Structure of N-alkyl chitosan membranes on water-permselectivity for aqueous ethanol solutions

N-Alkyl chitosans with different numbers of carbons and degrees of substitution of the N-alkyl group were prepared. The water-permselectivity for aqueous ethanol solutions through the N-alkyl chitosan membranes in evapomeation were studied. The permeation rate and separation factor for water-permselectivity were significantly influenced by the number of carbons in the N-alkyl group, in particular, one N-alkyl chitosan membrane showed a maximum in the permeation rate and separation factor. The degree of substitution in the N-alkyl group little affected the permeation rate, but significantly changed the separation factor. The characteristics of permeation and separation for an aqueous ethanol solution through the N-alkyl chitosan membranes with different N-alkyl groups and different degrees of substitution of the N-alkyl group are discussed from the viewpoints of physical and chemical structures of their membranes, such as, density, crystallinity, surface free energy and degree of swelling of the membrane.     

Synthesis and Structure of Environmentally Relevant Perfluorinated Sulfonamides

Alkylated perfluorooctanesulfonamides are compounds of environmental concern. To make these compounds available for environmental and toxicological studies, a series of N-alkylated perfluorooctanesulfonamides and structurally related compounds were synthesized by reaction of the corresponding perfluoroalkanesulfonyl fluoride with a suitable primary or secondary amine. Perfluoroalkanesulfonamidoethanols were obtained from the N-alkyl perfluoroalkanesulfonamides either by direct alkylation with bromoethanol or alkylation with acetic acid 2-bromo-ethyl ester followed by hydrolysis of the acetate. N-Alkyl perfluorooctanesulfonamidoacetates were synthesized in an analogous way by alkylation of N-alkyl perfluoroalkanesulfonamides with a bromo acetic acid ester, followed by basic ester hydrolysis. Alternatively, N-alkyl perfluoroalkanesulfonamides can be alkylated with an appropriate alcohol using the Mitsunobu reaction. Perfluorooctanesulfonamide was synthesized from the perfluorooctanesulfonyl fluoride via the azide by reduction with Zn/HCl. All perfluorooctanesulfonamides contained linear as well as branched C₈F₁₇ isomers, typically in a 10:1 to 30:1 ratio. The crystal structures of N-ethyl and N,N-diethyl perfluorooctanesulfonamide show that the S-N bond has considerable double bond character. This double bond character results in a significant rotational barrier around the S-N bond (ΔG^≠ = 62-71 kJ mol⁻¹) and a preferred solid state and solution conformation in which the N-alkyl groups are oriented opposite to the perfluorooctyl group to minimize steric crowding around the S-N bond.     

Synthesis of 4-N-alkyl and ribose-modified AICAR analogues on solid support

Herein, we report the solid-phase synthesis of several 5-aminoimidazole-4-(N-alkyl)carboxamide-1-ribosides (4-N-alkyl AICARs) and the corresponding 2′,3′-secoriboside derivatives. The method uses the N-1-dinitrophenyl-inosine 5′-bonded to a solid support. This inosine derivative has the C-2 of the purine base strongly activated towards the attack of N-nucleophiles thus allowing the preparation of several N-1 alkylated inosine supports from which a small library of 4-N-alkyl AICAR derivatives has been synthesized. A set of new 4-N-alkyl AICA-2′,3′-secoriboside derivatives have also been obtained in high yields by solid-phase cleavage of the 2′,3′-ribose bond.     

Coupling and cycloaddition of ynamides: homo- and Negishi coupling of tosylynamides and intramolecular [4+2] cycloaddition of N-(o-ethynyl)phenyl ynamides and arylynamides

N,N′-aryl- and N,N′-alkyl-buta-1,3-diyne-1,4-ditosylamides have been synthesized for the first time, in good to excellent yields, by copper-catalyzed dimerization of the corresponding N-aryl or N-alkyl tosylynamides. Negishi coupling of N-ethynylzinc tosylamides derivatives with (hetero)aryl iodides in the presence of Pd₂dba₃ and triphenylphosphine affords N-aryl and N-alkyl arylynamides in yields of up to 90%. Intramolecular [4+2] cycloaddition reactions of N-ethynylphenyl ynamides and arylynamides allow the synthesis of carbazoles and benzannulated and heteroannulated carbazoles in moderate-to-good yields.     

Chemistry of diazocarbonyl compounds: XXVIII. Reaction of acyclic N-arylsulfonylacetamides with Rh(II)-carbenoids as a new synthetic route to alkyl acetimidoates

A new procedure was proposed for the synthesis of alkyl acetimidoates via alkylation of the carbonyl group in N-arylsulfonylacetamides with Rh(II)-carbenoids. The procedure ensures preparation in good yield of acetimidoates having a polyfunctionalized O-alkyl group. The obtained alkyl acetimidoates in crystal exist as E isomers with respect to the C=N bond and as s-cis conformers relative to the C-OCHRR’ bond. Alkyl N-arylsulfonylacetimidoates react with ammonia and hydrazine hydrate to give in good yield the corresponding carboximidamides(hydrazides) via replacement of the O-alkyl group. Unlike structurally related compounds having simple alkyl or aryl groups on the nitrogen atom, N-arylsulfonylacetimidoates readily undergo hydrolysis in the presence of moisture and traces of acids.     

