Cyclobutene Formation in PtCl2‐Catalyzed Cycloisomerizations of Heteroatom‐Tethered 1,6‐Enynes

Aza(oxa)bicyclo[3.2.0]heptenes are accessed through the PtCl₂‐catalyzed cycloisomerizations of heteroatom‐tethered 1,6‐enynes featuring a terminal alkyne and amide as the solvent. It is shown that the weak coordinating properties of the solvent and alkyl substituent(s) at the propargylic carbon atom favor the formation of cyclobutenes instead of other possible cycloisomerization products such as 1,3‐diene derivatives or cyclopropane‐fused heterocycles.     

The Asymmetric Hetero‐Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds

The hetero‐Diels–Alder reaction is one of the most powerful transformations in the chemistry toolbox for the synthesis of aza‐ and oxa‐heterocycles embodying multiple stereogenic centers. However, as compared to other cycloadditions, in particular the dipolar cycloadditions and the Diels–Alder reaction, the hetero‐Diels–Alder reaction has been much less explored and exploited in organic synthesis. Nevertheless, this powerful transformation has opened up efficient and creative routes to biologically relevant small molecules and different natural products which contain six‐membered oxygen or nitrogen ring systems. Recent developments in this field, in particular in the establishment of enantioselectively catalyzed hetero‐Diels–Alder cycloadditions steered by a plethora of different catalysts and the application of the resulting small molecules in chemical biology and medicinal chemistry research, are highlighted in this Minireview.     

Benign Approaches for the Microwave‐assisted Synthesis of Five‐membered 1,2‐N,N‐heterocycles

The development of new strategies for the synthesis of small‐sized heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in the synthesis of two nitrogen atoms containing five‐membered heterocyclic compounds is presented, focusing on the developments in the last 5–10 years. This contribution covers the literature concerning the total synthesis of five‐membered 1,2‐N,N‐heterocycles.     

Microwave-accelerated Synthesis of Some (±)-1-Aryl-5-chloroisochromans

Solventless one-pot synthesis of some new (±)-1-aryl-5-chloroisochromans by cyclocondensation of 2-(2-chlorophenyl)ethanol with aromatic aldehydes via an acid catalyzed oxa-Pictet-Spengler reaction under microwave irradiation is described.     

Direct Syn Addition of Two Silicon Atoms to a C≡C Triple Bond by Si−Si Bond Activation: Access to Reactive Disilylated Olefins

A catalytic intramolecular silapalladation of alkynes affords, in good yields and stereoselectively, syn ‐disilylated heterocycles of different chemical structure and size. When applied to silylethers, this reaction leads to vinylic silanols that undergo a rhodium‐catalyzed addition to activated olefins, providing the oxa‐Heck or oxa‐Michael products, depending on the reaction conditions.     

Synthetic Studies on Actinorhodin and γ‐Actinorhodin: Synthesis of Deoxyactinorhodin and Deoxy‐γ‐actinorhodin/Crisamicin A Isomer

A strategy based on bidirectional Dötz benzannulation and the oxa‐Pictet–Spengler reaction toward the synthesis of actinorhodin and γ‐actinorhodin has been explored. This work has resulted in the synthesis of deoxyactinorhodin and deoxy‐γ‐actinorhodin. The latter is a regioisomer of crisamicin A (which has 10,10′‐dihydroxy groups).     

Synthesis of 2,3‐dihydro‐6H‐1‐oxa‐3a‐aza‐phenalene and its benzo/hetero‐fused analog

A simple and efficient method for the synthesis of highly substituted benzo‐ and hetero‐fused analog of 2, 3‐dihydro‐6H‐oxa‐3a‐aza‐phenalene was developed using 2H‐1, 4‐benzoxazine and α‐oxoketene dithio‐acetals. J. Heterocyclic Chem., (2011).     

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano‐γ‐lactone dimer, γ‐actinorhodin, in eleven steps. Two steps exploit pairs of peri‐MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa‐Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ‐unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ‐hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa‐Pictet–Spengler cyclization. Dimerization to the core of γ‐actinorhodin occurred by two Suzuki couplings.     

