Research on 1-azabicyclic systems

Epimeric 3-methylpyrrolizidines were separated preparatively. Competitive quaternization of the mixture of isomers with n-propyl iodide and catalytic isomerization were used to obtain trans-3, 8-H-3-methylpyrrolizidine. cis-3,8-H-3-Methylpyrrolizidine was isolated from the mixture by quaternization with benzyl chloride and subsequent hydrogenolysis of the resulting quaternary salt. The pK_a values of trans- and cis-3,8-H-3-methylpyrrolizidines, pyrrolizidine, and indolizidine were measured. It is shown that in a series of saturated amines with a tertiary nitrogen atom pyrrolizidine and 3-methylpyrrolizidines are among the strongest bases.See [1] for communication XII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1060–1064, August, 1976.     

Research on two-ring 1-aza compounds

5-Hydroxymethyl-1,2-dihydropyrrolizines were catalytically hydrogenated to 3(5)-hydroxymethylpyrrolizidines, and the ratios of the isomers in the products of the reaction, which proceeds stereoselectively, were determined. The configuration of the diastereomers was established on the basis of the results of catalytic isomerization, a study of the chromatographic behavior of the isomers on a polar stationary phase, and a discussion of the isomeric composition of the hydrogenation products in the light of the general principles of the stereochemistry of catalytic hydrogenation. trans- and cis-3,8-H-3-Hydroxymethylpyrrolizidine and trans-3,8-H-3-methyl-trans-5,8-H-5-hydroxymethylpyrrolizidine were isolated from the mixtures of isomers. The existence of an intramolecular hydrogen bond in trans-3,8-H-3-hydroxymethyl- and trans-3,8-H-3-methyl-trans-5,8-H-5-hydroxymethylpyrrolizidine was shown by IR spectroscopy.See [1] for communication XIITranslated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 484–489, April, 1976.     

1-azabicyclic compounds. 22. Stereochemistry and13C NMR spectra of salts of pyrrolizidine and its homologs with protonic acids

¹³C NMR spectra were obtained for pyrrolizidinium salts and their homologs and their signals were assigned. With the exception of highly strained cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine (VI), all the bases studied upon their direct mixing with CF₃CO₂H form salts only with cis-fused rings in the cation. Mixtures of salts with cis- and trans-fused pyrrolizidinium fragments are formed upon the reaction of cis-3,8-H-methy1- (III) and cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine (VI) under conditions close to those for kinetically-controlled amine protonation. The¹³C NHR spectra of the isomeric pyrrolizidinium salts obtained as a result of the absorption of base VI by sulfuric acid were used to evaluate the conformational equilibrium in the starting compound VI. The¹³C NMR chemical shifts of unsubstituted trans-fused pyrrolizidinium salts were predicted.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1638–1647, December, 1985     

Research on 1-aza two-ring systems

The physical properties and chromatographic behavior of homologs of pyrrolizidine were investigated with the aid of squalane, polyethylene glycol 20,000, and triethanolamine as liquid stationary phases. It was found that the properties of pairs of unstrained isomers are subject to the conformational rule. The retention times of the trans isomers of unstrained 1-methyl- and 3-alkylpyrrolizidines are shorter on all three stationary phases than the retention times of the cis isomers. The less significant (than in the case of other epimers) difference in the physical properties of cis- and trans-3,8-H-3-tert-butylpyrrolizidines and the peculiarity of their chromatographic behavior are explained by the distinct conformational heterogeneity of the ring fusion type of cis-3,8-H-3-tert-butylpyrrolizidine. With respect to all of the examined physical constants, strained cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine and its epimer do not comply with the conformational rule. In the liquid phase at ambient temperature and at the boiling point and in solutions in squalane, polyethylene glycol 20,000, and triethanolamine at –100°C, cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine contains significant amounts of the trans-fused form, which affect the entire set of properties. An empirical dependence of the properties of the pyrrolizidines on their properties can be used in the conformational assignment of analogous compounds.See [1] for communication 18.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 58–64, January, 1979.     

