Jeroen Jacobs

A Diversity‐Oriented Approach to Spiroindolines: Post‐Ugi Gold‐Catalyzed Diastereoselective Domino Cyclization

Gold-catalyzed carbocyclization and heteroannulation strategies have recently attracted much attention owing to the selective and efficient activation of the C C bond towards a wide range of nucleophiles that these methods provide. Domino approaches involving gold-catalysis lead to complex heterocyclic compounds under exceedingly mild reaction conditions. Although gold-catalyzed approaches are rising to prominence, they suffer in terms of diversity and procedural length. Multistep sequences are usually required for assembling the starting material for cyclization. We have recently reported a concise route to indoloazocines by a sequential Ugi/gold-catalyzed intramolecular hydroarylation approach. Inspired by these findings and as a result of our continued synthetic interest in the indole core, multicomponent reactions and transition metal-catalysis, we have developed a post-Ugi gold-catalyzed domino cyclization method to generate spiroindolines. The Ugi four-component reaction (4-CR) of indole-3carboxaldehyde (1a) with p-methoxybenzyl amine (2a), 2-butynoic acid (3a) and tert-butyl isonitrile (4a) in methanol at 50 8C gave Ugi-adduct 5a in 71% yield. When this was treated with 5 mol% of Au[PPh3]OTf (OTf= trifluoromethanesulfonate) in CDCl3 at RT, the expected outcome of the reaction was indoloazepinone 6a’ through an endo-dig cyclization followed by rearrangement (Scheme 1). Surprisingly, an exo-dig cyclization followed by intramolecular trapping of the spiro intermediate occurred instead, resulting in the diastereoselective formation of tetracyclic spiroindoline 6a in 61% yield (Scheme 1). This observation was remarkable, as the attack on the a-position of an alkyne conjugated with an amide is rare, and trapping of the spiro intermediate by a sterically hindered tert-butyl amide is rather unexpected, as was the diastereoselectivity observed. Spiroindolines are prominent molecular motifs that are frequently encountered among the large family of alkaloids; for example, it is present in communesines and perophoramidines (Figure 1), which display distinct pharmacological properties. These fused polycyclic systems, which feature quaternary stereocenters, present a nontrivial challenge for organic chemists to develop synthetic approaches.

8-HaloBODIPYs and Their 8-(C, N, O, S) Substituted Analogues: Solvent Dependent UV–Vis Spectroscopy, Variable Temperature NMR, Crystal Structure Determination, and Quantum Chemical Calculations

The UV-vis electronic absorption and fluorescence emission properties of 8-halogenated (Cl, Br, I) difluoroboron dipyrrin (or 8-haloBODIPY) dyes and their 8-(C, N, O, S) substituted analogues are reported. The nature of the meso-substituent has a significant influence on the spectral band positions, the fluorescence quantum yields, and lifetimes. As a function of the solvent, the spectral maxima of all the investigated dyes are located within a limited wavelength range. The spectra of 8-haloBODIPYs display the narrow absorption and fluorescence emission bands and the generally quite small Stokes shifts characteristic of classic difluoroboron dipyrrins. Conversely, fluorophores with 8-phenylamino (7), 8-benzylamino (8), 8-methoxy (9), and 8-phenoxy (10) groups emit in the blue range of the visible spectrum and generally have larger Stokes shifts than common BODIPYs, whereas 8-(2-phenylethynyl)BODIPY (6) has red-shifted spectra compared to ordinary BODIPY dyes. Fluorescence lifetimes for 6, 8, and 10 have been measured for a large set of solvents and the solvent effect on their absorption and emission maxima has been analyzed using the generalized Catalán solvent scales. Restricted rotation about the C8-N bond in 7 and 8 has been observed via temperature dependent (1)H NMR spectroscopy, whereas for 10 the rotation about the C8-O bond is not hindered. The crystal structure of 8 demonstrates that the short C8-N bond has a significant double character and that this N atom exhibits a trigonal planar geometry. The crystal structure of 10 shows a short C8-O bond and an intramolecular C-H···π interaction. Quantum-chemical calculations have been performed to assess the effect of the meso-substituent on the spectroscopic properties.

Synthesis and structural elucidation of diversely functionalized 5,10-diaza[5]helicenes.

Diversely functionalized diaza[5]helicenes have been synthesized starting from 6,9-dichloro-5,10-diaza[5]helicene, which was prepared from a readily available quinoline building block via Wittig reaction followed by photochemical electrocyclization. The helicene skeleton was substituted by a variety of O-, S-, N-, and C-centered nucleophiles using nucleophilic aromatic substitution reactions and palladium-catalyzed reactions like Suzuki coupling and Buchwald-Hartwig aminations. We have determined, using X-ray single-crystal diffraction, the crystal structures of the chloro- and methoxy-substituted diaza[5]helicenes. A resolution strategy based on diastereomeric separation by substitution of the dichloro derivative with a chiral amine has been shown.

