Orthoamides and Iminium Salts LXXII: N,N,N′,N′,N′′,N′′,N′′′,N′′′‐Octamethyl‐(but‐2‐yne)‐bis(amidinium) Tetrafluoroborate: The First Bis‐amidinium Salt of Acetylenedicarboxyclic Acid. A New Superelectrophile?

A method for the preparation of the first acetylenedicarboxamidinium salt from a bis‐orthoamide derivative of acetylenedicarboxyclic acid has been established. The salt reacted with cyclopentadiene and furan at room temperature to give bicyclic [4+2]‐cycloaddition products. The solid compounds were characterized by solution NMR spectroscopy and by single‐crystal X‐ray diffraction. Quantum‐chemical calculations of the isolated N,N,N′,N′,N′′,N′′,N′′′,N′′′‐octamethyl‐acetylene‐bis(carboxamidinium) ion showed very good agreement with the spectroscopic and diffraction data.     

N‐arylamides and N‐arylcarbamates N?CO internal rotation barrier study by molecular modeling

Amides and carbamates present an energetic barrier associated to N? C(O) bond rotation, which determines two different equilibrium geometries. In this work, the conformational equilibrium of formanilide, acetanilide, methyl and t‐butyl phenylcarbamates, and their N‐methylderivatives was studied by AM1 and B3LYP/6‐31G(d,p) calculations. The effect of aryl p‐substituents (MeO, Me, Cl, Br, CN, and NO₂) was also studied. Amide barriers were found by DFT calculation between 12 and 21 kcal/mol. Carbamates, on the other hand, showed barriers between 11 and 15 kcal/mol. AM1 underestimates the energetic barriers and provides values around half those obtained by B3LYP/6‐31G(d,p) calculations. Electron withdrawing substituents on aryl group decrease the barrier. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Practical Metal‐Free C(sp3)?H Functionalization: Construction of Structurally Diverse α‐Substituted N‐Benzyl and N‐Allyl Carbamates

Described is a practical and universal C H functionalization of readily removable N‐benzyl and N‐allyl carbamates, with a wide range of nucleophiles at ambient temperature promoted by Ph₃CClO₄. The metal‐free reaction has an excellent functional‐group tolerance, and displays a broad scope with respect to both N‐carbamates and nucleophile partners (a variety of organoboranes and C H compounds). The synthetic utility in target‐ as well as diversity‐oriented syntheses is demonstrated.     

Side‐Product of N‐Acryloyloxysuccinimide Synthesis or Useful New Bifunctional Monomer?

During the synthesis of the N‐acryloxysuccinimide (NAS) monomer, we observed the formation of a by‐product, resulting from the condensation of two NAS molecules via a Michael addition. Due to its bulky structure, this new bifunctional monomer shows a very poor ability to homopolymerize. On the contrary, it readily copolymerizes with N‐acryloylmorpholine (NAM), an hydrophilic acrylamide derivative, leading to functional polymer chains exhibiting a wide range of solubility and a high potential for biomolecule covalent binding.     

Rhodium(III)‐Catalyzed ortho Alkenylation of N‐Phenoxyacetamides with N‐Tosylhydrazones or Diazoesters through C?H Activation

A coupling reaction of N‐phenoxyacetamides with N‐tosylhydrazones or diazoesters through Rh^III‐catalyzed C H activation is reported. In this reaction, ortho‐alkenyl phenols were obtained in good yields and with excellent regio‐ and stereoselectivity. Rh–carbene migratory insertion is proposed as the key step in the reaction mechanism.     

Direct ortho‐Arylation of N‐Phenacylpyridinium Bromide by Palladium‐Catalyzed C?H‐Bond Activation

A novel palladium catalyzed direct ortho‐arylation of N‐phenacylpyridinium bromide was developed. The amazing N‐phenacyl group regioselectively activates the C? H bond of pyridine and automatically departs from the arylated products. A kinetic isotope effect study proved that the reaction went through a C? H‐bond activation pathway and 2,6‐diphenylpyridine was produced stepwise from 2‐phenylpyridine.     

Palladium‐Catalyzed C?H Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³) H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

N?O Bond as a Glycosidic‐Bond Surrogate: Synthetic Studies Toward Polyhydroxylated N‐Alkoxypiperidines

A series of novel polyhydroxylated N‐alkoxypiperidines has been synthesized by ring‐closing double reductive amination (DRA) of highly functionalized 1,5‐dialdehydes with various hydroxylamines. The required saccharide‐based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two‐step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3‐deoxyisofagomine, and numerous other N‐alkoxy analogues. The barrier to inversion in these polyhydroxylated N‐alkoxypiperidine derivatives was found by variable‐temperature NMR methods to be approximately 15 kcal mol^?1. With the exception of N‐hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond β‐glucosidase.     

