Cascade Oxidative Trifluoromethylthiolation and Cyclization of 3-Alkyl-1-(2-(alkynyl)phenyl)indoles.

Persulfate-promoted radical cascade trifluoromethylthiolation and cyclization of 3-alkyl-1-(2-(alkynyl)phenyl)indoles with AgSCF3 were investigated. This protocol provides a novel route to CF3S-substituted indolo[1,2-a]quinoline-7-carbaldehydes and CF3S-substituted indolo[1,2-a]quinoline-7-methanone derivatives via the formation of the C-SCF3 bond and C-C bond and benzylic carbon oxidation in a single step. This reaction can accommodate a broad range of functional groups. The single-crystal X-ray diffraction data confirm the chemical structure of the product. A scale-up experiment and radical inhibition experiments were operated in the reaction system. Photophysical properties of some selected 5-((trifluoromethyl)thio)indolo[1,2-a]quinoline-7-carbaldehydes were studied by UV-visible and fluorescence spectroscopy.

Electrochemical trifluoromethylation of 2-isocyanobiaryls using CF3SO2Na: synthesis of 6-(trifluoromethyl)phenanthridines.

An efficient trifluoromethylation of 2-isocyanobiaryls was developed through the constant current electrolysis, employing sodium trifluoromethanesulfinate (CF3SO2Na) as the trifluoromethyl source. The method enabled the syntheses of a series of 6-(trifluoromethyl)phenanthridine derivatives in moderate to high yields under metal- and oxidant-free conditions. A gram-scale synthesis highlights the synthetic versatility of the reported protocol.

Base-catalyzed diastereodivergent thia-Michael addition to chiral ß-trifluoromethyl-α,ß-unsaturated N-acylated oxazolidin-2-ones.

Base-catalyzed diastereodivergent thia-Michael addition of thiols to chiral ß-trifluoromethyl-α,ß-unsaturated N-acylated oxazolidin-2-ones is reported. By tuning the base-catalyst (i-Pr2NEt, DABCO, or P2-t-Bu), a range of chiral thia-Michael adducts was synthesized in good yields with high diastereoselectivities. A plausible mechanism was proposed on the basis of the experimental results. This work is complementary to the existing methods offering advantages, e.g., switchable diastereoselectivity using a readily synthesized chiral starting material, a cheap and readily available base catalyst, and a simple and practical operation, enabling synthetic application in organic synthesis.

Diastereoselective Addition of PhSCF2SiMe3 to Chiral N-tert-Butanesulfinyl Ketimines Derived from Isatins: Synthesis of Enantioenriched gem-Difluoromethylenated Spiro-pyrrolidinyl and Spiro-piperidinyl Oxindoles.

A convenient and efficient synthetic strategy to prepare enantioenriched gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles is described. Fluoride-mediated diastereoselective nucleophilic addition of PhSCF2SiMe3 to chiral N-tert-butanesulfinyl ketimines derived from isatins was a key step and provided diastereomeric adducts, which were readily separable. Removal of the chiral sulfinyl group followed by structural manipulation afforded chiral gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles.

Alkanethiol-Mediated Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Bis-Thiolated Indole Derivatives.

Reactions of o-alkynylisocyanobenzenes with a variety of alkanethiols (Alk-SH) provide the corresponding bis-thiolated indole derivatives. The advantages of the reaction include metal-free, room-temperature, mild reaction conditions and broad functional group compatibility. The reaction proceeds via nucleophilic addition of an alkanethiol to an isonitrile moiety, 5-exo cyclization, followed by nucleophilic addition of an alkanethiol to a 3-alkylidene indole intermediate. Density functional calculations on the electronic structures and relative free energies of 5-exo and 6-endo cyclization pathways support that the 5-exo cyclization is preferable.

Self-interrupted synthesis of sterically hindered aliphatic polyamide dendrimers.

