence of Lewis acids have been found. The reaction of dimethyl 2-phenylcyclopropan-1,1-dicarboxylate, a typical representative of this class of compounds, with an equimolar amount of anhydrous GaCl₃ gives, depending on the reaction time, (2-phenylethylidene)malonate or styrylmalonate after hydrolysis, whereas in the presence of 15-20 mol % GaCl₃ the starting cyclopropane undergoes dimerization to give the malonic derivative of 3,4-diphenylcyclopentane-1,1-dicarboxylate. In the presence of the GaCl₃·THF complex, the same cyclopropane gives a substituted 4-phenyltetraline-2,2-dicarboxylate in high yield, whereas in the presence of SnCl₄·THF it gives the dimer specified above along with products of chain oligomerization, the degree of which can be controlled by changing the concentration of the starting cyclopropane in solution.     

Heterocyclization of hydrazine with acetaldehyde and H2S

Hydrazine is regioselectively condensed with a mixture of acetaldehyde and H₂S at a temperature below −10 °C to form 2,4,6,8-tetramethyl-3,7-dithia-1,5-diazabicyclo[3.3.0]-octane. The reaction at 0 °C with the reverse order of mixing of the starting reagents affords 2,4,6-trimethyl(1,3,5-dithiazinan-5-yl)amine as the major product.     

Generation and metathesis of azomethine imines in reaction of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with het(aryl)methylidenemalononitriles

A new metathesis reaction of azomethine imines is found. Catalytic or thermal diaziridine ring opening of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes leads to azomethine imines reacting further with het(aryl)methylidenemalononitriles to give in situ new azomethine imines inaccessible by common synthetic methods. New azomethine imines are detected as pyrazolines formed via a 1,4-H shift and trapped by the [3+2] cycloaddition with various dipolarophiles to yield 1,5-diazabicyclo[3.3.0]octane derivatives bearing pharmacophoric heterocycles, e.g. furan, nitrofuran, thiophene, and indole. The best results are achieved in the Et₂O·BF₃-catalyzed reactions in ionic liquids.     

Dimerization of Dimethyl 2‐(Naphthalen‐1‐yl)cyclopropane‐1,1‐dicarboxylate in the Presence of GaCl3 to [3+2], [3+3], [3+4], and Spiroannulation Products

In the presence of a catalytic amount of GaCl₃, dimethyl 2‐(naphthalen‐1‐yl)cyclopropane‐1,1‐dicarboxylate 5 undergoes selective [3+2]‐annulation‐type dimerization to give a polysubstituted cyclopentane containing two naphthalenyl substituents in the vicinal position (Scheme 2). Treatment of the same cyclopropane with an equimolar amount of GaCl₃?THF results in dimerization with electrophilic attack on each of the benzene rings to give [3+3] and [3+4] annulation products. The latter represent a new type of dimerization of donor? acceptor cyclopropanes. Finally, under conditions of double catalysis with GaCl₃, 3,3,5,5‐tetrasubstituted 4,5‐dihydropyrazole, this cyclopropane‐dicarboxylate undergoes stereospecific dimerization as a result of electrophilic ipso‐attack to give a tetracyclic pentaleno[6a,1‐a]naphthalene derivative (Scheme 5). Possible reaction mechanisms are proposed.     

Thermolysis of 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes in the Presence of N-Arylmaleimides

Heating of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of N-arylmaleimides gives rise to 2,9-diarylperhydropyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-diones. It is presumed that thermal cleavage of the C-N bond in the diaziridine fragment of the 6-aryl-1,5-diazabicyclo[3.1.0]hexanes results in formation of labile azomethinimines that react with N-arylmaleimides to afford the products of 1,3-dipolar cycloaddition. The rate of accumulation thereof depends only on the character of substituents in the aromatic ring of the 1,5-diazabicyclo[3.1.0]hexanes and is independent of maleimide. The thermal isomerization of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes without 1,3-dipolarophiles yields the corresponding 2-pyrazolines.     

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.     

1,3-Dipolar cycloaddition ofin situ generated 2,2-dimethyl-and 2,2-dichlorodiazocyclopropanes to 3,3-dimethylcyclopropene

2,2-Dimethyl- and 2,2-dichlorocyclopropyl-N-nitrosoureas were synthesized for the first time. Under the action of MeONa/MeOH at ?10°C, these compounds generate the corresponding 2,2-dimethyl- and 2,2-dichlorodiazocyclopropanes, which are readily trapped by 3,3-dimethylcyclopropene to give the products of 1,3-dipolar cycloaddition,viz., isomeric substituted spiro(2,3-diazabicyclo[3. 1 .0] hex-2-ene-4,1 ′-cyclopropanes), in yields of about 70%,     

Reaction of donor-acceptor cyclopropanes with 1,3-diphenylisobenzofuran. Lewis acid effect on the reaction pathway

Reaction of donor-acceptor cyclopropanes with 1,3-diphenylisobenzofuran in the presence of lanthanide triflates, as well as CuOTf, Sn(OTf)₂, SnCl₂, ZnCl₂, GaCl₃, and MgI₂, proceeds as a formal [3+4]-cycloaddition leading to a newly formed seven-membered ring. This reaction was found to be typical of cyclopropane-1,1-diesters and dinitriles, as well as 1-nitrocyclo-propanecarboxylates containing aromatic, heteroaromatic, and vinylic substituents at the C(2) atom of the small ring. When Me₃SiOTf, TiCl₄, SnCl₄, or BF₃·OEt₂ were used as initiators, unusual cyclic hemiacetals were formed via the conjugate 1,4-addition of a cyclopropane and a nucleophile to the diene moiety.     

Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N′-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK_a of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74±0.05, which is 1.3 pK_a units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules.     

S5N5⊕[GaCl4]⊖ und S5N5⊕[Ga2Cl7]⊖. Synthesen,IR-Spektren und Kristallstrukturen

S₅N₅ ^⊕[GaCl₄]^? and S₅N₅ ^⊕[Ga₂Cl₇]^?. Synthesis, IR Spectra, and Crystal Structures . S₅N₅[GaCl₄] was obtained in high yields from gallium and trithiazyl chloride; depending on the solvent, different second products are formed: S₄N₄Cl[GaCl₄] in dichloromethane and S₃N₂Cl[GaCl₄] in carbon tetrachloride. These products can be separated due to their high solubility in CH₂Cl₂, S₅N₅[GaCl₄] being only slightly soluble. S₃N₂Cl[GaCl₄] can be converted to S₅N₅[GaCl₄] with additional (NSCl)₃. By the action of GaCl₃ on S₅N₅[GaCl₄], S₅N₅[Ga₂Cl₇] is formed. The IR spectra of the title compounds are reported; they differ considerably as well in number as in frequencies of the cation bands and show that the S₅N₅^⊕ ion has different structures depending on the anion. The crystal structures of both compounds were determined by X-ray diffraction. Crystal data: S₅N₅[GaCl₄], orthorhombic, a = 943.8, b = 1369.0, c = 2068.8 pm, space group Pnma, Z = 8 (1381 observed reflexions, R = 0.075); S₅N₅[Ga₂Cl₇], monoclinic, a = 847.5, b = 1298.2, c = 1654.0 pm, β = 93.51°, space group P2₁/n, Z = 4 (1359 observed reflexions, R = 0.065). S₅N₅[GaCl₄] is isotypic with S₅N₅[AlCl₄], showing a heartshaped S₅N₅^⊕ ion, but large ellipsoids of vibration suggest the presence of some kind of disorder (statical or dynamical). In S₅N₅[Ga₂Cl₇] the S₅N₅^⊕ has an azulene-like structure. In both cases the cations are planar, all S? N bond lengths being approximately equal.     

Gallium trichloride-mediated reactions of ‘double’ donor–acceptor cyclopropanes with alkenes and dienes

The reactions of ‘double’ donor–acceptor cyclopropanes containing a p- or m-phenylene moiety with alkenes or dienes in the presence of GaCl₃ comprise formation of gallium 1,2-zwitterionic intermediates, the structure of final products being substrate dependent. In contrast to the para-or meta-isomers, reaction of 2,2'-(1,2-phenylene)bis(cyclopropane-1,1-dicarboxylate) does not involve alkene and affords isomeric tricyclo[6.2.2.0^2,7]dodeca-2,4,6-triene-9,9,11,11-tetra-carboxylate, a product of intramolecular rearrangement.     

The average structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2]oct-2-ene

The average molecular structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2] oct-2-ene have been determined by electron diffraction in the gas phase. The structural parameters were obtained by applying a least squares analysis on the molecular scattering intensity functions. For 2,3-diazabicyclo[2.2.1]hept-2-ene, C_s symmetry was assumed in calculating the geometry of the molecule. The parameters thus determined are: N₃=N₂ = 1.221 Å, N₃- C₄ = 1.445 Å, C₄-C₅ = 1.538 Å, C-H_(ave.) = 1.112 Å, < C₁N₂N₃ = 116.3°, < N₃C₄C₅ = 105.2°, < C₁C₄C₅ = 71.5°, C₄-C₇ = 1.547 Å, C₅-C₆ = 1.530 Å, < C₁C₇C₄ = 108.0°. For 2,3-diazabicyclo[2.2.2]oct-2-ene, C_2vsymmetry was assumed. The geometrical parameters are: N₃ = N₂ = 1.243 Å, N₃-C₄ = 1.473 Å, C₄-C₅ = 1.550 Å, C₅-C₆ = 1.516 Å, C-H_(ave.) = 1.119 Å,< C₁N₂N₃ = 115.1°, < N₃C₄C₅ = 109.1°, < C₆C₁C₄ = 71.6°.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

Synthesis of novel perfluoroalkyl-containing polyethers

The synthesis of iodo(perfluoroalkyl)epoxides by radical addition of perfluoroalkyl iodides to allyl glycidyl ether and 1,2-epoxydec-9-ene is described. Dehydroiodination of additional products upon treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gives unsaturated products. The use of Bu₃SnH/Bz₂O₂ as a reduction reagent of iodo(perfluoroalkyl)allyl glycidyl ethers allows to save oxirane ring. Cationic polymerization of saturated or functional (with iodine or double bond) fluoroalkyl oxiranes under action of catalytic amount of BF₃^.Et₂O proceeds only on epoxide group. In case of poly(9-iod-10-(perfluoroalkyl)-1,2-epoxyalkane) iodine atoms are removed by standard zinc reduction.     

Synthesis and separation of stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes

Heterocyclization of hydrazine with aldehydes R-CHO (R = Me, Et, Prⁿ, Buⁿ, n-C₅H₁₁, Ph, 4-MeOC₆H₄, 3-Py) and H₂S leads to stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes, which were separated by column chromatography. The trans-transoid-trans-configuration of tetramethyl(-ethyl,-propyl)-3,7-dithia-1,5-diazabicyclo-[3.3.0]octanes was inferred from the X-ray diffraction and ¹H and ¹³C NMR spectroscopic data.