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.     

Iron-catalyzed carbonylation–arylation of N-arylacrylamides for synthesis of oxindole derivatives

An efficient method for oxindole synthesis is established by iron-catalyzed carbonylation–arylation of N-arylacrylamides with aldehydes. 3-Functionalized oxindoles are synthesized smoothly using FeCl₃ as catalyst and TBHP as oxidant. The obtained oxindoles can be used for further transformations to give diverse indole alkaloid structure motifs.     

Orthoamides by selective borohydride reduction of N,N′,N″-triacyl- and N,N′,N″-tri(alkoxycarbonyl)-guanidines

N,N′,N″-Triacylguanidines and N,N′,N″-tri(alkoxycarbonyl)guanidines were prepared and reduced with borohydride salts in a mixture of tetrahydrofuran and acetic acid to give triacyl and tri(alkoxycarbonyl) orthoamides in yields of 40–85%. However, similar reduction of N,N′,N″-tri(t-butoxycarbonyl)guanidine did not give orthoamide but the aminal di(t-butyl) methylenedicarbamate.     

On the accuracy of numerical Hartree–Fock energies

It is demonstrated that numerical Hartree–Fock (HF) energies reported in the literature in some cases have errors in the milliHartree range. The main cause of these errors is due to the use of too small a value for the practical infinity parameter in the finite difference method for generating the results. By systematically investigating the convergence with respect to the computational parameters, HF energies accurate to at least 1 microHartree are generated for 42 diatomic systems containing first and second row elements, encompassing both cationic, neutral and anionic systems.     

Computational study of Rh(I)-Catalyzed Cycloaddition–Fragmentation of N-cyclopropylacrylamides

Rh-catalyzed cycloaddition–fragmentation of N-cyclopropylacrylamides is an effective method to directly obtain substituted azocanes. In this transformation, the challenging step is insertion of CO and alkene into the more hindered proximal cyclopropane CC bond while avoiding competitive less hindered proximal CC activation. Given the importance of this novel strategy, we performed a density functional theory study to clarify the catalytic mechanism. The calculations confirm that cleavage of the more hindered bond is more favorable than cleavage of the less hindered bond for Rh-catalyzed (7 + 1) cycloaddition of N-cyclopropylacrylamides. Comparison between Rh-catalyzed (3 + 1 + 2) and (7 + 1) cycloaddition shows that the coordination mode with different ligand plays a crucial role in enabling different CC cleavage. The main factors responsible for the occurrence of β-hydride elimination rather than CC reductive elimination are also discussed. The kinetic preference for β-hydride elimination can be attributed to the transition state of CC reductive elimination being more distorted and forming in a much more concerted fashion than that of β-hydride elimination. Additionally, C4H elimination is disfavored owing to weaker interaction energy compared with C7H elimination by analyzing using the distortion/interaction model.     

Synthesis of N-alkyl-N′-aryl-piperazines via copper-catalyzed C–N bond formation

An efficient copper-catalyzed tandem synthesis of N-alkyl-N′-aryl-piperazines from 1,4-diaza-bicyclo[2.2.2]octane, alkyl halides, and aryl halides in the presence of copper(I) iodide and potassium tert-butoxide in DMSO is described.     

A perspective on the localizability of Hartree–Fock orbitals

A common perception about molecular systems with a nonlocal electronic structure (as manifested by a nonlocal Hartree–Fock (HF) density matrix), such as conjugated π-systems, is that they can only be described in terms of nonlocal molecular orbitals. This view is mostly founded on chemical intuition, and further, this view is strengthened by traditional approaches for obtaining local occupied and virtual orbital spaces, such as the occupied Pipek–Mezey orbitals, and projected atomic orbitals. In this article, we discuss the limitations for localizability of HF orbitals in terms of restrictions posed by the delocalized character of the underlying density matrix for the molecular system and by the orthogonality constraint on the molecular orbitals. We show that the locality of the orbitals, in terms of nonvanishing charge distributions of orbitals centered far apart, is much more strongly affected by the orthogonality constraint than by the physical requirement that the occupied orbitals must represent the electron density. Thus, the freedom of carrying out unitary transformations among the orbitals provides the flexibility to obtain highly local occupied and virtual molecular orbitals, even for molecular systems with a nonlocal density matrix, provided that a proper localization function is used. As an additional consideration, we clear up the common misconception that projected atomic orbitals in general are more local than localized orthogonal virtual orbitals.     

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.     

Efficient synthesis of N-Me, N-Boc-protected α-hydrazinoacids: access to 1:1:1 [N-Me α-hydrazino/α/N-Me α-hydrazino]trimers

The preparation of optically pure N^α-Me, N^β-Boc-protected α-hydrazinoacids in large scale is described via a S_N2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N^α-Me α-hydrazino/α/N^α-Me α-hydrazino]trimers.     