2,2-Bis(azidomethyl)propionic acid was prepared in four steps and 85% yield from the commercially available 2,2-bis(hydroxymethyl)propionic acid and used as the starting building block for the divergent, convergent, and double-stage convergent-divergent iterative methods for the synthesis of dendrimers and dendrons containing ethylenediamine (EDA), piperazine (PPZ), and methyl 2,2-bis(aminomethyl)propionate (COOMe) cores. These cores have the same multiplicity but different conformations. A diversity of synthetic methods were used for the synthesis of dendrimers and dendrons. Regardless of the method used, a self-interruption of the synthesis was observed at generation 4 for the dendrimer with an EDA core and at generation 5 for the one with a PPZ core, whereas for the COOMe core, self-interruption was observed at generation 6 dendron, which is equivalent to generation 5 dendrimer. Molecular modeling and molecular-dynamics simulations demonstrated that the observed self-interruption is determined by the backfolding of the azide groups at the periphery of the dendrimer. The latter conformation inhibits completely the heterogeneous hydrogenation of the azide groups catalyzed by 10% Pd/carbon as well as homogeneous hydrogenation by the Staudinger method. These self-terminated polyamide dendrimers are enzymatically and hydrolytically stable and also exhibit antimicrobial activity. Thus, these nanoscale constructs open avenues for biomedical applications.

Self-Sorting Supramolecular Polymerization: Helical and Lamellar Aggregates of Tetra-Bay-Acyloxy Perylene Bisimide.

A new perylene bisimide (PBI), with a fluorescence quantum yield up to unity, self-assembles into two polymorphic supramolecular polymers. This PBI bears four solubilizing acyloxy substituents at the bay positions and is unsubstituted at the imide position, thereby allowing hydrogen-bond-directed self-assembly in nonpolar solvents. The formation of the polymorphs is controlled by the cooling rate of hot monomer solutions. They show distinctive absorption profiles and morphologies and can be isolated in different polymorphic liquid-crystalline states. The interchromophoric arrangement causing the spectral features was elucidated, revealing the formation of columnar and lamellar phases, which are formed by either homo- or heterochiral self-assembly, respectively, of the atropoenantiomeric PBIs. Kinetic studies reveal a narcissistic self-sorting process upon fast cooling, and that the transformation into the heterochiral (racemic) sheetlike self-assemblies proceeds by dissociation via the monomeric state.

Supramolecular Spheres Self-Assembled from Conical Dendrons Are Chiral.

Frank-Kasper phases and liquid quasicrystals self-organize from supramolecular spheres of dendrimers, block copolymers, surfactants and other self-assembling molecules. These spheres are expected to be achiral due to their isotropic shape. Nevertheless, supramolecular spheres from short helical stacks of crown-like dendrimers self-organize a Pm3̅ n cubic (Frank-Kasper A15) phase which exhibits chirality on the macroscopic scale. However, the chirality of classic isotropic supramolecular micellar-like spheres, generated from conical dendrons, is unknown. Here we report a library of second and third generation biphenylpropyl dendrons with chiral groups at their apex that produces single-handed chiral supramolecular spheres. Up to 480 conical dendrons self-assemble to form micellar-like spheres, with a molar mass of up to 1.1 × 106 g/mol, that self-organize into a Pm3̅ n phase with chirality detectable on the macroscopic scale. This demonstration of chirality in micellar-like spheres of a Frank-Kasper phase raises the fundamental question whether micellar-like spheres forming 3D phases generated from other soft matter such as block copolymers, surfactants, and other molecules are chiral.

Sequence-Defined Dendrons Dictate Supramolecular Cogwheel Assembly of Dendronized Perylene Bisimides.

