Efficient regioselective functionalizations of cyclodextrins carried out under microwaves or power ultrasound

Regioselective syntheses of differently functionalized cyclodextrins (CDs) were efficiently carried out under ultrasound or microwave irradiation. 6^I-Deoxy-6^I-thio-β-CD, 6^I-deoxy-6^I-formyl-β-CD, and 6^A,6^D-dideoxy-6^A,6^D-dithio-β-CD were prepared under microwave irradiation. A new rapid and efficient ultrasound-assisted protocol is described for the synthesis of 3^I-azido-3^I-deoxy-, -β, and -γ-CD by selective tosylation followed by azide substitution.     

Efficient post-macrocyclization functionalizations of oxacalix[2]arene[2]pyrimidines

Diversely functionalized oxacalix[2]arene[2]pyrimidines have been synthesized starting from a bis(methylsulfanyl)-substituted oxacalix[4]arene by two efficient post-macrocyclization pathways. Functionalized aryl groups were introduced on the pyrimidine building block via Liebeskind-Srogl cross-coupling reactions, while a variety of O-, S-, N-, and C-nucleophiles were inserted on the calixarene skeleton by nucleophilic aromatic substitution reactions on the bis(methylsulfonyl)oxacalix[4]arene analogue.     

Efficient functionalizations of heteroatom-bridged calix[2]arene[2]triazines on the larger rim

Heteroatom-bridged dichlorinated calix[2]arene[2]triazines, which were synthesized from the fragment coupling reactions of cyanuric chloride and various aromatic dinucleophiles, are a unique type of platform for the construction of functional macrocyclic host molecules. Utilizing a very convenient and straightforward nucleophilic displacement reaction of dichlorinated tetraoxacalix[2]arene[2]triazine by various chelating group-containing amines, a number of functionalized tetraoxacalix[2]arene[2]triazines on the larger rim were efficiently synthesized in good yields. The resulting tetraoxacalix[2]arene[2]triazines armed with two 2,2'-bi(pyridinyl)amino or two bis(2-pyridinemethyl)amino groups selectively formed 1:1 complexes with Cu2+ ion through most probably a chelating interaction effect.     

Efficient synthetic approaches to the common scaffold of indole alkaloids

Birch reductive alkylation of 2-aminobiphenyls affords access to highly functionalized polyenes that react through a Pd(II)-catalyzed oxidative amination cascade or through a double 1,4-addition process to provide the tetracyclic skeleton of indole alkaloids with up to four stereogenic centers created in a single-pot operation.     

Multiple regioselective functionalizations of quinolines via magnesiations

A wide range of polyfunctionalized quinolines was prepared via chemo- and regioselective magnesiation reactions using appropriate Mg reagents, such as i-PrMgCl.LiCl, MesMgBr.LiCl, Mes2Mg.2LiBr, TMPMgCl.LiCl, and TMP2Mg.2LiCl. An application to the total synthesis of the biologically active compound talnetant was performed (six steps, 28%).     

Prediction of NHC-catalyzed chemoselective functionalizations of carbonyl compounds: a general mechanistic map

Generally, N-heterocyclic carbene (NHC) complexed with carbonyl compounds would transform into several important active intermediates, i.e., enolates, Breslow intermediates, or acylazolium intermediates, which act as either a nucleophile (Nu) or an electrophile (E) to react with the other E/Nu partner. Hence, the key to predicting the origin of chemoselectivity is to compute the activity (i.e., electrophilic index ω for E and nucleophilic index N for Nu) and stability of the intermediates and products, which are suggested in a general mechanistic map of these reactions. To support this point, we selected and studied different cases of the NHC-catalyzed reactions of carbonyl compounds in the presence of a base and/or an oxidant, in which multiple possible pathways involving acylazolium, enolate, Breslow, and α,β-unsaturated acylazolium intermediates were proposed and a novel index ω + N of the E and Nu partners was employed to exactly predict the energy barrier of the chemoselective step in theory. This work provides a guide for determining the general principle behind organocatalytic reactions with various chemoselectivities, and suggests a general application of the reaction index in predicting the chemoselectivity of the nucleophilic and electrophilic reactions.

A novel index ω + N can be used to predict the chemoselectivity according to the general NHC-catalyzed reaction mechanism.     

Enantioselective synthesis of an aziridinomitosane and selective functionalizations of a key intermediate

An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic resolution of an advanced secondary alcohol was then accomplished by using a peptide-based asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates. Optically pure material was then converted to the mitosane core, which was the subject of additional studies on the selective modification to produce several substituted compounds containing a mitosane ring system.     

Novel functionalizations of [60]fullerene-fused lactones

Reactions of [60]fullerene-fused lactones with methylmagnesium bromide and diisobutylaluminum hydride afforded rare fullerene hemiketals and hemiacetals, which were dehydrated by p-toluenesulfonic acid monohydrate or polyphosphonic acid to the corresponding [60]fullerene-fused dihydrofurans. Thus obtained alkyl-substituted and especially unsubstituted [60]fullerene-fused dihydrofurans are difficult to prepare by other methods. The unsubstituted [60]fullerene-fused lactone could react with aliphatic amines to give fullerols.     

Gas-liquid flow hydrogenation of nitroarenes: Efficient access to a pharmaceutically relevant pyrrolobenzo[1,4]diazepine scaffold

Using a Tube-in-Tube device based on the amorphous Teflon AF-2400 fluoropolymer, a series of nitroarenes was hydrogenated to afford the corresponding aniline compounds. The system was then applied to the construction of a pyrrolobenzo[1,4]diazapene scaffold through a tandem hydrogenation-condensation-hydrogenation sequence.     

