Ionic Liquids Controlled Switchable Synthesis of Diverse Bio-Based N-Heterocycles via Tandem Dehydrogenative Cyclization

A tandem transformation that involves the formation of three bonds and two heterocyclic rings in a one-pot fashion through amino-alkylation of an ionic-liquid-immobilized diamine with keto acids followed by successive double intramolecular cyclizations to afford a tricyclic framework has been explored. This tandem cyclization has been utilized to develop a rapid and efficient method to synthesize various pyrrolo[1,2-a]benzimidazolones and pyrido[1,2-a]benzimidazolones on an ionic-liquid support by using focused microwave irradiation. The application of this tandem cyclization was further extended to the aromatic keto acids to provide isoindolinone-fused benzimidazoles, a structurally heterogeneous library with skeletal diversity. The outcome of the cascade reaction was confirmed by the X-ray crystallographic study of the product directly attached to the ionic-liquid support. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by regular conventional spectroscopic methods, whereas application of microwave irradiation greatly accelerates the rate of the reactions.

A tandem reaction of new type Baylis-Hillman adducts 1 was prompted by ionic liquid [Hmim]HSO4/NaNO3 system and the unexpected products 6-aryl-2H-pyran-3-carboxylates 2 and imidazolium salts 3 were efficiently formed via the rearrangement and substitution reaction. While mediated by [Emim]HSO4/NaNO3 system, the key intermediates 4 were isolated. A plausible mechanism for the transformation was given. INTRODUCTION Tandem reactions are of great importance in organic synthesis due to generation of some important products in a single operation with high atom economy and bond-forming efficiency. Recently, more and more novel types of tandem reactions, including tandem Michael addition, substitution, cyclization and rearrangement reaction, were extensively applied to organic synthesis, especially the synthesis of natural optically active products and heterocyclic compounds. The Baylis-Hillman reaction is a synthetically useful method for carbon-carbon bond-forming reactions to yield functionalized allylic alcohols, thereby providing handles for further manipulation in a multitude of synthetic organic transformations. In continuation of our research on new type Baylis-Hillman adducts 1 prepared from aryl methyl ketones via a combination of the Vilsmeier and the Baylis-Hillman reactions, we investigated the tandem reaction of new type Baylis-Hillman adduct 1 under the [Hmim]HSO4/NaNO3 system (Scheme 1). To our surprise, the unexpected products 6-aryl-2H-pyran-3-carboxylates 2 and/or imidazolium salt 3 were isolated. HETEROCYCLES, Vol. 85, No. 1, 2012 43

A rhodium/chiral diene catalytic system is reported for the reaction of enone-diones and arylboronic acids that allows the switchable synthesis of chiral bicyclic products and acyclic products in a controlled manner. The production of bicyclic products containing four contiguous stereocenters is assumed to proceed through the enantioselective arylrhodation of enone-diones with Cs2CO3, forming a rhodium-enolate intermediate, followed by desymmetrization of the diastereotopic diones via aldol cyclization with quantitative diastereoselection and excellent enantiomeric excess. The production of acyclic products is assumed to proceed through the enantioselective hydroarylation of enone-diones with excellent enantiomeric excess in which the aldol cyclization is significantly inhibited by the choice of Et3N as a base. The selectivity for bicyclic products (via tandem arylation-aldol cyclization) and acyclic products (via hydroarylation) is rationalized by the proposed model.

A copper-catalyzed radical cascade dehydrogenative cyclization of N-tosyl-8-ethynyl-1-naphthylamines under air is described herein for the synthesis of thioazafluoranthenes. The reaction proceeds smoothly with high efficiency and a broad reaction scope. The product is indeed a new fluorophore and its photophysical properties are also investigated. Based on the results, we are pleased to find that the Stokes shift of amino-linked thioazafluoranthenes in dilute tetrahydrofuran is determined to be 143 nm (4830 cm-1).

