N,N-1,2-Benzenedisulfonylimide,a new cyclic leaving group for the stereoselective nucleophilic substitution of amines

We hereby report the preparation and nucleophilic substitutions of the N,N-1,2-benzenedisulfonylimide derivatives 1a and 2a of the chiral amines 1 and 2. The nucleophilic attack of KNO₂ afforded the respective alcohols 3 and 4 with 84–90% inversion of configuration. Nucleophilic attack by the azide ion afforded the azide products 5 and 6 which were reduced to the corresponding inverted amines 1 and 2 (94–98.5% inversion). The improved leaving group ability of the N,N-1,2-benzenedisulfonylimides compared with previously reported N,N-disulfonylimides is discussed. Chiral GLC analysis of all products is summarized and the alternative chiral analysis of product 3 by ¹³C NMR using heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin as a chiral solvating agent (CSA) is discussed.     

Stereoselective transformation of amines via chiral 2,4,6-triphenylpyridinium intermediates

We herein report the preparation and the nucleophilic substitution of the chiral 2,4,6-triphenylpyridinium tetrafluoroborates 2a and 2b. The triphenylpyridinium intermediates were generated from homochiral amines (1a, 1b) and 2,4,6-triphenylpyrylium tetrafluoroborate and used as substrates for stereoselective nucleophilic substitution. The degree of inversion in the substitution reactions has been studied. The alcohol (3a, 3b) and azide (4a, 4b) products were obtained with >99 and 96–98% inversion of configuration, respectively.     

Synthese und Reaktivität von Silicium-übergangsmetall-Komplexen: XXI. Ferrio-azidosilane and Ferriosilyl-iminophosphorane

Reaction of the ferriochlorosilanes R₅C₅(CO)₂FeSiR′_3-nCl_n (1a–1f) with sodium azide in tetrahydrofuran yields the ferrio- (mono-, bis-, and tris-azido)silanes R₅C₅(CO)₂FeSiR′_3-n(N₃)_n (R = H, Me; R′ = Me, H; n = 1–3) (2a–2f). CCl₄ converts Cp(CO)₂FeSiMe(H)N₃ (2a) into the ferrioazido(chloro)silane Cp(CO)₂-FeSiMe(Cl)N₃ (3). Treatment of 2d, 2f with Me₃P results in the formation of the ferriosilyl-iminophosphoranes Cp(CO)₂FeSi(N₃)(R)NPMe₃ (R = Me, N₃), (4a, 4b) by N₂ elimination.     

A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotic levofloxacin

A series of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 8a-g were synthesized via- a copper-catalyzed intramolecular N-aryl amination reaction on substituted 2-(2-bromophenylthio)-ethanamines which were synthesized by the nucleophilic substitution reaction of 2-bromobenzenethiol with Boc-protected amino alcohol derivatives. This strategy provides a short and an efficient entry to (S)-3-methyl-1,4-benzoxazine 12, an advanced synthetic intermediate for the synthesis of levofloxacin.     

Ladders,rings and cubes as structural motifs in three new zinc(II) azide complexes: Synthesis,spectral and structural characterization

Three new zinc(II) azide complexes, namely {[Zn₂(N₃)₄(py-tetrazole)₂](py-tetrazole)}_n (1), {[Zn₂(N₃)₄(3-OHpy)] · 2H₂O}_n (2) and [Zn(N₃)₂(pym)]_n (3), where py-tetrazole = tetrazolo[1,5-a]pyridine, 3-OHpy = 3-hydroxypyridine and pym = pyrimidine, have been synthesized by the hydrothermal methods and structurally characterized. The ligand py-tetrazole was obtained through the interaction of 2-chloropyridine with the azide ion under hydrothermal condition. The structure of 1 consists of a ladder-like arrangement of 1D double chain zinc(II) azide. In the coordination chain, each zinc atom binds di-EO azide bridges connecting another zinc atom in opposite chain, and two EO bridges, one on each side, and the fifth position is occupied by a N atom of py-tetrazole ligand. The structure of 2 features 2D sheets composed of tetranuclear zinc(II) ring and octanuclear zinc(II) ring interconnected by EO azide bridges. The 2D carrying into 3D supramolecular network by the help of several hydrogen bonding interactions. The 3-OHpy molecule acts in the tautomeric keto-form as O,O-bidentate bridging ligand. Complex 3 features distorted octahedral geometry around each zinc center, N,N′-bidentate pyrimidine ligand and EE azido bridges leading to 3D network structure. The IR spectra are measured and discussed. Complex 2 only exhibits photoluminescence properties whereas the other two complexes do not luminesce at room temperature.     

Solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives

A general method is reported for the solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives based on the cyclization of resin-bound chlorophthalazines 4 with various hydrazides or sodium azide. The resin-bound chlorophthalazines 4, produced by nucleophilic aromatic substitution reaction of dichlorophthalazine with the secondary amine resins 2, served as the key intermediate for subsequent triazolophthalazine resins 6 and tetrazolophthalazine resins 8, which provided the desired products 7 and 9 in good yields and purities.     

Synthesis of spirocyclic azacycles from the cyclization of furan tethered N-acyliminium ions

The protic and Lewis acid promoted cyclization reactions of tethered furan-4,5-dihydroxypiperid-2-ones, furan-4,5-diacetoxypiperid-2-ones and furan-3,4-diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied. In the case of the furan-4,5-dihydroxypiperid-2-one 2a and its diacetate derivative 2b, macrocyclic products were formed from an initial intermolecular reaction between 2a or 2b, via the nucleophilic C5 furan carbon, and their corresponding N-acyliminium ion intermediates. When the furan C5 position of 2b was blocked by substitution with bromine then TFA or Sc(OTf)₃ catalysed cyclization reactions gave a spirotricyclic product (a 5-6-6-tricycle) in a highly diastereoselective manner. Cyclization of the analogous C5-Br-furan-pyrrolidone 29 with TFA resulted in a related spirotricyclic (a 5-6-5 tricycle) product. Attempts to prepare an analogous azepine system, a 5-7-5 tricycle, were not successful. Cyclization reactions of the C5-PhS-furan- or C5-phenylsulfonyl-pyrrolidone analogues of 29 with TFA were also not successful.     

Steric constraints against [3,3]-sigmatropic rearrangement of allylic azides. A convenient approach to β-l-4-aminopent-2-enoglyceropyranosides

Starting from alkyl α-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 13a–c, nucleophilic substitution carried out with polymer-supported azide ion led to regioisomeric mixtures of the azides 14a–c and 15a–c. An analogous result, due to a [3,3]-sigmatropic rearrangement, was observed starting from methyl α-d-hex-2-enoerythropyranoside derivatives 6a and 6b. On the contrary, starting from alkyl β-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 21a–c, azides 22a–c were exclusively obtained, and subsequently converted into the corresponding amino derivatives 23a–c. The behaviour of β-anomers 21a–c was ascribed to steric interactions in the cyclic transition state, as supported by ab initio calculations.     

BF3·Et2O catalyzed diastereoselective nucleophilic reactions of 3-silyloxypiperidine N,O-acetal with silyl enol ether and application to the asymmetric synthesis of (+)-febrifugine

The asymmetric BF₃·Et₂O catalyzed nucleophilic reactions of 3-silyloxypiperidine N,O-acetal 10 with silyl enol ethers derived from ketones are described. (+)-Febrifugine 1, an antimalarial alkaloid, was successfully synthesized based on this nucleophilic substitution. In addition, N,O-acetal 10 was synthesized from l-benzyl glutamate in 11 steps.     

Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and scope

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.     

Nitropyrazoles 22. On reactivity of 3,5-dinitro-4-(phenylsulfonyl)pyrazole and its N-methyl derivative

3,5-Dinitro-4-(phenylsulfonyl)pyrazole (5) obtained by oxidation of 3,5-dinitro-4-(phenylthio)pyrazole with 30% H₂O₂ in AcOH was involved into nucleophilic substitution reaction with thiophenol, which proceeded with substitution of the phenylsulfonyl group at position 4. N-Methyl-3,5-dinitro-4-(phenylsulfonyl)pyrazole obtained by methylation of 5 with dimethyl sulfate was involved into nucleophilic substitution reaction with thiophenol, p-bromophenol, and morpholine with the regioselective substitution of the nitro group at position 5 to form 5-R-3-nitro-4-(phenylsulfonyl)pyrazoles.     