Multi-step reactions of N-monosubstituted (polyfluoroalkane)thioamides with alkyllithium reagents

Reactions of N-alkyl- or N-aryl(perfluoroalkyl)thiocarboxamides with alkyl lithium reagents are described. Trifluorothioacetamides are converted into the corresponding lithium salts. Compounds bearing a long polyfluorinated chain terminated by a CHF₂ group and compounds containing an N-alkyl substituent with a proton adjacent to nitrogen react further via a multi-step reaction sequence involving HF elimination and then vinylic fluorine substitution and/or S_N′ type fluorine substitution. These transformations led to unsaturated N-monosubstituted polyfluorinated thioamides.     

Peptoids bearing tertiary amino residues in the n-alkyl side chains: synthesis of a potent inhibitor of Semaphorin 3A

A study on the preparation of N-alkylglycines (peptoids) that contain tertiary amino residues on the N-alkyl side chains is reported. The appropriate combination of the submonomer strategy with N-alkylglycine monomer couplings depending upon the structure of the N-alkyl side chain that must be incorporated into the peptoid is determinant for the efficiency of the synthetic pathway. The application of this strategy to the preparation of SICHI, an N-alkyglycine trimer containing tertiary amino residues in the three N-alkyl branches, and that has been identified as a potent Semaphorin 3A inhibitor, is presented.     

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

Complex N-alkyl (heteroaryl)onium salts are accessed via heterocyclic group transfer reactions of N-ligated I(iii) reagents with alkenoic acids. The reactions proceed in excellent yields, under mild conditions, and with broad substrate scope.     

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru(diamine) complexes as catalysts: the counteranion and solvent effects,and substrate scope

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines catalyzed by chiral cationic η⁶-arene-(N-monosulfonylated diamine) Ru(II) complexes has been investigated. Strong counteranion and solvent effects on the enantioselectivity were observed. The ruthenium catalyst bearing non-coordinating BArF^? anion was found to be particularly effective for the hydrogenation of acyclic and exocyclic N-alkyl ketimines in the presence of (Boc)₂O in dichloromethane or even under solvent-free conditions, providing chiral amines with up to >99% ee and full conversions. Alternatively, the ruthenium catalyst bearing achiral phosphate anion together with corresponding phosphoric acid as the additive was also efficient for the hydrogenation of N-alkyl ketimines in the absence of (Boc)₂O with excellent enantioselectivities and full conversions. For N-aryl ketimines lower enantiomeric excesses were observed by using the ruthenium catalyst bearing BArF^? anion. This catalytic protocol thus provides a facile and practical access to optically active amines and has been successfully employed in the gram-scale synthesis of enantiomerically pure (+)-sertraline.     

N,N′,N″-Tri-Boc-guanidine (TBG): a common starting material for both N-alkyl guanidines and amidinoureas

In this Letter, we describe the unexpected reaction pattern of N,N′N″-tri-Boc-guanidine (TBG) with amines at room temperature and under reflux conditions affording N-substituted guanidines and amidinoureas, potentially important compounds with extensive applications in medicinal chemistry. This investigation shows that TBG is an excellent, readily available common starting material for the synthesis of various N-alkyl guanidines as well as N-alkyl-N′-substituted amidinoureas by simply manipulating the reaction conditions.     

Development of aqueous oxidative Ugi-type reactions by copper-catalyzed surfactant-promoted C(sp)–H direct functionalization in water

Direct assembly of α-amino amides from N-alkyl amines and isocyanides through oxidative Ugi-type reactions in aqueous conditions, has been achieved in a Cu(I)–TBHP–surfactant catalysis system. Various N-alkyl amines and isocyanides could be tolerated in this reaction and furnish α-amino amides in moderate yields.     

A concise synthesis of asymmetrical N,N′-disubstituted guanidines

We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and triethylamine.     

Structural study of oxalamide compounds: H, C, and DFT calculations

The conformational properties of some N-alkyl, N,N′-dialky, and tetraalkyloxalamides have been investigated, in vacuo and in solvent using DFT methods at the B3LYP/6-31G^∗∗ computational level. Special emphasis has been given on oxalamides with substituents of the type -CH₂CH₂OH. In oxalamides with the N-H group (N-alkyl and N,N′-dialky), the most stable conformations are those in which the oxalamide moiety adopts a planar s-trans arrangement and the amide bonds are trans. A different situation appears in the case of tetraalkyloxalamides, in which the oxalamide moiety always adopts a skewed arrangement and there are conformations with similar energy. A careful study of ¹³C and ¹H NMR spectra together with theoretical calculations (GIAO method) allowed the assignment of the signals of these conformers. The presence of the -CH₂CH₂OH chain produces numerous rotamers. The most stable rotamers, in vacuo, are those with strong intramolecular hydrogen bonds, however in solvent, hydrogen bonds are not crucial to establish the most stable specie and depend on the solvent used.     