A dendronized perylene bisimide (PBI) that self-organizes into hexagonal arrays of supramolecular double helices with identical single-crystal-like order that disregards chirality was recently reported. A cogwheel model of self-assembly that explains this process was proposed. Accessing the highly ordered cogwheel phase required very slow heating and cooling or extended periods of annealing. Analogous PBIs with linear alkyl chains did not exhibit the cogwheel assembly. Here a library of sequence-defined dendrons containing all possible compositions of linear and racemic alkyl chains was employed to construct self-assembling PBIs. Thermal and structural analysis of their assemblies by differential scanning calorimetry (DSC) and fiber X-ray diffraction (XRD) revealed that the incorporation of n-alkyl chains accelerates the formation of the high order cogwheel phase, rendering the previously invisible phase accessible under standard heating and cooling rates. Small changes to the primary structure, as constitutional isomerism, result in significant changes to macroscopic properties such as melting of the periodic array. This study demonstrated how changes to the sequence-defined primary structure, including the relocation of methyl groups between two constitutional isomers, dictate tertiary and quaternary structure in hierarchical assemblies. This led to the discovery of a sequence that self-organizes the cogwheel assembly much faster than even the corresponding homochiral compounds and demonstrated that defined-sequence, which has long been recognized as a determinant for the complex structure of biomacromolecules including proteins and nucleic acids, plays the same role also in supramolecular synthetic systems.

Synthesis of Indolo- and Benzothieno[2,3-b]quinolines by a Cascade Cyclization of o-Alkynylisocyanobenzene Derivatives.

A new synthetic approach for the synthesis of indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines has been developed by employing the freshly prepared o-alkynylisocyanobenzenes derived from o-alkynylformamide derivatives as substrates. The synthetic transformations involved chloride-ion-triggered 6-endo cyclization of o-alkynylisocyanobenzenes to generate 2-chloroquinolines in situ, which further cyclized intramolecularly with nitrogen or sulfur atom via a cascade process to provide the corresponding indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines, respectively, in moderate to excellent yields.

Sulfinates and thiocyanates triggered 6-endo cyclization of o-alkynylisocyanobenzenes.

Diverse 2-sulfonyl- and 2-thiocyanato-3-substituted quinolines were synthesized from o-alkynylisocyanobenzenes by nucleophilic addition of the respective sulfinate sodium salts and ammonium thiocyanate to the isocyanide moiety followed by cyclization. The salient features of the methodology include metal-free, ambient temperature and mild reaction conditions, ease of reagent handling, and broad functional group tolerance.

Synthesis of 3-substituted quinolin-2(1H)-ones via the cyclization of o-alkynylisocyanobenzenes.

A facile synthesis of various functionalized 3-substituted quinolin-2(1H)-ones through Ag(i) nitrate-catalyzed cyclization of o-alkynylisocyanobenzenes is described. The reaction allows rapid and convenient access to 3-substituted quinolin-2(1H)-one scaffolds in moderate to good yields.

Synthesis of N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles by cascade annulation of 2-alkynyl-N,N-dialkylanilines.

An efficient and metal-free approach to N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles from 2-alkynyl-N,N-dialkylanilines has been developed. In the presence of iodine and tert-butylhydroperoxide (TBHP), a variety of 2-alkynyl-N,N-dialkylanilines underwent a cascade radical annulation to yield 3-arylsulfonylindoles. In contrast, 3-arylsulfanylindoles were conveniently prepared by iodine mediated electrophilic annulation reactions. The present protocol uses the economical and environmentally friendly I2-TBHP or I2 system, and potentially bioactive N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles with various functional groups were successfully synthesized in moderate to good yields.

A Columnar Liquid-Crystal Phase Formed by Hydrogen-Bonded Perylene Bisimide J-Aggregates.

A new perylene bisimide (PBI) dye self-assembles through hydrogen bonds and π-π interactions into J-aggregates that in turn self-organize into liquid-crystalline (LC) columnar hexagonal domains. The PBI cores are organized with the transition dipole moments parallel to the columnar axis, which is an unprecedented structural organization in π-conjugated columnar liquid crystals. Middle and wide-angle X-ray analyses reveal a helical structure consisting of three self-assembled hydrogen-bonded PBI strands that constitute a single column of the columnar hexagonal phase. This remarkable assembly mode for columnar liquid crystals may afford new anisotropic LC materials for applications in photonics.