Microwave-enhanced and metal-catalyzed functionalizations of the 4-aryl-dihydropyrimidone template

Progress in organometallic catalysis and recent advancements in the development of carbonylative reaction protocols without direct use of carbon monoxide have been utilized for efficient functionalizations of 4-aryl-dihydropyrimidone structures. The use of modern microwave technology enabled both high reaction rates and convenient handling. Examples of palladium-catalyzed cross-couplings, Heck reactions, amino- and alkoxycarbonylations, and direct N-amidations of 4-(bromophenyl)-dihydropyrimidones were performed. Further, the first N3-arylations of the dihydropyrimidone ring system were successfully completed using the copper-catalyzed Goldberg reaction. Altogether, these protocols provide new tools for rapid generation of novel and diverse dihydropyrimidone derivatives.     

Regioselective C-H bond functionalizations of acridines using organozinc reagents

Despite the recent advance in C-H bond functionalization chemistry, the C-H bonds in the acridine ring system, which is an important scaffold in medicinal and material science, have met with limited success, due, in part, to the lack of activated C-H bonds adjacent to the ring nitrogen atom. Herein, several protocols that can effect the regioselective arylation and alkylation of acridines at the C-4 and C-9 positions are described.     

Copper-catalyzed aerobic oxidative C-H functionalizations: trends and mechanistic insights

The selective oxidation of C-H bonds and the use of O(2) as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a wide range of oxidative coupling reactions initiated by single-electron transfer (SET) from electron-rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu-catalyzed C-H oxidation reactions feature substrates that are electron-deficient or appear unlikely to undergo single-electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic C-H oxidation reactions of this type represent important new opportunities for the field of Cu-catalyzed aerobic oxidations.     

Silver-catalyzed enantioselective functionalizations of alkenes and alkynes: A short review

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Exploring Photoredox-Catalyzed (Re)functionalizations with Core-Modified Benziodoxolones

Alkynes and nitriles are valuable building blocks in organic synthesis and also have multiple applications in chemical biology and materials science. Due to the high availability of tertiary alcohols, developing methods for their conversion into alkynes and nitriles is particularly attractive. In a previous communication, our group has reported the conversion of alcohols into alkynes through cesium oxalates based on the powerful combination of photochemistry with Ethynyl BenziodoXolones (EBXs). Herein, we report further investigations into this transformation, including our findings on the effect that backbone modification of EBXs has on the deoxyalkynylation of cesium oxalates. In addition, we disclose preliminary data on the development of new deoxycyanation and dethioalkynylation processes. We also report the serendipitous discovery of the C−H alkynylation of 1,2-dichloroethane.     

Synthesis of small carboranylsilane dendrons as scaffolds for multiple functionalizations

Small carbosilane dendrons in which a closo-carborane is located at the focal point have been prepared by a sequence of steps involving hydrosilylation and reduction reactions. These compounds are used as scaffolds for peripheral functionalization with styrene, chlorovinylstyrene, or suitable carboranes, while keeping the C(cluster)-Si (C(c)-Si) bond. Modification of the core by reduction of the carborane with Mg/BrCH2CH2Br was also achieved.     

Selective alkane C-H-bond functionalizations utilizing oxidative single-electron transfer and organocatalysis

Alkane C-H-bond functionalization methods not utilizing metal-catalysis are discussed based on experimental and computational data, beginning with molecule-induced homolysis (reactions of alkanes with dioxiranes). Electrophilic reactions are elaborated next with an emphasis on mechanistic details that reveal that many so-called electrophilic C-H or C-C-bond insertions can be rationalized by electron-transfer reactions (inner sphere, H-coupled, and outer sphere). Finally, radical functionalizations utilizing carbon-centered (relatively stable) radicals generated under organocatalytic (phase-transfer catalysis, PTC) conditions are presented as valuable alternatives to other radical-chain alkane functionalizations. The remarkable chemo- and regioselectivities of these PTC radical reactions and the tolerance of high strain in certain aliphatic hydrocarbons make them particularly useful for laboratory-scale halogenations, in particular, iodinations of unactivated alkane C-H-bonds.     

The scaffold tree--visualization of the scaffold universe by hierarchical scaffold classification

A hierarchical classification of chemical scaffolds (molecular framework, which is obtained by pruning all terminal side chains) has been introduced. The molecular frameworks form the leaf nodes in the hierarchy trees. By an iterative removal of rings, scaffolds forming the higher levels in the hierarchy tree are obtained. Prioritization rules ensure that less characteristic, peripheral rings are removed first. All scaffolds in the hierarchy tree are well-defined chemical entities making the classification chemically intuitive. The classification is deterministic, data-set-independent, and scales linearly with the number of compounds included in the data set. The application of the classification is demonstrated on two data sets extracted from the PubChem database, namely, pyruvate kinase binders and a collection of pesticides. The examples shown demonstrate that the classification procedure handles robustly synthetic structures and natural products.     

Synthesis of a novel tricyclic peptidomimetic scaffold

An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones has been discovered. The scaffold can function as a peptide backbone mimetic (highlighted) with two substituents independently variable to fine-tune biological response. Halogenation of the pyrazolo ring followed by Suzuki couplings made it possible to introduce substituents with variable electronic properties late in the synthetic route, which is preferable in library synthesis.