Selective C-N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS)

Demethylation of N-methyl group in N-methyl-N-arylmethyl-α-amino esters was accomplished by the oxidation of the amino group using the N-iodosuccinimide (NIS)/acetonitrile system followed by treatment with O-methylhydroxylamine hydrochloride. This combination of reagents could provide a complementary method to catalytic hydrogenolysis, which certainly cleaves N-arylmethyl groups, in organic synthesis.     

Hybrid stochastic simulations of intracellular reaction–diffusion systems

With the observation that stochasticity is important in biological systems, chemical kinetics have begun to receive wider interest. While the use of Monte Carlo discrete event simulations most accurately capture the variability of molecular species, they become computationally costly for complex reaction–diffusion systems with large populations of molecules. On the other hand, continuous time models are computationally efficient but they fail to capture any variability in the molecular species. In this study a hybrid stochastic approach is introduced for simulating reaction–diffusion systems. We developed an adaptive partitioning strategy in which processes with high frequency are simulated with deterministic rate-based equations, and those with low frequency using the exact stochastic algorithm of Gillespie. Therefore the stochastic behavior of cellular pathways is preserved while being able to apply it to large populations of molecules. We describe our method and demonstrate its accuracy and efficiency compared with the Gillespie algorithm for two different systems. First, a model of intracellular viral kinetics with two steady states and second, a compartmental model of the postsynaptic spine head for studying the dynamics of Ca+2 and NMDA receptors.     

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.     

Palladium-catalyzed C–H alkenylation of quinoxaline N-oxide enabled by a mono-N-protected amino acid

The efficient alkenylation of quinoxaline N-oxide was achieved via Pd-catalyzed C–H activation, using the assistance of a mono-N-protected amino acid. Further deoxygenation of the 2-styrylquinoxaline-N-oxides yielded the corresponding styrylquinoxaline derivatives.     

Diastereoselective electrophilic α-amination of camphor N-acyl N-phenylpyrazolidinones: the metal enolate-dependent synthesis of two possible hydrazide diastereomers

Complementary approaches under enolate amination reactions for the synthesis of both α-hydrazidoacyl diastereomers have been achieved. Both isomers are obtained with high to excellent chemical yields and high stereoselectivities (up to >95:5 dr) when aryl-substituted camphor N¹-acyl N²-phenylpyrazolidinone was treated with potassium hexamethyldisilylamide (KHMDS) and lithium hexamethyldisilylamide (LHMDS), respectively, followed by the addition of di-tert-butyl azodicarboxylate. The nondestructive removal of the chiral auxiliary, which can be carried out under mild condition, afforded the hydrazido alcohol with high enantiomeric ratio. The facial stereoselectivity and stereochemical course of the reactions are discussed.     

Synthesis of N-Sulfonylformamidines by tert-butyl Hydroperoxide–Promoted,metal-free,direct oxidative dehydrogenation of aliphatic amines

A direct and convenient metal-free method to prepare sulfonyl amidines in the presence of aqueous tert-butyl hydroperoxide (T-HYDRO) has been developed. Different tertiary and secondary amines were tested for compatibility with the oxidative conditions and could be coupled with sulfonyl azides to form the corresponding amidines in moderate to good yields.     

Design and synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as glycosidase inhibitors

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N–acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six-membered carbasugars showed moderate glycosidase inhibitory activity and one of the compounds was found selective towards β-galactosidase inhibitory activity.     

N-Heterocyclic carbene–gold(I)-catalyzed carboheterofunctionalization of alkenes with arylboronic acids

A new approach to the synthesis of pyrrolidine, tetrahydrofuran, and imidazolidin-2-one via N-heterocyclic carbene–gold(I)-catalyzed intramolecular amino- or oxyarylation reactions from a wide variety of alkene substrates such as N-allyl amides, alcohols, carboxylic acids, and ureas in the presence of Selectfluor under mild conditions has been developed.     

Photocatalytic aerobic cross-coupling reaction of N-substituted anilines with N-aryl glycine esters: Synthesis of α-aryl α-amino esters

A novel photocatalytic cross dehydrogenative coupling reaction of N-aryl glycine esters with N-substituted anilines has been developed. The reaction proceeds effectively using methylene blue as a photocatalyst under visible light irradiation without any metal, chemical oxidant or additive. A variety of α-aryl α-amino derivatives were prepared in moderate to excellent yields with a high para-regioselectivity.     

Convenient synthesis of N-substituted β-lactam-4-carboxylates

When simple β-amino esters were treated with cyanate ion, dihydrouracils were formed. However, the presence of the α-carboxylate group in aspartic ester substrates hinders the formation of the pyrimidine ring. Instead, treatment of aspartic esters with carbonate bases yields N-substituted β-lactam-4-carboxylates in excellent yields, representing a green, convenient, and efficient synthesis of these biologically interesting molecules.     

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.