Synthesis of 2-(N-arylimino-κN-methyl)pyrrolide-κN complexes of nickel

2-(N-aryliminomethyl)pyrrole precursors (2,6-R₂-C₆H₃-NCH-2-C₄H₃NH) (R = Me, IH; R = ⁱPr, IIH) were prepared and transformed into their corresponding sodium salts (Na⁺I⁻ and Na⁺II⁻) by treatment with NaH. Both salts readily react with [NiBr₂(DME)] (DME = 1,2-dimethoxyethane) to give the respective bis{2-(N-arylimino-κN-methyl)pyrrolide-κN}nickel(II) complexes (1, 2) in almost quantitative yields. The oxidative addition of IH to [Ni(COD)₂] (COD = 1,5-cyclooctadiene) results in the formation of 3, which is a mono(iminomethylpyrrolide)-η³-(cyclic-allyl)-type organonickel(II) complex. The crystal structure of compound 1 has been established by X-ray diffraction studies.     

A facile metal-free approach to N,N′-bis(1-oxidopyrimidin-4-yl)diamines with promising biological activity

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Diastereoselective carbonyl phosphonylation using chiral N,N′-bis-[(S)-α-phenylethyl]-bicyclic phosphorous acid diamides

Addition of aldehydes to the P-anion derivatives of chiral phosphorous acid diamides (1S,2S,1′S,1″S)-2 and (1R, 2R,1′S,1″S)-2 in THF gave α-hydroxyphosphonamides in good yield (64-100%) and moderate diastereoselectivities.     

N,3,4-Trisubstituted pyrrolidines by electron transfer-induced oxidative cyclizations of N-allylic β-amino ester enolates

Oxidative radical cyclizations starting from easily accessible N-allylic β-alanine esters are reported. Deprotonation generates the corresponding enolates, which are transformed efficiently into α-ester radicals by single electron transfer mediated by ferrocenium hexafluorophosphate. The stereochemistry of the radical 5-exo cyclization can be switched by the configuration of the enolate precursor. First examples of asymmetric oxidative radical cyclizations using N-(1-phenylethyl)-substituted β-amino esters are reported. Only two of the four possible diastereomers are formed from the (E)-enolate with high cis-selectivity. From (Z)-enolates, an additional diastereomer is formed, which is likely to be formed only under chelation control.     

Chiral N,N′-dioxide-iron(II) complexes catalyzed enantioselective oxa-Michael addition of α,β-unsaturated aldehydes

The enantioselective oxa-Michael addition reaction of 1-(4-methoxyphenyl) ethanone oxime to various α,β-unsaturated aldehydes was accomplished by using chiral N,N′-dioxide-FeSO₄·7H₂O (1:1) complex. Aromatic acid was employed as additive to increase the yield of the reaction. The corresponding adducts were obtained in moderate yields with up to 76% ee under mild conditions.     

Visible-light photo-catalytic C–C bond cleavages: preparations of N,N-dialkylformamides from 1,2-vicinal diamines

A range of 1,2-vicinal diamines were smoothly converted into N,N-dialkylformamides under the synergistic actions of Ru(bpy)₃Cl₂ photo-catalyst, 45 W household lighting bulb, and Cs₂CO₃ basic additive under very mild reaction conditions. The process involves visible light-enabled photo-catalytic cleavage of C–C bond as the strategic event.     

An efficient one-pot synthesis of N,N′-disubstituted phenylureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid

We have developed an efficient one-pot method for the microwave-assisted synthesis of ureas and carbamates via a proposed Lossen rearrangement. Herein we report the first examples of the direct conversion of benzoyl chlorides into N,N′-disubstituted ureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid as reagent. Using our general method, we have produced 11 examples of N,N′-disubstituted phenylureas in yields up to 95% using various substituted anilines, and primary and secondary amines. Additionally, we were able to generate a series of N-aryl carbamates in moderate yields using primary, secondary and tertiary alcohols.     