Studies of reactions of dimethylphosphoramidic difluoride withtrans-2-(N,N-dialkylamino)cycloalkanols in the presence of various sulfur-containing nucleophiles

The reactions of dimethylphosphoramidic difluoride (1) withtrans-2-(N,N-dialkylamino)cycloalkanols were studied in the presence of various sulfur-containing nucleophiles and Et₃N. WhenO,O-diisopropyl thiophosphoric acid was used as a nucleophile, the correspondingO,O-diisopropylS-[2-(N,N-dialkylamino)cycloalkyl] thiophosphates were obtained in satisfactory yields. The direction of this reaction in the presence ofO-isopropyl toluenephosphonothioic acid depends on the pK _a of aminoalcohol, namely, the amount ofO-isopropyl tolylphosphonofluoridate that was formed along withO-isopropylS-[2-(N,N-dialkylamino)cycloalkyl] tolylphosphonothioates was increased as the pK _a increased. The reactions of compound1 withtrans-2-(N,N-dialkylamino)cycloalkanols and thioacetic acid afforded 2-(N,N-dialkylamino)cycloalkanethiols, certain of which were readily oxidized to the corresponding disulfides. In the case of potassium ethyl xanthate, the composition of the reaction products depends on the nature of aminoalcohol. X-ray diffraction analysis ofS-(2-piperidinocyclohexyl)N,N-dimethyldithiocarbamate demonstrated that this compound exists as thetrans isomer. This fact supports the reaction mechanism, which we have suggested previously and which involves the formation of aziridinium cations followed by their opening under the action of nucleophilic agents.     

Absence of triazirine intermediates in the photolytic formation of azides from mesoionic 3-substituted 1,2,3,4-oxatriazolylio-5-oxides : Isotope labelling experiments

Irradiation of 3-phenyl-1,2,3,4-oxatriazolylio-5-oxide (1) leads to formation of CO₂, N₂O, phenyl azide and phenyl isocyanate. The two latter compounds are observed only in low yields because of secondary photolytic reactions. Photolysis in CCl₄ or Cl₂CCCl₂ of 2-¹⁵N labelled (1) leads almost exclusively to the formation of 3-¹⁵H labelled phenyl azide identified by IR spectroscopy on comparison with authentic 1-¹⁵N, 2-¹⁵N and 3-¹⁵N labelled phenyl azides, respectively. These results show that phenyl azide is formed photolytically from (1) via phenyl migration and not via “antiaromatic”, phenyl triazirine (2).     

Palladium complexes of N-aryl-2-pyridylamines

Palladium complexes of N-phenyl-2-pyridylamine (4) and dipyridylamine substrates (7, 11) have been studied. Due to the coordination ability of the pyridine-nitrogen atoms, the pyridyl substrates, 4, 7, 11 were subjected to Pd(OAc)₂ complexations and a number of N-aryl-2-pyridylamine Pd complexes (13-17) were isolated and characterised, in particular by NMR and ESI-MS. A new method for the preparation of the acetato-bridged six-membered ring palladacycle complex (13) of 4 is reported. The dipyridyl amines 7, 11 formed cis/trans bis-dentate acetato-bridged dimeric Pd₂Lig₂(OAc)₂ (14a,b/16a,b) and Pd₃Lig₂(OAc)₄ complexes (15a,b/17a,b). The N-aryl-2-pyridylamine substrates (4, 7, 11) were prepared by oxidative nucleophilic substitution, by 1,3-cycloaddition reaction or by Buchwald amination.     

Regiospecific nucleophilic substitution in 2,3,4,5,6-pentafluorobiphenyl as model compound for supramolecular systems. Theoretical study of transition states and energy profiles, evidence for tetrahedral SN2 mechanism

2,3,4,5,6-Pentafluorobiphenyl (PFBi) was modified by the nucleophilic substitution of one fluorine using a series of O-, S- and N-nucleophiles, viz. alkaline salts of 2,2,2-trifluoro-ethanol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol, 1,2;3,4-di-O-isopropylidenexylitol, allylsulfane, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctane-1-thiol, 3-aminopropan-1-ol (7), and tert-butyl N-(3-aminopropyl)carbamate (8). All the substitutions took place exclusively at the position para to the phenyl group. (3-Amino-propyl)amino derivative of PFBi (15) was further modified at the terminal amino group by acylation or fluoroalkylation. The reaction of 8 was applied to meso-5,10,15,20-tetrakis-(pentafluorophenyl)porphyrin (20) to afford tris- (21) and tetrakis-substituted (22) products with complete para-regioselectivity. Theoretical studies of the reaction pathways of PFBi with ammonia, microsolvated lithium fluoride or lithium hydroxide revealed that no Meisenheimer-type intermediates are formed in the course of the simulated reactions: instead, tetrahedral S_N2 mechanism was found. Significant regioselectivity of the nucleophilic aromatic substitution, leading to 4-substituted products, was predicted based on relative transition state energies in agreement with the observed experimental results.     