Rare‐Earth‐Metal Alkylaluminates Supported by N‐Donor‐Functionalized Cyclopentadienyl Ligands: C?H Bond Activation and Performance in Isoprene Polymerization

Homoleptic tetramethylaluminate complexes [Ln(AlMe₄)₃] (Ln=La, Nd, Y) reacted with HCp^NMe2 (Cp^NMe2=1‐[2‐(N,N‐dimethylamino)‐ethyl]‐2,3,4,5‐tetramethyl‐cyclopentadienyl) in pentane at ?35 °C to yield half‐sandwich rare‐earth‐metal complexes, [{C₅Me₄CH₂CH₂NMe₂(AlMe₃)}Ln(AlMe₄)₂]. Removal of the N‐donor‐coordinated trimethylaluminum group through donor displacement by using an equimolar amount of Et₂O at ambient temperature only generated the methylene‐bridged complexes [{C₅Me₄CH₂CH₂NMe(μ‐CH₂)AlMe₃}Ln(AlMe₄)] with the larger rare‐earth‐metal ions lanthanum and neodymium. X‐ray diffraction analysis revealed the formation of isostructural complexes and the C? H bond activation of one aminomethyl group. The formation of Ln(μ‐CH₂)Al moieties was further corroborated by ¹³C and ¹H‐¹³C HSQC NMR spectroscopy. In the case of the largest metal center, lanthanum, this C? H bond activation could be suppressed at ?35 °C, thereby leading to the isolation of [(Cp^NMe2)La(AlMe₄)₂], which contains an intramolecularly coordinated amino group. The protonolysis reaction of [Ln(AlMe₄)₃] (Ln=La, Nd) with the anilinyl‐substituted cyclopentadiene HCp^AMe2 (Cp^AMe2=1‐[1‐(N,N‐dimethylanilinyl)]‐2,3,4,5‐tetramethylcyclopentadienyl) at ?35 °C generated the half‐sandwich complexes [(Cp^AMe2)Ln(AlMe₄)₂]. Heating these complexes at 75 °C resulted in the C? H bond activation of one of the anilinium methyl groups and the formation of [{C₅Me₄C₆H₄NMe(μ‐CH₂)AlMe₃}Ln(AlMe₄)] through the elimination of methane. In contrast, the smaller yttrium metal center already gave the aminomethyl‐activated complex at ?35 °C, which is isostructural to those of lanthanum and neodymium. The performance of complexes [{C₅Me₄CH₂CH₂NMe(μ‐CH₂)AlMe₃}‐ Ln(AlMe₄)], [(Cp^AMe2)Ln(AlMe₄)₂], and [{C₅Me₄C₆H₄NMe(μ‐CH₂)AlMe₃}Ln(AlMe₄)] in the polymerization of isoprene was investigated upon activation with [Ph₃C][B(C₆F₅)₄], [PhNMe₂H][B(C₆F₅)₄], and B(C₆F₅)₃. The highest stereoselectivities were observed with the lanthanum‐based pre‐catalysts, thereby producing polyisoprene with trans‐1,4 contents of up to 95.6 %. Narrow molecular‐weight distributions (M_w/M_n<1.1) and complete consumption of the monomer suggested a living‐polymerization mechanism.     

A Functional Role for Aβ in Metal Homeostasis? N‐Truncation and High‐Affinity Copper Binding

Accumulation of the β‐amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer′s disease (AD). The Aβ1–x (x=16/28/40/42) peptides have been the primary focus of Cu^II binding studies for more than 15 years; however, the N‐truncated Aβ4–42 peptide is a major Aβ isoform detected in both healthy and diseased brains, and it contains a novel N‐terminal FRH sequence. Proteins with His at the third position are known to bind Cu^II avidly, with conditional log K values at pH 7.4 in the range of 11.0–14.6, which is much higher than that determined for Aβ1–x peptides. By using Aβ4–16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu^II with a conditional K_d value of 3×10^?14 M at pH 7.4, and that both Aβ4–16 and Aβ4–42 possess negligible redox activity. Combined with the predominance of Aβ4–42 in the brain, our results suggest a physiological role for this isoform in metal homeostasis within the central nervous system.