Complex columnar hexagonal polymorphism in supramolecular assemblies of a semifluorinated electron-accepting naphthalene bisimide.

Simple synthetic methods for a strongly electron-accepting naphthalene bisimide (NBI) derivative functionalized with a new environmentally friendly chiral racemic semifluorinated alkyl group and with AB3 minidendrons containing the same semifluorinated group are reported. The semifluorinated dendron was attached to the imide groups of the NBI via one, two, and three (m = 1, 2, 3) methylenic units. The NBI-containing semifluorinated groups and the dendronized NBI with m = 1 and 2 self-organize into lamellar crystals. The dendronized NBI with m = 3 self-assembles into an unprecedentedly complex and ordered column that self-organizes in a columnar hexagonal periodic array. This array undergoes a continuous transition to a columnar hexagonal superlattice that does not display a first-order phase transition during analysis by differential scanning calorimetry at heating and cooling rates of 10 and 1 °C/min. These complex columnar hexagonal periodic arrays with intramolecular order could be elucidated only by a combination of powder and fiber X-ray diffraction studies and solid-state NMR experiments. The lamellar crystals self-organized from m = 1 and the two highly ordered columnar hexagonal periodic arrays of m = 3 are assembled via thermodynamically controlled processes. Since strongly electron-accepting derivatives are of great interest to replace fullerene acceptors in organic photovoltaics and for other supramolecular electronic materials, the multitechnique structural analysis methodology elaborated here must be taken into consideration in all related studies.

Increasing 3D Supramolecular Order by Decreasing Molecular Order. A Comparative Study of Helical Assemblies of Dendronized Nonchlorinated and Tetrachlorinated Perylene Bisimides.

A nonplanar, twisted, and flexible tetrachlorinated perylene bisimide (Cl4PBI) was functionalized with two AB3 minidendrons containing hydrogenated or semifluorinated dodecyl groups. The hydrogenated dendron was attached to the imide groups of Cl4PBI via m = 0, 1, and 2 methylenic units, whereas the dendron containing semifluorinated groups was attached via m = 3 or a di(ethylene oxide) linker (m = 2EO). The supramolecular structures of these compounds, determined by a combination of differential scanning calorimetry, X-ray diffraction, and solid-state NMR, were compared with those of nonchlorinated planar and rigid PBI reported previously, which demonstrated the thermodynamically controlled formation of 2D periodic arrays at high temperatures and 3D arrays at low temperatures. The molecularly less ordered Cl4PBI containing hydrogenated dendrons self-organize into exclusively 3D crystalline periodic arrays under thermodynamic control for m = 0 and 2, while the more highly molecularly ordered PBI produced less stable and ordered 3D crystals and also 2D assemblies. This induction of a higher degree of 3D order in supramolecular assemblies of the less well-ordered molecular building blocks was unanticipated. The semifluorinated dendronized Cl4PBI with m = 3 formed a 2D columnar hexagonal array under kinetic control, whereas the compound with m = 2EO formed an unusual 2D honeycomb-like hexagonal phase under thermodynamic control. These Cl4PBI compounds provide a new route to stable crystalline assemblies via thermodynamic control at lower temperatures than previously obtained with PBI, thus generating 3D order in an accessible range of temperature of interest for structural analysis and for technological applications.

Homochiral columns constructed by chiral self-sorting during supramolecular helical organization of hat-shaped molecules.