The first synthesis of cis-N,N′-dialkylisoindigo derivatives from 3-indolyl-2-oxindoles with DDQ

cis-N,N′-Dialkylisoindigo derivatives were synthesized for the first time by the reaction of 3-indolyl-2-oxindoles with DDQ in aqueous 1,4-dioxane. cis-Isoindigo derivatives were completely isomerized to the corresponding trans-isomers by heating the solution in short time.     

Syntheses and lipophilicity measurement of N/N-terminus-1,1-dihydroperfluoroalkylated α-amino acids and small peptides

(1,1-Dihydroperfluoroalkyl)phenyliodonium N,N-bis(trifluoromethylsulfonyl)imides (4, n = 0-2) were synthesized and used to transfer the corresponding 1,1-dihydroperfluoroalkyl groups to the α-amino group of (l)tyrosine. The obtained N^α-2,2,2-trifluoroethylated (l)tyrosine (6, n = 0) was further used as the N-terminus in the solid phase peptide synthesis of leucine enkephalin analogue. The lipophilicity of the N^α-1,1-dihydroperfluoroalkylated (l)tyrosines (6, n = 0-2) and N-terminus-2,2,2-trifluoroethylated leucine enkephalin analogue (7), as well as the corresponding parent compounds, was measured.     

In vitro and in vivo studies of N,N′-bis[2(2-pyridyl)-methyl]pyridine-2,6-dicarboxamide–copper(II) and rheumatoid arthritis

The thermodynamic equilibria of copper(II), zinc(II) and calcium(II) with N,N′-bis[2(2-pyridyl)-methyl]pyridine-2,6-dicarboxamide (L1) have been studied at 25 °C and an ionic strength of 0.15 mol dm⁻³. Spectroscopic studies suggest metal ion complexation promotes deprotonation and coordination of the amide nitrogens resulting in overall tetragonal coordination of Cu²⁺. Blood–plasma modelling predicts that Cu(II) competes effectively against Zn(II) and Ca(II) for L1 in vivo. Octanol–water partition coefficient studies show that Cu(II)–L1 complexes are reasonably lipophilic. However, the CuL1H₋₂ species which predominates at the physiological pH of 7.4 has poor superoxide dismutase activity. Bio-distribution experiments showed activity accumulation and retention in the body of about 50% of the injected dose for the [⁶⁴Cu]Cu(II)–L1 complex after 24 h.     

Cyclisation at very high temperature. Thermal transformations of N-alkyl and N, N-dialkyl amides of α,β-unsaturated acids into mono- and bicyclic heterocycles under FVT conditions

Cyclisations of N-alkyl and N,N-dialkyl cinnamic amides to the corresponding pyrrolidin-2-ones under the conditions of flash vacuum thermolysis (FVT), are described. It was found that these reactions proceed at 950-1000 °C affording in various yields the mixtures of isomeric mono and bicyclic γ-lactams, which were separated chromatographically and analysed by means of NMR spectroscopy. Two alternative mechanisms for the title process are proposed.     

Catalytic syntheses of γ-functionalized α-keto esters from thioacetals and N,O-acetals

Ethyl 2-(trimethylsilyloxy)acrylic ester (1a) reacts with thioacetals providing the corresponding α-keto-γ-thio esters in good to satisfactory yields. Whereas aminals do not react, N,O-acetals lead to γ-amino-α-keto esters in good to excellent yields. All reactions proceed under mild reaction conditions, and no additional work up is required. Subsequent transformations of the obtained products to the corresponding α-oximes have been demonstrated.     

Restricted open-shell Kohn–Sham theory: N unpaired electrons

We present an energy expression for restricted open-shell Kohn–Sham theory for N unpaired electrons. It is shown that it is possible to derive an explicit energy expression for all low-spin multiplets of systems that exhibit neither radial nor cylindrical symmetry. The approach was implemented in the CPMD code and tested for iron complexes.     

