Current Organic Synthesis - Volume 10, Issue 5, 2013

Spiroisoxazolines of natural and synthetic origin are of recurring interest to researchers engaged in the areas of natural product synthesis and methodology. The spiroisoxazoline motif is a ubiquitous feature for a number of marine natural products of the order Verongida and display an array of interesting properties ranging from central nervous system (CNS) to antitumor and antifungal effects. Many of these natural products include a framework derived from isoxazoline and are characterized by unique spiro junction at C-5 position to an isoxazoline. Inspired from these secondary active metabolites, additional analogs resembling spiroisoxazoline structural pattern were designed and developed for the exploration of possible bioactivity. The current review provides an overview of various methodologies applied in the construction of spiroisoxazolines of pharmacological and biomedical interest.

Alkylboronate derivatives are important intermediates in organic synthesis and medicinal chemistry. The research of synthesizing alkylboronic acid derivatives has attracted great attention of chemists and many papers have reported various methods for preparing alkylboronates based on transition-metal-catalyzed hydroboration. In this review, we summarize the methods of synthesizing alkylboronate derivatives with different catalysts, such as Rhodium, Palladium, Copper, Iridium, Iron, Magnesiu, Platinum, Nickel and so on. Pinacolborane, bispinacolatodiboron and catecholborane are applied as important reagents and substrates with different skeleton structures and functional groups are employed to prepare diversity of alkylboronates.

The use of ZnO is a topic of continuing interest due to numerous applications in many areas of the chemical industry. In addition, with the development of industrialization, organic chemists have been confronted with a new challenge of finding novel methods in organic synthesis that can reduce and finally eliminate the impact of volatile organic solvents and hazardous toxic chemicals in the environment. Due to this, great efforts have been made by different research groups to achieve the goal of employing catalytic amounts of ZnO in organic transformations. Interesting results have been achieved, such as the use of catalytic amounts of ZnO alone or ZnO in combination with another metal ormetal oxide. In fact, ZnO as a heterogeneous catalyst can be easily separated from the reaction mixture and reused; it is generally not corrosive and does not produce problematic side products. Different classes of organic transformations have been studied and utilized using ZnO. Owing to the great interest in ZnO, reviews can be found on the properties and applications of ZnO, but to the best of our knowledge there is not a reported review on the application of ZnO as a catalyst in organic syntheses and transformations on which the author’s group has also contributed significantly. Hence, the present review focuses on fine and specialty chemicals synthesis catalyzed by ZnO. It is out of the scope of this review to cover comprehensively all reactions that have ever been reported in the presence of mixed metals or metal oxides with ZnO.

Fullerenes are fascinating carbon molecules that attract an increasing attention due to their interesting properties and possibilities of application. For these applications fullerenes need to be connected to the macroscopic world via their exterior. Hence, the modification of fullerenes to acquire the desired exterior functionality is of major importance to utilize them effectively as bulk materials in practical applications. In last years, the copper-catalyzed Huisgen’s 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC) has been revealed as an efficient tool for the preparation of a variety of fullerene derivatives with interesting applications. In this review we will brush up the variety of fullerene building blocks developed to be used in CuAAC reactions and we will critically examine the variety of reaction conditions that have been used to perform the CuAAC in connection with the nature of the moieties attached to the fullerene core. Moreover, the properties and applications of [60]fullerene derivatives obtained via the CuAAC “click” methodology will be reviewed including their use as mimics of the photosynthetic antenna-reaction center, their biological activity, their use as thermoresponsive water-soluble polymers and their role in the preparation of supramolecular fullerene motifs.

Cyanoacetylindoles (CAIs) are easily obtained from the reaction of indoles and cyanoacetic acid, and are used as versatile starting materials in the synthesis of different heterocycles. This review focuses on the application of CAIs to generate a large diversity of indolyl heterocycles such as pyrazoles, triazoles, pyridines, dihydropyridines, pyrimidines, ozathiols, thiophenes, oxazoles, quinolines and many other complex heterocycles.

In this review, the relevance of the combined use of the microwave (MW) and phase transfer catalytic (PTC) techniques is studied within alkylations. In the solid–liquid phase C-alkylation of a series of simple CH-acidic compounds including P=O containing derivatives, in most cases there is no need to use a phase transfer catalyst, as MW promotes the reaction in itself. In the MW-assisted solid–liquid phase alkylation of phenol derivatives, the presence of an onium salt as a phase transfer catalyst ensures the predominance of the O-alkylation. In the absence of base and catalyst, the alkylation of phenol derivatives proved to be C-selective. As regards the MWpromoted solid–liquid phase alkylating esterification of phosphinic acids, the use of a phase transfer catalyst was beneficial in case of alkylating agents of normal reactivity. In MW-assisted N-alkylations there is no general rule for the relevance of a phase transfer catalyst. In the alkylation of phenotiazine, the presence of an onium salt promotes the formation of the N-alkylated product, while in the absence of catalyst, the C-alkylation is predominant. Most of the C- and O-alkylations was performed under solvent-free conditions.