Radical CH Alkylation of BODIPY Dyes Using Potassium Trifluoroborates or Boronic Acids

A one-step synthetic procedure for the radical CH alkylation of BODIPY dyes has been developed. This new reaction generates alkyl radicals through the oxidation of boronic acids or potassium trifluoroborates and allows the synthesis of mono-, di-, tri-, and tetraalkylated fluorophores in a good to excellent yield for a broad range of organoboron compounds. Using this protocol, multiple bulky alkyl groups can be introduced onto the BODIPY core thus creating solid-state emissive BODIPY dyes.

Supported gold nanoparticles as efficient and reusable heterogeneous catalyst for cycloisomerization reactions

We report the utilization of a novel catalyst for cycloisomerizations. The novel catalyst system contains gold nanoparticles supported on Al-SBA15, which was prepared by the ball-milling process. We developed a greener methodology for synthesizing spiroindolines under heterogeneous conditions, using this novel class of supported gold nanoparticles in combination with microwave irradiation. The catalyst is highly reusable and selective. Cycloisomerization reaction yields ranged from good to excellent leading to the formation of two novel classes of six- and seven-membered heterocycles, which have been unprecedented so far. The selectivity of the catalyst towards the desired products is high and the reaction can be performed in ethanol as the solvent. A one-pot cascade reaction could be established commencing with the Ugi-reaction to ensure diversity.

Synthetic and Structural Exploration of [24]Tetrathiacalix[2]arene[2]pyrimidines

A novel class of two atom bridged metacyclophanes-[2(4)]thiacalix[2]arene[2]pyrimidines-has been synthesized via a straightforward S(N)Ar reaction. The conformational properties and intra-annular dimensions of the [2(4)]thiacalix[2]arene[2]pyrimidines were evaluated by X-ray structure analysis and compared with known homothia- and thiacalixarenes. Post-macrocyclization oxidation of the bridging sulfur moieties resulted in a [2(4)]sulfonylcalix[2]arene[2]pyrimidine, which gave access to an unexplored cavity size among sulfonylcalixarenes.

Enantioselective Assembly of a Ruthenium(II) Polypyridyl Complex into a Double Helix

Evolution can increase the complexity of matter by self-organization into helical architectures, the best example being the DNA double helix. One common aspect, apparently shared by most of these architectures, is the presence of covalent bonds within the helix backbone. Here, we report the unprecedented crystal structures of a metal complex that self-organizes into a continuous double helical structure, assembled by non-covalent building blocks. Built up solely by weak stacking interactions, this alternating tread stairs-like double helical assembly mimics the DNA double helix structure. Starting from a racemic mixture in aqueous solution, the ruthenium(II) polypyridyl complex forms two polymorphic structures of a left-handed double helical assembly of only the Λ-enantiomer. The stacking of the helices is different in both polymorphs: a crossed woodpile structure versus a parallel columnar stacking.

Diastereoselective Strategies towards Thia[n]helicenes

In the present study, we have investigated different strategies for diastereoselective synthesis of thia[n]helicenes. We describe the introduction of different chiral auxiliaries at various positions and investigated their effect in the photocyclization reaction. Different chiral groups were placed at the sterically hindered position of the helical core and their interactions with various solvents and metals like copper were investigated. The use of Cu(I) salts has led to high diastereoselectivity in the photocyclization process and we were successful in obtaining the thia[5]helicene in enantiomerically pure form in good yield. The single diastereomer obtained was characterized by X-ray crystallography. From the study of the barrier of racemization of these thia[5]helicenes, the stability was found to be comparable to unsubstituted tetrathia[7]helicenes and substituted diazadithia[7]helicenes. This approach provides an easy access to enantiopure helicenes.

Dichlorido{N-[2-(diphenylphosphanyl)benzylidene]-2-methylaniline}palladium(II) acetonitrile monosolvate

The title imino-phosphine compound, [PdCl2(C26H22NP)]·CH3CN, was prepared by reaction of N-[2-(diphenylphosphanyl)benzylidene]-2-methylaniline with dichlorido(cycloocta-1,5-diene)palladium(II) in dry CH2Cl2. The Pd(II) cation is coordinated by the P and N atoms of the bidentate chelating ligand and by two chloride anions, generating a distorted square-planar coordination geometry. There is a detectable trans influence for the chloride ligands. The methyl group present in this structure has an influence on the crystal packing.

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

A practical three-step protocol for the assembly of triazolobenzodiazepine-fused diketopiperazines and hydantoins has been developed. The synthesis of these tetracyclic ring systems was initiated by an Ugi reaction, which brought together all necessary functionalities for further transformations. The Ugi adducts were then subjected to a base-induced ring closing and an intramolecular azide–alkyne cycloaddition reaction in succession to obtain highly fused benzodiazepine frameworks.