An improved synthesis of fused 1,2,3-benzothiadiphospholes and a proposed reaction pathway

A fresh look has been taken at the reaction of PCl₃ with thioanisole 1b and AlCl₃ that gives, after treatment with water, the title compounds cis- 2b in 38% yield together with small amounts of the isomeric cis- 3b (2%). The course of this reaction has been studied by ³¹P-NMR spectroscopy. A multistep pathway, governed by the formation of several AlCl₃ complexes with sulfur and phosphorus containing intermediates, has been proposed. The crucial step of this reaction is very reasonably an intramolecular electrocyclic ring closure of a diphosphane intermediate. From this plausible mechanism, an improved procedure that gives only the cis- 2b isomer in 42% yield has been realized. In addition, an alternative synthesis using p-thiocresol that gives compounds cis- 2b and cis- 3b in a ratio of about 2:1 has been effected. © 1997 John Wiley & Sons, Inc. Heteroatom Chem 8: 551–556, 1997     

Investigation of 1-azabicycles

The composition of mixtures of epimeric 3-methylpyrrolizidines obtained by four methods was determined by gas-liquid chromatography (GLC). The data presented make it possible to select a method for the preparation of a mixture of isomers of 3-methylpyrrolizidine with predominance of trans- or cis-3,8-H-3-methylpyrrolizidine.See [1] for communication IX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 329–331, March, 1973.     

Research on 1-AZA two-ring systems. 21. Basicities,stereochemistry, and 1H and 13C NMR spectra of pyrrolizidine and its homologs in aqueous and aqueous acetonitrile solutions. Prediction of the pKa value of trans-fused pyrrolizidine

The basicities of pyrrolizidine and its homologs in aqueous and aqueous acetonitrile solutions at 25 ° C were determined. It is shown that among 3-alkylpyrrolizidines, the isomers with cis configurations have higher pK_a values than the isomers with trans configurations. On the basis of a comparative study of the ¹H and ¹³C NMR spectra it was concluded that cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine in aqueous solutions exists chiefly in the trans-fused form, whereas conformationally heterogeneous pyrrolizidines with primarily cis-fused rings experience a shift of the equilibrium to favor an increase in the cis-fused conformations when a nonpolar solvent is replaced by a polar solvent. The basicity of the trans-fused conformation of pyrrolizidine is predicted on the basis of the data obtained.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 39–46, January, 1982.     

Co-Mo/Al<Subscript>2</Subscript>O<Subscript>3</Subscript> and Ni-W/Al<Subscript>2</Subscript>O<Subscript>3</Subscript> catalysts: Potential and prospects for use in hydrotreating of light cycle oil from catalytic cracking

Со-Мо/Al₂O₃ and Ni-W/Al₂O₃ catalysts were tested in hydrotreating of light cycle oil from catalytic cracking, of the straight-run gasoil, and of their mixture under typical hydrotreating conditions used in industry. The catalysts prepared using PMo₁₂ and PW₁₂ heteropoly acids exhibit high catalytic activity. The Со-Мо/Al₂O₃ catalyst is more active in hydrodesulfurization and hydrogenation of olefin and diene hydrocarbons, whereas the Ni-W/Al₂O₃ catalysts are more active in hydrogenation of mono- and polycyclic aromatic hydrocarbons. Comparison of the quality characteristics of the hydrogenizates obtained with the requirements of the technical regulations shows that the required levels of the sulfur content and cetane number of the hydrogenizates at practically accessible process parameters can be reached for mixtures of the straight-run gasoil and light cycle oil from catalytic cracking with high content of the latter component only when the process with the Со-Мо/Al₂O₃ system and Ni-W/Al₂O₃ catalysts is performed in two steps.     

Synthesis of eight-membered aminocyclitol analogues

The first syntheses of four stereoisomeric diaminocyclooctane diols, as well as a chlorocyclooctane aminodiol, are reported. In the first part, photooxygenation of cis,cis-1,3-cyclooctadiene gave a bicyclic endoperoxide, which was reduced with zinc followed by mesylation of the hydroxyl groups. Treatment with sodium azide afforded 1,4- and 1,2-cyclooctene diazides. Oxidation of the double bonds in the isomeric diazides with OsO₄, followed by hydrogenation of the azide groups, led to 3,8-diaminocyclooctane-1,2-diol and 3,4-diaminocyclooctane-1,2-diols. In the second part, cis-3,8-diazidocyclooctene was converted into the corresponding epoxide. Stereospecific hydrolysis of the epoxide ring with HCl_(g) in methanol, and hydrogenation of the azide groups gave 3,8-diamino-2-chloro-cyclooctan-1-ol. Bromination of the double bond in cyclooctene diacetate, followed by acetate deprotection, azidolysis of the bromides, and hydrogenation of the azide groups resulted in the formation of 2,3-diaminocyclooctane-1,4-diol.     