Tandem Three‐Component Synthesis of syn‐1,2‐ and syn‐1,3‐Diol Derivatives

The development of efficient methods for stereocontrolled synthesis of polyol derivatives has been of continuing interest for the synthetic community. We describe herein tandem olefin cross‐metathesis/hemiacetalization/intramolecular oxa‐Michael addition of allylic/homoallylic alcohols, α,β‐unsaturated ketones, and aldehydes, which enabled the synthesis of syn‐1,2‐ and syn‐1,3‐diol derivatives in a step‐economical manner. A series of differentially protected polyol derivatives could be obtained in subsequent transformations via chemoselective/regioselective cleavage of the acetal moiety of the tandem reaction products.     

Oxygen‐Doped Zig‐Zag Molecular Ribbons

The synthesis of a zig‐zag oxygen‐doped molecular rhombic ribbon has been achieved. This includes oxidative C?C and C?O bond formations that allowed the stepwise elongation and planarization of an oxa‐congener of 2,7‐periacenoacene. X‐ray diffraction analysis corroborated the flat structure and the zig‐zag topology of the O‐doped edges. Photophysical and electrochemical investigations showed that the extension of the peri‐xanthenoxanthene (PXX) into the molecular ribbon induces a noticeable shrinking of the molecular band gap devised by a rising of the HOMO energy level, a desirable property for p‐type organic semiconductors.     

Transition‐metal‐free N‐arylation: A general approach to aza‐fused poly‐heteroaromatics

A new and efficient method for the synthesis of various aza‐fused poly‐hetero aromatics has been described. This protocol includes an intermolecular condensation followed by metal‐free base‐promoted intramolecular C―N coupling reaction. The advantage of this one‐pot transformation lies in the use of simple cyclic amidines‐like compounds without prefunctionalization of the starting heterocycles.     

Preparation of 6‐, 7‐, and 8‐substituted derivatives of 2‐Oxa‐1,3,4,10‐tetraazacyclopenta[b]fluoren‐9‐one

The preparation of a variety of derivatives of 2‐oxa‐1,3,4,10‐tetraazacyclopenta[b]fluoren‐9‐one 1 is described. A series of substituted indan‐1‐ones were prepared and oxidized with N‐bromosuccinimide and dimethyl sulfoxide to the corresponding ninhydrin derivatives. Cyclization of the ninhydrins with furazan‐3,4‐diamine yielded the target tetracycles. Appropiate choice of substituents in ninhydrins led to a preference for one regioisomer in the target tetracycles. This permitted the synthesis of a variety of 8‐substituted hetero‐cycles. In those instances where isomer formation was possible, structural assignments were confirmed by X‐ray crystallography.     

Basic Alumina‐Supported Synthesis of Aryl‐Heteroarylmethanes via Palladium Catalyzed Cross‐Coupling under Microwave Irradiation

A basic alumina‐supported microwave assisted simple methodology has been developed for the synthesis of aryl‐heteroaryl methanes (benzylated quinolones) via transition metal catalyzed cross‐coupling reaction of halo substituted polynuclear oxa‐aza quinolones with benzyl indium, an organometallic reagent easily derived from commercially available benzyl bromide.     

Paving the Way to Novel Phosphorus‐Based Architectures: A Noncatalyzed Protocol to Access Six‐Membered Heterocycles

Phosphorus‐based heterocycles provide access to materials with properties that are inaccessible from all‐carbon architectures. The unique hybridization of phosphorus gives rise to electron‐accepting capacities, a large variety of coordination reactions, and the possibility of controlling the electronic properties through phosphorus postfunctionalization. Herein, we describe a new noncatalyzed synthetic protocol to prepare fused six‐membered phosphorus heterocycles. In particular, we report the synthesis of novel phosphaphenalenes. These fused systems exhibit the benefits of both five‐ and six‐membered phosphorus heterocycles and enable a series of versatile postfunctionalization reactions. This work thus opens up new horizons in the field of conjugated materials.     

Reagent‐Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic‐ and Fused Heterocyclic Ring Systems

Herein, we report a diversity‐oriented‐synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N‐heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N‐heterocycles. The two‐step sequence starts with a chiral‐bicyclic‐lactam‐directed enolate‐addition/substitution step. This step is followed by a ring‐closure onto the built‐in scaffold electrophile, thereby leading to stereoselective carbocycle‐ and spirocycle‐formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug‐like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell‐lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.     

