A tautomeric ligand enables directed C‒H hydroxylation with molecular oxygen.

Hydroxylation of aryl carbon-hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon-hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

Synthesis of Some New Folic Acid-Based Heterocycles of Anticipated Biological Activity.

To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2-6a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10-15, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH2 group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16-20a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21-24a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25-30, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi.

Mesoporous silicas templated by heterocyclic amino acid derivatives: Biomimetic synthesis and drug release application.

The present paper reported a biomimetic synthesis of mesoporous silicas (BMSs) at room temperature by using synthesized polymers (C16-l-His, C16-l-Pro and C16-l-Trp) which derived from amino acid with ring structures as template under basic condition via co-structural-directing-agent method. The formation mechanism of BMSs and effect of initial synthesis conditions (such as surfactant structure, pH and co-solvents) on morphology and structure of BMSs were systematically studied. Synthesized BMSs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and nitrogen adsorption/desorption isotherms. The results showed that the surfactant structure was the dominant factor to direct the final mesostructure of BMSs, since the structure of surfactant affected the structure and size of clusters. Meanwhile the generation of BMSs required very rigorous alkaline condition which controlled the ionization degree of the surfactant and thus contributing to adequate stacking energy. Higher pH resulted in construction of channels with higher curvature. The presence of ethanol was found to facilitate the formation of BMSs with larger particle size. In application, aspirin can be loaded into BMSs with high efficiency, and the drug crystalline state of aspirin transformed from crystalline state to amorphous state during this process, which undoubtedly lead to the improvement of drug dissolution from 72.8% to 100% within 90 min. It is convincible that the biomimetic method presented here provided novel insight on precisely control of mesoporous silica and undoubtedly promoted the application of mesoporous silica materials.

Ruthenium(η6,η¹-arene-CH2-NHC) Catalysts for Direct Arylation of 2-Phenylpyridine with (Hetero)Aryl Chlorides in Water.

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N-CH2-arene group. The benzimidazolium halides were readily converted into ruthenium(II)-NHC complexes with the general formula [RuCl2(η6,η¹-arene-CH2-NHC)]. The structures of all new compounds were characterized by ¹H NMR (Nuclear Magnetic Resonance), 13C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C-Ru bond and two Ru-Cl bonds. The catalytic activity of [RuCl2(η6,η¹-arene-CH2-NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient.

Enantiospecific Solvolytic Functionalization of Bromochlorides.

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

Ruthenium-NHC-Diamine Catalyzed Enantioselective Hydrogenation of Isocoumarins.

A novel and practical chiral ruthenium-NHC-diamine system is disclosed for the enantioselective hydrogenation of isocoumarins, which provides a new concept to apply (chiral) NHC ligands in asymmetric catalysis. A variety of optically active 3-substituted 3,4-dihydroisocoumarins were obtained in excellent enantioselectivities (up to 99% ee). Moreover, this methodology was utilized in the synthesis of O-methylmellein, mellein, and ochratoxin A.

Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation.

A Sustainable Approach to the Stereoselective Synthesis of Diazaheptacyclic Cage Systems Based on a Multicomponent Strategy in an Ionic Liquid.

The microwave-assisted three-component reactions of 3,5-bis(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones, acenaphthenequinone and cyclic α-amino acids in an ionic liquid, 1-butyl-3-methylimidazolium bromide, occurred through a domino sequence affording structurally intriguing diazaheptacyclic cage-like compounds in excellent yields.

Thiophene, Selenophene, and Tellurophene-based Three-Dimensional Organic Frameworks.

3D frameworks are important because of their potential to combine the advantageous properties of porous materials with those associated with polymers. A series of novel 3D aromatic frameworks are presented that incorporate the heterocycles thiophene, selenophene, and tellurophene. The specific surface area and pore width of frameworks depends on the element that is used to build the framework. Optoelectronic properties are element-dependent, with heavy atoms red-shifting the optical properties and decreasing the energy gap of the solid. The metalloid nature of tellurophene allows the properties of this material to be tuned based on its oxidation state, even as an insoluble solid. The incorporation of the optoelectronic active thiophene, selenophene, and tellurophene units and the effect that they have on properties was studied. A supercapcitor device was fabricated using these frameworks, showing that these 3D frameworks are promising for optoelectronic uses.

Noncovalent Lone Pair⋠⋠⋠(No-π!)-Heteroarene Interactions: The Janus-Faced Hydroxy Group.

A comparative study using NMR spectroscopy and designed top-pan molecular balances demonstrates that the noncovalent interaction of a hydroxy group with π-deficient pyrazine and quinoxaline units involves a lone pair-heteroarene interaction which is much stronger and solvent independent when measured relative to the classical π-facial hydrogen bond to a benzene ring. Alkyl fluorides also prefer the heteroarene rings over the benzene ring. The attractive interaction between a quinoxaline and a terminal alkyne is also stronger than the intramolecular hydrogen bond to an arene.

Zinc-Catalyzed Alkyne Oxidation/C-H Functionalization: Highly Site-Selective Synthesis of Versatile Isoquinolones and ß-Carbolines.