Preparation,spectral characterization,and single crystal X-ray structures of cis and trans isomers of 2,4,6-trifluoroethoxy-1,3,5-triethyl-1,3,5,2λ5, 4λ5, 6λ5-triazatriphosphorinane-2,4,6-trioxide, [ETNP(O)(OCH2CF3)]3

Oxidation of the cis isomer of the λ³-cyclotriphosphazane [EtNP(OCH₂CF₃)]₃ with trimethylamine-N-oxide (TMNO) gives the cis isomer of trioxo-λ⁵-cyclotriphosphazane [EtNP(O)(OCH₂CF₃)]₃; the trans isomer of [EtNP(O)(OCH₂CF₃)]₃ is obtained by the treatment of a cis and trans mixture of [EtNP(OCH₂CF₃)]₃ with aqueous H₂O₂. The two trioxocyclotriphosphazanes have been characterized by elemental analysis, IR, and NMR (¹H, ¹³C, ¹⁹F, and ³¹P) spectroscopy. The solid state structures of both the isomers have been determined by single crystal X-ray diffraction. The six-membered P₃N₃ ring in both the isomers exhibits a twist-boat conformation; in the cis isomer, the trifluoroethoxy substituents lie on the same side of the ring, whereas, in the trans isomer, two trifluoroethoxy groups are on one side of the ring and the third on the other side of the ring. Crystal data for cis-[EtNP(O)(OCH₂CF₃)]₃: monoclinic, P 2₁/ n , a = 13.593(3), b = 9.721(2), c = 17.539(3) Å, β = 99.49(2)°, V = 2286(1) ų, Z = 4, and Final R = 0.047. Crystal data for trans-[EtNP(O)(OCH₂CF₃)]₃: monoclinic, P 2₁/ n , a = 11.685(4), b = 15.115(5), c = 13.233(5) Å, - = 102.21(3)°, V = 2284(1) ų, Z = 4, and Final R = 0.078.     

Reassignment of configurations for 5-bromo-2,3-dioxabicyclo[2.2.1]heptanes and its mechanistic implications

The configuration of the 5-bromo-2,3-dioxabicyclo[2.2.1]heptane obtained by treating 3,4-dibromocyclopentyl hydroperoxide with AgO₂CCF₃ and that of the isomer obtained using Ag₂O have been reassigned after identifying which 4-bromocyclopentane-1,3-diol is obtained from each upon catalytic hydrogenation. This implies a bromonium ion mechanism for the AgO₂CCF₃-induced dioxabicyclization in contrast to the S_N2-type displacements found for related compounds.     

Enantiomeric products formed via different mechanisms: asymmetric hydrogenation of an α,β-unsaturated carboxylic acid involving a Ru(CH3COO)2[(R)-binap] catalyst

Hydrogenation of (Z)-3-phenyl-2-butenoic acid with a Ru(CH₃COO)₂[(R)-binap] (BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) catalyst in methanol gives (S)-3-phenyl-2-butanoic acid and its R enantiomer in a 97:3 (4 atm) to 94:6 (100 atm) ratio in quantitative yield. Both hydrogen gas and protic methanol participate in the saturation of the olefinic bond. Analysis of the products obtained using (Z)-3-phenyl-2-butenoic acid-3-¹³C and either H₂, a 1:1 H₂-D₂ mixture, or D₂ in CH₃OD indicates that several catalytic cycles are operative, showing different reactivity and stereoselectivity. The major S enantiomer was formed primarily by the standard Ru monohydride mechanism, whereas the minor R isomer is produced via more complicated routes.     