tert-Alcohol-functionalized imidazolium ionic liquid: catalyst for mild nucleophilic substitution reactions at room temperature

Encouraged by a synergistic effect on nucleophilic fluorination, an imidazolium mesylate salt (1a) possessing two different solvent properties in one molecule—tert-alcohol and ionic liquid was utilized in various nucleophilic substitution reactions. By a comparison study with 1-n-butyl-3-methylimidazolium ionic liquids, 1a has proved to be a better phase transfer catalyst even under room temperature conditions. It was successfully applied to other nucleophilic substitution reactions such as fluorination, chlorination, bromination, iodination, acetoxylation, azidation, and cyanation.     

1,3-Dipolar cycloaddition reaction of a d-galactose derived nitrone with allyl alcohol: synthesis of polyhydroxylated perhydroazaazulene alkaloids

Diastereofacial intermolecular 1,3-dipolar cycloaddition of d-galactose derived nitrone with allyl alcohol followed by tosylation afforded, in a 1:1 ratio endo- and exo-isooxazolidines 4a and 4b with complete diastereoselectivity at the nitrone carbon. The N–O bond reductive cleavage and S_N2 displacement afforded the pyrrolidine ring with a galactose appendage that on acetonide cleavage and reductive amino-cyclization afforded pentahydroxylated perhydroazaazulenes 1a and 1b.     

A facile approach for the synthesis of novel substituted 4H-chromenes and condensation reactions of 4H-chromenes leading to chromenopyrrolones and triazolylchromenopyrrolones

A facile method has been developed for the synthesis of 4H-chromene-3-carboxylates 3a–d by the nucleophilic substitution reaction of 2-hydroxy-2H-chromene-3-carboxylates 2a–d with triethylsilane in the presence of BF₃·O(C₂H₅)₂. Cyclocondensation of 4H-chromene-3-carboxylates 3a–d with benzylamines 4a–d afforded a series of 2,3-dihydrochromenopyrrolones 5a–p and with propargylamine afforded 2-propynyl-2,3-dihydrochromenopyrrolones 6a–d. Click reaction of 6a–d with benzyl azides 7a–d provided a series of 1H-1,2,3-triazolylmethyl-2,3-dihydrochromenopyrrolones 8a–p. Thus synthesized compounds 3a–d, 5a–p, 6a–d, and 8a–p are novel heterocyclic compounds and being reported for the first time.     

[5]Ferrocenophane based ligands for stereoselective Rh-catalyzed hydrogenation and Cu-catalyzed Michael addition

A series of homochiral [5]ferrocenophane based N/P, N/S, N/Se, Se/P and P/P ligands was prepared from (R)-N,N-dimethylamino[5]ferrocenophane. These ligands were tested in the Rh-catalyzed hydrogenation of dimethyl itaconate and in Cu-catalyzed Michael addition of Et₂Zn to cyclohex-2-enone. The best results in terms of conversion and enantioselectivity in the Rh-catalyzed hydrogenation provided bis(diphenylphosphine) ligand 2h (100% conversion and 95% ee) and aminophosphine 2a in the Cu-catalyzed conjugate addition (100% conversion 84% ee). The enantioselectivity of the Rh-catalyzed hydrogenation of methyl 2-acetamidoacrylate was lower (41% ee).     

N-dealkylation of electronically excited coumarins by nitrobenzenes

When excited (monochromatically or with λ ⩾ 280 nm) in benzene solution in the presence of nitroaromatic acceptors, several 7-dialkylamino-coumarins undergo moderately efficient mono-N-dealkylation to form 7-alkylaminocoumarins, accompanied by the reduction of the nitro function in the acceptor. For 7-(N,N-diethylamino)-4-methylcoumarin (1a) a linear plot of ø_P⁻¹ versus the reciprocal of the concentration of the starting material suggests that two molecules of 1a are involved in the dealkylation of irradiated 1a by ground state 3-chloronitrobenzene. When the concentration of 1a is kept constant but that of the acceptor is varied, ø_P goes through a maximum at intermediate concentrations. Furthermore, ø_P is found to be larger for weaker acceptors (more negative reduction potential) than for stronger acceptors (less negative reduction potential). The rigid dye Coumarin 102 does not show any analogous decomposition. All results are interpreted in terms of the interference of the nitroaromatic with the self-quenching mechanism of coumarin N-dealkylation put forward recently by Jones and coworkers.