A Brønsted acidic ionic liquid (BAIL)-catalyzed one-pot tandem reduction of quinoline to tetrahydroquinoline (THQ) followed by reductive alkylation by the aldehyde has been demonstrated under mild reaction conditions with a shorter reaction time. This step-economical synthetic approach is suitable for late-stage functionalization of complex bioactive molecules. The reaction is highly chemoselective and tolerates a wide range of reducible-sensitive functional groups. The current reductive N-alkylation approach was also successfully utilized to synthesize novel tricyclic oxazino-fused-tetrahydroquinoline/benzoxazine compounds via tandem reductive cyclization of 1-aryl-2-(8-quinolinyloxy) ethanones. Further reductive protocol has been applied for the synthesis of antiarrhythmic drug nicainoprol and tubulin polymerization inhibitor efficiently. Notably, BAIL was easily recovered and reused multiple times without a considerable loss in catalytic activity. The elucidation of the underlying mechanism was achieved through a combination of several control experiments, kinetic studies, and isotopic labelling experiments. This study offers a new reaction pathway for the reduction of quinoline, in which BAIL facilitates proton transfer through a distinctive hydrogen bonding ion-pair mechanism.

An acid‐functionalized ionic liquid‐catalyzed annulation of 2‐arylaniline and diazo compound was developed via cascade Wolff rearrangement, which is different from the precedent transformations mediated by metal or acid involving a NH bond insertion. A spectrum of diverse diazos were well compatible, in particular, the unsymmetrical diazos provided exclusive product through selective Wolff rearrangement. Mechanistic studies disclosed that the reaction proceeded through tandem Wolff rearrangement, nucleophilic addition, oxidation, and cyclization via the electrostatic interaction and hydrogen‐bonding effect of ionic liquid.

Thioxanthone-based ionic liquid as photocatalyst for a tandem cyclization reaction to synthesize pyrroloquinolinones

Achieving controllable C–H functionalization to elaborate valuable compounds from simple chemicals is attractive and highly desirable, especially if nonprecious transition metal catalysts can be used. However, controlling selectivity in these transformations remains a continuous challenge to synthetic chemists. Herein, we show for the first time that control over the reactive organometallic intermediate enables the switchable synthesis of quinoline and indole from amides and alkynes through C–H activation using Cp*Co(III). The keys to this strategy are (1) introducing a Lewis acid to greatly accelerate the dehydrative cyclization, which can outcompete dehydrogenative cyclization, and (2) tuning the directing group to facilitate the dehydrogenative cyclization and inhibit dehydrative cyclization.

A convenient and straightforward regioselective synthesis of pi‐conjugated pyrazolo[1, 5‐ a ]pyrimidines has been achieved via Brønsted acidic ionic liquid catalyzed tandem cyclization between 3‐aminopyrazole and chalcone derivatives in high yields. Task specific ionic liquid [1‐methyl‐3‐(4‐sulfobutyl)imidazolium‐4‐methylbenzenesulfonate] is found to be an effective catalyst for the cyclization, and the presence of both C2‐H of imidazolium moiety and acidic proton drastically enhance the catalytic activity. Substituted aminopyrazoles reacted with a wide range of functionalized α,β ‐unsaturated ketones to variety of pyrazolo[1, 5‐ a ]pyrimidine derivatives. The present protocol offers a broad substrates scope, use of non‐hazardous reagent, metal‐free environmentally benign conditions and catalyst recyclability. Comparative photophysical studies have shown high quantum yields for certain derivatives.

Oxindoles and dihydroquinolinones are pivotal heterocyclic scaffolds in medicinal and synthetic chemistry. Herein, we describe a controllable visible-light-induced, copper-catalyzed carbonylative cyclization of arylthianthrenium salts with alkenes, enabling the efficient synthesis of structurally diverse oxindoles and dihydroquinolinones. Notably, this transformation proceeds under mild conditions without the need for expensive photocatalysts, and regioselective acyl radical addition is achieved simply by tuning the substitution pattern of the alkene, which enables the switchable synthesis of carbonylated five- and six-membered heterocycles. Mechanistic studies indicate that blue-light irradiation promotes the copper-mediated reduction of arylthianthrenium salts, generating aryl radicals that subsequently capture CO to afford acyl radicals and initiate a tandem cyclization sequence. This method exhibits broad functional-group tolerance and offers a versatile platform for the late-stage functionalization of bioactive molecules.

A facile protocol using an acidic ionic liquid as the catalyst allows the synthesis of pyranoquinoline derivatives through tandem cyclization of substrate (I) with chalcones.

Ionic Liquids Controlled Switchable Synthesis of Diverse Bio-Based N -Heterocycles Via Tandem Dehydrogenative Cyclization