Studies on the catalytic hydrogenation of Baylis-Hillman derivatives of substituted isoxazolecarbaldehydes. Unusual retention of isoxazole ring during Pd-C-promoted hydrogenation of Baylis-Hillman adducts

Results of the catalytic hydrogenation of Baylis-Hillman adducts obtained from substituted 3-, 4- and 5-isoxazolecarbox-aldehydes and their corresponding acetates in the presence of Raney-Ni and Pd-C are presented. The hydrogenation of Baylis-Hillman adducts of substituted 5-isoxazolecarbaldehydes and 3-isoxazolecarbaldehydes in the presence of Raney-Ni furnishes diastereoselectively syn enaminones over anti and in the presence of boric acid as an additive further enhancement of diastereoselectivity in favor of syn isomer is observed. The Pd-C-promoted hydrogenation of these substrates is also diastereoselective in favor of syn isomer but occurs without the hydrogenolysis of isoxazole-ring. The presence of boric acid as an additive in this hydrogenation exhibits no pronounced effect on diastereoselectivity. The Raney-Ni-mediated hydrogenation of Baylis-Hillman adducts of substituted 4-isoxazolecarbaldehydes yield pyridone derivatives and Pd-C-promoted hydrogenation of the same substrate is diastereoselective to afford the anti isomer of the resulting products. The enaminones derived from Baylis-Hillman adducts of 3- and 5-isoxazolecarbaldehydes serve as versatile precursors for α′-hydroxy-1,3-diketones, which undergo acid-catalyzed ring-closure reaction to afford the furanone derivatives in excellent yields.     

Synthesis of heteroaryl imines: theoretical and experimental approach to the determination of the configuration of C=N double bond

The reaction between an iminophosphorane with furan-2-carbaldehyde, thiophene-2-carbaldehyde, furan-3-carbaldehyde, and thiophene-3-carbaldehyde at 60 degrees C gives the corresponding trans imines in 53-84% yields, while the same reaction at 100 degrees C gives a mixture of the corresponding trans and cis imines. Whether the iminophosphorane reacted with 5-nitrofuran-2-carbaldehyde or 5-nitrothiophene-2-carbaldehyde only the trans imines were obtained in 85-89% yields. The irradiation of the imines obtained from thiophene-2-carbaldehyde and thiophene-3-carbaldehyde gave the corresponding photocyclization products. Cis/trans stereochemistry of the imines can be assigned simulating the UV-vis spectra. In the case of the imine from furan-2-carbaldehyde the computed spectra are characterized by an intense absorption at 361 and 357 nm respectively for the trans-1 and trans-2 structures. No other absorptions of comparable intensity have been predicted: the agreement with the experimental spectrum can be considered good. Furthermore, the experimental weak peaks at 280 and 270 nm can be associated to the computed transitions at 278 and 260 nm for the trans-1 isomer. Several minima of the energy surface can be assigned to the cis isomer, and they all present a very similar energy. The structures of the cis-1 and cis-2 isomers present quite coincident computed electronic spectra. In both cases, the computed spectrum shows two principal features. For the cis-1 structure, the first characteristic absorption is located at 414 nm and the second one at 284 nm. For the cis-2 structure, the first feature is located at 412 nm and the second one at 286 nm. The second transition is computed somewhat more intense. The experimental spectrum could be the consequence of similar populations of the planar cis structure (cis-3) and nonplanar cis structures (cis-1, cis-2, and their enantiomers).     

Hydrogenation of the ansa-Chain of Rifamycins. X-ray crystal structure of (16S)-16,17,18,19-tetrahydrorifamycin S

The catalytic hydrogenation of rifamycin S ( 2 ) over Pd/C, followed by oxidation with K₃[Fe(CN)₆], generates a pair of 16,17,18,19-tetrahydrorifamycins S ( 3/4 ), epimeric at C (16). The use of PtO₂ as catalyst leads to the hydrogenation also of the C(28)?C(29) bond giving, after oxidation by K₃[Fe(CN)₆], a mixture of the epimers (16R)- and (16S)-16,17,18,19,28,29-hexahydrorifamycins S ( 5/6 ). Furthermore, we synthesized the (16R)- and (16S)-3-bromo derivatives 7/8 and (16R)- and (16S)-3-(piperidin-1-yl) derivatives 9/10 . The determination of the X-ray crystal structure of the most abundant epimer 4 of the tetrahydrorifamycins allowed the assignment of the absolute configuration at C(16) of all derivative. A Structure-activity relationship study showed that in general the (16R)-epimers are more potent inhibitors of bacterial RNA polymerase than the (16S)-epimers.     