Bergman cycloaromatization of imidazole-fused enediynes: the remarkable effect of N-aryl substitution

A series of N-aryl substituted `imidazole-fused' (Z) 3-ene-1,5-diynes was prepared and kinetic parameters for their Bergman cycloaromatization reactivities were determined. N-Arylation enhanced rates relative to N-alkyl derivatives by up to sevenfold (ANOVA p<0.0001). The greatest enhancement was exhibited by the N-phenyl derivative (sevenfold at 145 °C).     

Efficient one-pot synthesis of 2-azetidinones from acetic acid derivatives and imines using methoxymethylene-N,N-dimethyliminium salt

A cheap, versatile and convenient method for synthesis of β-lactams using methoxymethylene-N,N-dimethyliminium salt as an acid activator in Staudinger reaction is reported. This method is used for the preparation of monocyclic, spirocyclic, N-alkyl and three-electron-withdrawing group β-lactams. The products are obtained in good to excellent yields.     

Structural studies of {Li} 2-lithiopyrrolidines using NMR spectroscopy

A selection of N-substituted 2-lithiopyrrolidines were prepared and their structures were investigated by ⁶Li and ¹³C NMR spectroscopy. Evidence is presented for aggregation and dynamic solvation effects, depending on the nature of the N-substituent and substituents on the pyrrolidine ring. Studies were performed with N-Boc (coordinating carbonyl group), N-methoxyethyl (coordinating methoxy group) and N-alkyl (no coordinating group) heterocycles to represent three different classes of organolithiums: dipole-stabilized, unstabilized and chelated, and unstabilized.     

Construction of dihydropyrimidine skeleton using 1,2,4-trisubstituted-1,3-diaza-1,3-butadienes

Construction of a dihydropyrimidine ring was developed that involved the cyclization of 1,3-diaza-1,3-butadienes having an N-protecting group (N-Cbz, N-Boc, N-alkyl, or N-benzyl) with α,β-unsaturated carbonyl compounds such as ethyl acrylate and p-chlorophenyl vinyl ketone. Consequently, 4-dimethylamino-2-phenyl-1,4,5,6-tetrahydropyrimidines were synthesized in good yields. Subsequently, the β-elimination of the dimethylamino group was carried out with MeI or SiO₂ to afford various N-protecting-2,5-disubstituted-1,6-dihydropyrimidines in good yields. Remarkably, the use of 4-chlorophenyl vinyl ketone directly provided the dihydropyrimidine without the tetrahydropyrimidine intermediate in excellent yield.     

Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis

N-Butyl-deoxynojirimycin (NB-DNJ) has been approved for clinical trials as a potential therapy for Gaucher disease, a glycolipid lysosomal storage disorder. As this compound has both glycoprotein processing α-glucosidase and ceramide glucosyltransferase inhibitory activity, we have sought to determine the molecular basis for these two activities. NB-DNJ is known to resemble the positively charged oxocarbonium-like transition state for α-glucosidase I and the structure–function relationships we present now help to define the recognition epitope for the enzyme. Inhibition of ceramide glucosyltransferase by NB-DNJ was competitive for ceramide (K_i=7.4 μM) and non-competitive for UDP-glucose, indicating inhibitory activity is by ceramide mimicry. The presence of an N-alkyl chain was obligatory for transferase inhibition and increases in alkyl chain length provided a modest increase in inhibitory potency.By contrast, α-glucosidase inhibition was independent of the N-alkyl chain and changes in chain length. The effects of ring substitutions identified the C₃ hydroxyl group as being critical for both enzymes but C₁ and C₆ modifications led to a loss of transferase inhibition only. Attempts to rationalise these data for transferase inhibition using an energy minimised molecular model of NB-DNJ and ceramide predicted structural homology of three stereogenic centres and the N-alkyl chain of NB-DNJ, with the trans-alkenyl and N-acyl chain of ceramide. On the basis of these studies, modifications to imino sugar inhibitors can be suggested that allow a more selective approach for molecular inhibition of both ceramide glucosyltransferase and α-glucosidase I, leading to improved compounds for the potential treatment of lysosomal glycosphingolipid storage disorders and viral infections, respectively.     

trans-4-Hydroxy-l-proline: a novel starting material for N-alkylpyrroles synthesis

The reaction of aldehydes with trans-4-hydroxy-l-proline was studied for the first time, resulting in the formation of N-alkylpyrroles in good to excellent yields, via decarboxylation followed by redox isomerization under neutral conditions. The neutral conditions allow access to efficient synthesis of N-alkyl pyrroles with high functional group tolerance.     

Factors affecting the efficiency and stereoselectivity of α-amino acid synthesis by the Petasis reaction

The use of chiral secondary amines containing only one branched substituent has been shown to give optimal yields and stereoselectivities in the preparation of α-amino acids using the Petasis reaction. While the use of chiral primary amines generally gives products in low to moderate diastereoselectivity, chiral secondary amines generally give products in >95:5 diastereoselectivity. Additionally, the use of amines with two chiral (and by definition, branched) N-alkyl substituents results in significantly reduced yields with respect to to secondary amines with one or no branched N-alkyl substituents.