An efficient zinc(II)-catalyzed alkyne oxidation/C-H functionalization sequence was developed, thus leading to highly site-selective synthesis of a variety of isoquinolones and ß-carbolines. Importantly, in contrast to the well-established gold-catalyzed intermolecular alkyne oxidation, over-oxidation can be completely suppressed in this system and the reaction most likely proceeds by a Friedel-Crafts-type pathway. Mechanistic studies and theoretical calculations are described.

Organocatalytic Asymmetric 1,6-Addition/1,4-Addition Sequence to 2,4-Dienals for the Synthesis of Chiral Chromans.

A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4-dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium-ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.

Catalytic asymmetric synthesis of enantioenriched heterocycles bearing a C-CF3 stereogenic center.

Given the important agricultural and medicinal application of optically pure heterocycles bearing a trifluoromethyl group at the stereogenic carbon center in the heterocyclic framework, the exploration of efficient and practical synthetic strategies to such types of molecules remains highly desirable. Catalytic enantioselective synthesis has one clear advantage that it is more cost-effective than other synthetic methods, but remains limited by challenges in achieving excellent yield and stereoselectivities with a low catalyst loading. Thus far, numerous models of organo- and organometal-catalyzed asymmetric reactions have been exploited to achieve this elusive goal over the past decade. This review article describes recent progress on this research topic, and focuses on an understanding of the catalytic asymmetric protocols exemplified in the catalytic enantioselective synthesis of a wide range of complex enantioenriched trifluoromethylated heterocycles.

5-membered cyclic hydroxamic acids as HDAC inhibitors.

The new histone deacylases inhibitors (HDACi) were synthesized in the class of 5-membered cyclic hydroxamic acids (5-CHA), showing medium size CHA as a new Zn-binding group. New reaction sequence was proposed for the synthesis of 5-membered alkylidene-cyclic-hydroxamic acids starting from butyrolactone. Compound 10c showed low µM activity on HeLa cell extracts. From these results, cyclic hydroxamic acids will be further investigated to find more potent compounds.

Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes.

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.

Multistep flow synthesis of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles.

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

Cooperative N-heterocyclic carbene (NHC)-Lewis acid-mediated regioselective umpolung formal [3 + 2] annulations of alkynyl aldehydes with isatins.

A novel and regioselective umpolung synthesis of spirooxindoles has been developed by cooperative NHC-Lewis acid-mediated formal [3 + 2] annulations of alkynyl aldehydes with isatins. In most cases, the reactions proceeded via a(3)-d(3) umpolung of alkynyl aldehydes resulting in spirooxindole butenolides. In a few cases, spirooxindole furan-3(2H)-ones were formed as the major products via an a(1)-d(1) umpolung process by controlling the reaction temperature. These newly formed spirooxindoles could provide promising candidates for chemical biology and drug lead discovery.

Intramolecular metal-free oxidative aryl-aryl coupling: an unusual hypervalent-iodine-mediated rearrangement of 2-substituted N-phenylbenzamides.

Hypervalent-iodine-mediated oxidative coupling of the two aryl groups in either 2-acylamino-N-phenyl-benzamides or 2-hydroxy-N-phenylbenzamides, with concomitant insertion of the ortho-substituted N or O atom into the tether, has been described for the first time. This unusual metal-free rearrangement reaction involves an oxidative C(sp(2))-C(sp(2)) aryl-aryl bond formation, cleavage of a C(sp(2))-C(O) bond, and a lactamization/lactonization. Furthermore, unsymmetrical diaryl compounds can be easily obtained by removing the tether within the cyclized product.

Enantioselective total synthesis of (-)-lansai B and (+)-nocardioazines A and B.

The concise total syntheses of the bis(pyrroloindolines) (-)-lansai B and (+)-nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)-nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation.

Synthesis, electrochemistry, and photophysics of a family of phlorin macrocycles that display cooperative fluoride binding.

A homologous set of 5,5-dimethylphlorin macrocycles in which the identity of one aryl ring is systematically varied has been prepared. These derivatives contain ancillary pentafluorophenyl (3H(Phl(F))), mesityl (3H(Phl(Mes))), 2,6-bismethoxyphenyl (3H(Phl(OMe))), 4-nitrophenyl (3H(Phl(NO2))), or 4-tert-butylcarboxyphenyl (3H(Phl(CO2tBu))) groups at the 15-meso-position. These porphyrinoids were prepared in good yields (35-50%) and display unusual multielectron redox and photochemical properties. Each phlorin can be oxidized up to three times at modest potentials and can be reduced twice. The electron-donating and electron-releasing properties of the ancillary aryl substituent attenuate the potentials of these redox events; phlorins containing electron-donating aryl groups are easier to oxidize and harder to reduce, while the opposite trend is observed for phlorins containing electron-withdrawing functionalities. Phlorin substitution also has a pronounced effect on the observed photophysics, as introduction of electron-releasing aryl groups on the periphery of the macrocycle is manifest in larger emission quantum yields and longer fluorescence lifetimes. Each phlorin displays an intriguing supramolecular chemistry and can bind 2 equiv of fluoride. This binding is allosteric in nature, and the strength of halide binding correlates with the ability of the phlorin to stabilize the buildup of charge. Moreover, fluoride binding to generate complexes of the form 3H(Phl(R))·2F(-) modulates the redox potentials of the parent phlorin. As such, titration of phlorin with a source of fluoride represents a facile method to tune the ability of this class of porphyrinoid to absorb light and engage in redox chemistry.