The catalytic asymmetric vinylogous-type reactions of γ-butenolides, have received growing attention, because the resulting enantiomerically pure γ-substituted butenolides are versatile building blocks for various natural products and biologically active compounds. The related reactions, such as vinylogous aldol reaction, vinylogous Mannich reaction, vinylogous Michael reactions, as well as allylic alkylation reaction, have been well developed in the past two decades. Both chiral metal complex catalysts and organocatalysts have proven to be useful. Among the plethora of catalytic systems developed so far, vinylogous Mukaiyama-type reactions using 2- silyloxfurans as the nucleophiles are popular for the synthesis of γ-substituted butenolides. On the other hand, the direct version of such reactions using simple butenolides is appreciated in recent years, due to the fact of the synthetic convenience and efficiency. Some advances have also been made in the catalytic direct enantioselective addition of simple butenolides and the analogues. In this microreview, recent progresses regarding the various types of reaction, substrate scope, and probable reaction mechanisms are discussed. In addition, the application of the methodology to the synthesis of natural products and useful intermediates is also presented briefly wherever appropriate.

A synthesis of novel three-, four-, and sixfold branched triazoles 3-5 and triazolothiadiazines 7, 8 and 10, which are linked to a benzene core via sulfanylmethylene spacers was reported. The reaction proceeded via initial treatment of the appropriate poly(bromomethyl)arenes 2 with the corresponding equivalents of 4-amino-4H-1,2,4-triazoles 1 in refluxing ethanolic KOH to give poly(triazolyl)arenes 3-5. Subsequent reaction of 4b and 5b with phenacyl bromide in refluxing DMF-ethanol mixture afforded poly(triazolothiadiazinyl)arenes 7 and 8, respectively. Compounds 7 and 8 were alternatevely obtained by the reaction of 2b and 2c with 6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 9 in refluxing EtOH/DMF containing KOH. Similarly, threefold substitution of 2a with three equivalents of 9 afforded 10 in good yield.

Reaction of ethyl propiolate with benzylidenemalononitrile 1a in the presence of L-proline was observed to produce the pyran derivative 7 in 80% yield. In contrast, diethyl acetylenedicarboxylate (6b) does not react with 1a in presence of L-proline. However when DABCO is used as the amine nucleophile, 6b reacts with 1a to form diethyl 5-amino-4,6-dicyano-3-phenyl-2,3-phthalate (20a). The structures of 7 and 20a were assigned by using X-ray crystallographic analysis. 2-aminoprop-1-ene-1,1,3-tricarbonitrile (28) reacts with diethyl acetylenedicarboxylate (6b) to yield (4-Cyano-5-dicyanomethyl-2-oxo-1,2-dihydro-pyrrol-3-ylidene)-acetic acid ethyl ester (31) whose structure was confirmed by X-Ray crystal structure.

We report a convenient access to tertiary carbinamines bearing a gem-diaryl group by Cu-catalyzed aryl Grignard addition to cyclic sulfamidate imines and sulfamide imines. The synthesis of hetero-functionalized 1,2-ethylene derivatives by ring-opening of the resulting sulfamidates is also described.

A highly efficient formal inverse electron demand aza Diels–Alder reaction of 1,2-diaza-1,3-dienes (DDs) is accomplished using dehydroalanine esters (DhAs) as electron-rich dienophiles. Both diastereoisomers of unprecedented α,α-disubstituted cyclic tetrahydropyridazine amino acids were obtained in excellent yields, in refluxing acetonitrile without activation.

Grignard reactions with the Weinreb amide (N-methoxy-N-methylamide) of indole-3-acetic acid provide a facile access to indol- 3-yl ketones, which are potential agonists of the human aryl hydrocarbon receptor ("dioxin receptor"). Addition of one equivalent of the MgBr2•THF complex avoids discolorations and oxidative side reactions, for which the 3-indolyl system is notorious. The product ketones carry aliphatic, olefinic, as well as (hetero)aromatic residues. The reaction conditions were thoroughly optimized, and full sets of analytical data including example crystal structures are presented.