A novel method to synthesize docetaxel and its isomer with high yields

Side chains of docetaxel and its isomer were obtained through Staudinger cycloaddition and catalytic hydrogenation of chlorophenyl intermediates, using chlorobenzaldehyde as starting material. Syntheses of three novel chiral azetidinone derivatives through the Staudinger cycloaddition reaction of chlorophenyl chi‐ral amine Schiff base with different substituted positions were described and their ring‐opening reaction under the catalysis of Pd/MgCO₃ or Pd/C to afford side chains of docetaxel and its isomer in high yields was investigated. Finally, docetaxel and its isomer were obtained. Single crystal of (3S,4R)‐3‐hydroxy‐N‐[(S)‐(l‐phenyl)ethyl]‐4 ‐(2′‐chlorophenyl) ‐2‐azetidinone ( 4c ) was obtained, the configuration of which was determined by X‐ray diffraction. Because of the mild cyclization reaction condition and convenient asymmetric resolution operation when p‐chlorobenzaldehyde was employed instead of benzaldehyde, the yield of cyclization and hydrogenation increased dramatically and the total yield of docetaxel was higher than the result in literature. When o‐chlorobenzaldehyde was employed instead of benzaldehyde an isomer of docetaxel was obtained by the same way.     

Toluene methylation on AlPO4-Al2O3 catalysts (5–15 wt.% Al2O3)

The alkylation of toluene with methanol over AlPO₄-Al₂O₃ (5–15 wt.% Al₂O₃) catalysts produces a mixture of xylenes (XYL) although trimethylbenzenes (TMB) were also found. The TMB selectivity increased with temperature at the expense of XYL selectivity. Isomer distribution was approximately 48, 24 and 27 mol% foro-, m- andp-XYL, and 74, 26 and 0 mol% for 1,2,3-, 1,2,4- and 1,3,5-TMB, both quite different from the equilibrium isomer composition. The catalytic activity increased with alumina content, however, it decreased on increasing the calcination temperature in the 923–1273 K range. Good correlations between catalytic activity and the increase in acidic properties with Al₂O₃ loading (as determined by base chemisorption, in the gas phase,versus pyridine and 2,6-dimethylpyridine) have been obtained.     

Scope and limitations of the stereoselective homogeneous hydrogenation of methylenecyclohexanols by cationic rhodium complexes

Homogeneous catalytic hydrogenation of 3-methylenecyclohexanol gives $\text{trans}$-3-methylcyclohexanol with 98% stereoselectivity. but low selectivity is observed for 2-methylenecyclohexanol and 2-methylenecyclohexanemethanol.     

Generalized structural and kinetic relationships for 1,2-shifts of a hydrogen atom in carbocations and neutral compounds

Dynamic PMR has been used in a kinetic study of degenerate rearrangement of 5,6-X₂-1-H-1, 2-dimethylacenaphthylenonium ions (X=CH₃, Br), accomplished by means of a 1,2-shift of the hydrogen atom. It has been found that the free energy of activation of the 1,2-shift of the H atom in the 5,6-X₂-1-H-1,2-dimethylacenaphthylenonium cation (X=H, CH₃, Br), in the 1-H-1,2-dimethylcyclopentyl cation, and in 5-H-1,2, 3,4,5-pentamethyl-1,3-cyclopentadiene exhibits a linear correlation with parameters characterizing the electron density on the atom to which the migrant is shifted.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1352–1358, June, 1991.     

Unusual pathway of the tantalum-catalyzed carboalumination reaction of alkenes with triethylaluminum

Carboalumination of 1-alkenes (1-hexene, 1-octene, 1-decene) with Et₃Al in the presence of catalytic amounts of TaCl₅ results in a mixture of 2-(R-substituted)- and 3-(R-substituted)-n-butylaluminums (1:1 ratio) in total yields of 75–85%. The TaCl₅-catalyzed reaction of bicyclo[2.2.1]hept-2-ene, endo-tricyclo[5.2.1.0^2,6]deca-3,8-diene, and (exo/endo)-5-methylbicyclo[2.1.1]hept-2-ene with Et₃Al leads to the formation of diethyl[2-exo-(2′-norbornylethyl)]aluminums in high yields. DFT calculations confirm the thermodynamic preference of the final exo product. The multistep reaction mechanisms for the formation of the resultant organoaluminums through tantalacyclopentanes as key intermediates are also discussed.