One pot synthesis of α,α-bis(N-arylamido) lactams via iodide-catalyzed rearrangement of β,β-bis(N-arylamido) cyclic ketene-N,O-acetals

Five and six-membered cyclic ketene-N,O-acetals, generated in situ from 2,3-dimethyl-2-oxazolinium iodide or 2,3-dimethyl-2-oxazinium iodide and triethylamine, reacted with aryl isocyanates in refluxing THF producing α,α-bis(N-arylamido) lactams via the iodide-catalyzed rearrangement of β,β-bis(N-arylamido) cyclic ketene-N,O-acetal intermediates. The cyclic ketene-N,O-acetal generated in situ from 2,3,4,4-tetramethyl-2-oxazolinium iodide reacted with isocyanates to give β,β-bis(N-arylamido) cyclic ketene-N,O-acetals, which do not readily rearrange. The two methyls at C-4 hindered the nucleophilic attack of iodide on C-5, which is required for rearrangement.     

Synthesis of 2,3-disubstituted benzofurans and indoles by π-Lewis acidic transition metal-catalyzed cyclization of ortho-alkynylphenyl O,O- and N,O-acetals

The PtCl₂-catalyzed cyclization reaction of ortho-alkynylphenyl acetals 1 in the presence of COD (1,5-cyclooctadiene) produces 3-(α-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cycloocatadiene in toluene at 30 °C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively. Moreover, the reaction of N-methoxymethyl-2-alkynylanilines 3 was catalyzed by PdBr₂, affording the corresponding 2,3-disubstituted indoles 4 in moderate yields. For example, the reaction of N-methoxymethyl-2-(1-pentynyl)-N-tosylaniline (3a) and N-methoxymethyl-2-(phenylethynyl)-N-tosylaniline (3b) in the presence of 10 mol % of PdBr₂ in toluene at 80 °C gave 3-methoxymethyl-2-propyl-1-tosylindole (4a) and 3-methoxymethyl-2-phenyl-1-tosylindole (4b) in 33 and 33% yields, respectively.     

Lewis acid-catalyzed [3+3] cycloadditions of donor‒acceptor aziridines with N,N-dialkyl-3-vinylanilines via carbon-carbon bond cleavage

A Lewis acid-catalyzed [3 + 3] cycloaddition reaction of donor?acceptor aziridines with N,N-dialkyl-3-vinylanilines has been developed for the stereoselective synthesis of tetrahydroisoquinolines (THIQs). The reaction performed using Gd(OTf)₃ as the Lewis acid catalyst was tolerant to various N-tosylaziridine and N,N-dialkyl-3-vinylaniline substrates and provided access to highly functionalized THIQs in typically high yields with moderate-to-excellent diastereoselectivities.     

Vaporization and thermal decomposition of B,B′,B″-tribromoborazine

Vapor pressure as a function of temperature above solid and liquid (BrBNH)₃ and the thermodynamic parameters of (BrBNH)₃ sublimation and vaporization have been determined using static tensimetry with membrane null-manometer. The thermal decomposition of tribromoborazine has been studied in the saturated and unsaturated vapor regions. Irreversible decomposition occurred at noticeable rates at temperatures higher than 343 K and was accompanied by HBr evolution. In the unsaturated vapor region, thermal decomposition has far lower rates than in the saturated vapor region because of diffusion limitations. The activation energy of condensed-phase thermal decomposition of B,B′,B″-tribromoborazine is 65 ± 3 kJ/mol, and this value proves that tribromoborazine decomposition at low temperatures is not accompanied by opening of the boron-nitrogen cycle.     

Unexpected cleavage of the Cpy–Cpy bond in the reaction of 2,2′-bipyridine N,N′-diimines with acetylenes

An unusual cleavage of the C_py–C_py bond in the reaction of 2,2′-bipyridine N,N′-diimine and its C-methyl substituted derivatives with acetylenes is described. The effect of the solvent on the yield of 7,7′-bipyrazolo[1,5-a]pyridine-2,2′,3,3′-tetracarboxylates and the products of cleavage of the C_py–C_py bond has been studied. The mechanism of the cleavage reaction is discussed on the basis of DFT calculations.     

Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.     

Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones into N-(α-ketoacyl)anthranilic acids

N-(α-Ketoacyl)anthranilic acids were prepared by oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones by using paraperiodic acid (H₅IO₆) or sodium periodate (NaIO₄). The optimisation of the reaction conditions is described as well as the utilisation of N-(α-ketoacyl)anthranilic acids in the preparation of anthranilic acid hydrochlorides.