A library of dendronized cyclotriveratrylene (CTV) crowns substituted with chiral, racemic, or achiral peripheral alkyl chains, including enantiopure R and S branched alkyls, "racemic by mixture", "racemic by synthesis", n-octyl, and n-dodecyl groups was synthesized. In solvophobic solvents and in bulk they self-assemble in helical columns. Their solution and bulk shape-persistent supramolecular structures were determined by a complementary combination of circular dichroism (CD) and UV in solution and thin film, microspot CD in thin film, differential scanning calorimetry combined with fiber X-ray diffraction, computer simulation, and molecular models. In solution, self-assembly via a cooperative mechanism generates single-handed columns from enantiopure CTVs and mixtures of right- and left-handed columns from racemic by mixture, racemic by synthesis, other combinations of R and S, and even from achiral compounds. In bulk state all supramolecular columns form a 3D hexagonal crystalline phase, Φ(h)(k) (P63 symmetry), that can be obtained only from single-handed columns and a columnar hexagonal 2D liquid crystal, Φ(h). The highest order Φ(h)(k) consists of enantiopure single-handed columns that are slightly distorted 12-fold triple helices. The "hat-shaped" dendronized CTV assembles in bent-branch pine-tree columns that allow interdigitation of alkyl groups in adjacent columns regardless of their direction. Enantiomerically rich, racemic, and achiral compositions undergo deracemization in the crystal state by transfer of the transient disc-like conformer of dendronized CTV from column to column during crown inversion. Solid state NMR experiments identified motional processes that allow such transfer. This unprecedented supramolecular chiral self-sorting will impact the creation of functions in complex systems.

Mimicking biological membranes with programmable glycan ligands self-assembled from amphiphilic Janus glycodendrimers.

An accelerated modular synthesis produced 18 amphiphilic Janus glycodendrimers with three different topologies formed from either two or one carbohydrate head groups or a mixed constellation with a noncarbohydrate hydrophilic arm. By simple injection of their THF solutions into water or buffer, all of the Janus compounds self-assembled into uniform, stable, and soft unilamellar vesicles, denoted glycodendrimersomes. The mixed constellation topology glycodendrimersomes were demonstrated to be most efficient in binding plant, bacterial, and human lectins. This evidence with biomedically relevant receptors offers a promising perspective for the application of such glycodendrimersomes in targeted drug delivery, vaccines, and other areas of nanomedicine.

Electro-oxidative Methylation of 2-Isocyanobiaryls Using N,N-dimethylformamide (DMF) as Carbon Source: Synthesis of 6-Methylphenanthridines.

A benign electrochemical method to access 6-methylphenanthridines from 2-isocyanobiaryls using N,N-dimethylformamide (DMF) as a methyl source is reported. The protocol operates at ambient temperature without the need for harmful methylating reagents. Mechanistic studies suggested that DMF delivered a methylene synthon, followed by reduction at the cathode and tautomerization. The method offers environmental benefits by avoiding metal-based reagents and harsh conditions.

Transformation from kinetically into thermodynamically controlled self-organization of complex helical columns with 3D periodicity assembled from dendronized perylene bisimides.

The dendronized perylene 3,4:9,10-tetracarboxylic acid bisimide (PBI), (3,4,5)12G1-1-PBI, was reported by our laboratory to self-assemble into complex helical columns containing dimers of dendronized PBI with one molecule in each stratum, with different intra- and interdimer rotation angles but identical intra- and interdimer distance of 3.5 Å, exhibiting a four-strata 2(1) helical repeat. A thermodynamically controlled 2D columnar hexagonal phase with short-range intracolumnar order represents the thermodynamic product at high temperature, while a kinetically controlled monoclinic columnar array with 3D periodicity is the thermodynamic product at low temperature. With heating and cooling rates higher than 10 °C/min to 1 °C/min, at low temperature the 2D columnar periodic array is the kinetic product for this dendronized PBI. Here the synthesis and structural analysis of a library of (3,4,5)nG1-m-PBI with n = 12 to 6 and m = 1 are reported. A combination of differential scanning calorimetry, X-ray diffraction on powder and orientated fibers, including pattern simulation and electron density map reconstruction, and solid-state NMR, all as a function of temperature and heating and cooling rate, was employed for their structural analysis. It was discovered that at low temperature the as-prepared n = 12 to 10 exhibit a 3D layered array that transforms irreversibly into columnar periodicities during heating and cooling. Also the kinetically controlled 3D columnar phase of n = 12 becomes thermodynamically controlled for n = 10, 9, 8, 7, and 6. This unprecedented transformation is expected to facilitate the design of functions from dendronized PBI and other self-assembling building blocks.