Continuous‐flow syntheses of heterocycles

This review surveys the synthesis of heterocycles under continuous‐flow conditions, including the use of chip‐based microreactors, coil‐based flow reactors, and capillary or tubular devices. J. Heterocyclic Chem., 2011.     

Hydrogen‐Bonding Catalyzed Ring‐Closing C−O/C−O Metathesis of Aliphatic Ethers over Ionic Liquid under Metal‐Free Conditions

O‐heterocycles have wide applications, and their efficient and green synthesis is very interesting. Herein, we report hydrogen‐bonding catalyzed ring‐closing metathesis of aliphatic ethers to O‐heterocycles over ionic liquid (IL) catalyst under metal‐ and solvent‐free conditions. The IL 1‐butylsulfonate‐3‐methylimidazolium trifluoromethanesulfonate ([SO₃H‐BMIm][OTf]) is discovered to show outstanding performance, better than the reported catalysts. An interface effect plays an important role in mediating the reaction rate due to the immiscibility between the products and the IL catalyst, and the products can be spontaneously separated. NMR analysis and DFT calculation suggest that a pair of cation and anion of [SO₃H‐BMIm][OTf] could form three strong H‐bonds with an ether molecule, which catalyze the ether transformation via a cyclic oxonium intermediate. A series of O‐heterocycles including tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be obtained from their corresponding ethers in excellent yields (e.g., >99 %). This work opens an efficient and metal‐free way to produce O‐heterocycles from aliphatic ethers.     

External‐Photocatalyst‐Free Visible‐Light‐Mediated Synthesis of Indolizines

A visible‐light‐mediated synthesis of valuable polycyclic indolizine heterocycles from easily accessed brominated pyridine and enol carbamate derivatives has been developed. This process, which operates at room temperature under irradiation from readily available light sources, does not require the addition of an external photocatalyst. Instead, an investigation into the reaction mechanism indicates that the indolizine products themselves may be in some way involved in mediating and accelerating their own formation. Preliminary studies also show that these simple heterocyclic compounds may be capable of facilitating other visible‐light‐mediated transformations.     

Transition Metal‐Participated Synthesis and Utilization of N‐containing Heterocycles: Exploring for Nitrogen Sources

This account aims to describe our recent efforts on the synthesis and utilization of N‐containing heterocycles, where transition metals participate in the synthesis. A variety of nitrogen sources, including amines, amides, hydrazones, pyrimidines, isocyanides, and copper nitrate, have been disclosed for the synthesis of diverse bioactive and pharmacologically interesting N‐containing heterocycles under the participation of transition metals. The well‐known nitrogen sources, such as amines and amides, were used for the construction of indoles, isatins, and quinolones. Dihydrophthalazines, isoquinolines, indazoles, and pyrazoles were obtained from hydrazones, while various pyrimidine‐containing heterocycles were afforded through regioselective C?H functionalizations using pyrimidine as the directing group. Recent research has focused on the chemistry of isocyanides to achieve several kinds of heterocyclic compounds with high efficiency under the catalysis of transition metals (Pd, Rh, Mn, Cu), through oxidative cyanation reactions, sequential isocyanide insertions into C?H, N?H, or O?H bonds, and tandem radical annulation. More recently, an efficient route to isoxazolines has been reported using copper nitrate as a novel nitrogen source.     

Highly Convergent One‐Pot Four‐Component Regioselective Synthesis of Spiro‐pyranopyrazoles and Oxa‐aza‐[3.3.3]propellanes

A concise and efficient route for the synthesis of spiro‐pyranopyrazoles and oxa‐aza‐[3.3.3]propellanes by simple regioselective multicomponent reaction of ninhydrin, malononitrile, hydrazine derivatives, and β‐keto esters or dimethyl acetylenedicarboxylate was developed. This protocol provides an alternative method for combinatorial and parallel syntheses in drug discovery. The value of this method lies in its simplicity, regioselectivity, and good yields. The structures of 3 and 4 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Schemes 2 and 3).