Methodology In Organic Synthesis Research Articles

ChemInform Abstract: Green Methodologies in Organic Synthesis: Recent Developments in Our Laboratories

AbstractReview: 88 refs.

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis

Catalyst-free reactions developed during the last decade and the latest developments in this emerging field are summarized with a focus on catalyst-free reactions in-water and on-water. Various named reactions, multi-component reactions and the synthesis of heterocyclic compounds are discussed including the use of various energy input systems such as microwave- and ultrasound irradiation, among others. Organic chemists and the practitioners of this art both in academia and industry hopefully will continue to design benign methodologies for organic synthesis in aqueous media under catalyst-free conditions by using alternative energy inputs based on fundamental principles.

Editorial: Drug Discovery …︁ The Third in the Band!

Editorial: Drug Discovery …︁ The Third in the Band!

Easily Modified Directing Groups for the Palladium-Catalyzed C—H Functionalization

Palladium-catalyzed C—H functionalization is one of the hot topics in the field of organic synthesis methodology. Directing groups play an important role in the regioselectivity of C—H activation. Herein, this review presents the recent pro- gress on the removable and transformable directing groups for the palladium-catalyzed C—H bonds activation and their appli- cations in the synthesis of complicate molecules. Moreover, the research trend of this area is also prospected. Keywords C—H functionalization, palladium catalyzed, directing groups, regioselectivity

Room Temperature Solid-Phase Ionic Liquid-Immobilized Enzyme for Biocatalysis in Organic Solvent: Markedly Enhanced Enantioselectivity

Nonaqueous biocatalysis provides a useful component of methodology in organic synthesis. For example, lipase catalysis in organic solvents is of great use for the synthesis of optically active compounds such as chiral alcohols, acids, and their esters. However, biocatalysis in nonaqueous media often suffers from reduced activity, selectivity or stability of enzymes. To overcome these limitations, many approaches have focused on the development of more efficient enzymes. Among them, the use of ionic liquids as an alternative solvent for the biotransformations in nonaqueous solvents enhanced the activity, selectivity, and stability of enzymes. And novel approach with ionic liquid-coated enzyme (ILCE), which was readily prepared by mixing the enzyme powder with a room temperature solid phase ionic liquid (RTSPIL) at elevated temperature, was previously reported showing enhanced enantioselectivity and stability in organic solvents. Also, we have recently reported that the enzyme coated by RTSPIL during lyophilization in aqueous medium exhibited better activity. Although it was difficult to clarify the reason that why ionic liquids increase significantly the catalytic activity as well as the selectivity of the lipase for enzyme-catalyzed transesterifications, we have speculated that the ionic environments by ionic liquid could improve activity and selectivity of the enzyme in biotransformations. On the other hands, numerous methods have been developed for the immobilization of enzymes onto various supports such as ceramic, polymer, gels, membranes, and microcapsules to increase the stability and recyclability of the biocatalyst in organic syntheses. To extend our knowledge of the application with ionic liquids for biocatalysis, we have expected that the immobilized enzyme in ionic environments could be more efficient during immobilizing of enzymes on supporting materials compared to that in non-ionic environments. Herein, we wish to report the synthesis of new RTSPIL composed of imidazolium cation modified with the methacryloyl group and hexafluorophosphate (PF6) anion and the biocatalysis in an organic solvent using lipase immobilized on this RTSPIL, which is an aggregate of small molecules. The novel RTSPIL, [MOPMIM]-[PF6], ([MOPMIM] + = 1-(3’ -methacryloyloxypropyl)-3-methylimidazolium) was synthesized according to the following procedure reported previously to immobilize the lipase, which was modified with methacryloyl group that can readily interact with the functional moieties such as thiol, amine, and alcohol on the surface of lipase.(Scheme 1). [MOPMIM]-[PF6] is very stable in moisture and melts at temperature of 70 C. The remarkable property of [MOPMIM]-[PF6] is low solubility in water due to hydrophobic character of PF6 anion, which lets us immobilize the lipase on RTSPIL in a buffer solution. Indeed, Burkholderia cepacia lipase (BCL, native) was immobilized on [MOPMIM]-[PF6] through interaction between [MOPMIM][PF6] and BCL in a phosphate buffer. The enantioselectivity of BCL/[MOPMIM]-[PF6] was examined in the transesterification reaction of bulky secondary alcohols (A-E) with vinyl acetate in toluene at 25 C (Scheme 1). For comparison, the same reactions were carried out with non-immobilized BCL. After the reaction reached 10-50% completion, the enzymes were removed by filtration and the resulting solution was concentrated. The organic residues were subjected to silica gel chromatography to obtain unreacted substrate and acetylated product. Their optical purities were then determined by high-performance liquid chromatography (HPLC) using a chiral column, which allowed us to measure the enantiomeric excess (ee) up to > 99.5%. The E values were calculated using the equation, E = ln[1-c(1+eep)]/ln[1c(1-eep)], were c = ees/(ees + eep). 14 The results are described in Table 1. The data from Table 1 indicate that the transesterification of A-E catalyzed by BCL/[MOPMIM]-[PF6] proceeded with better enantioselectivity in toluene than by BCL (Table 1, entry 1-10). The best enantioselectivity (E = 1194) was ob-

Green methodologies in organic synthesis: Microwave assisted solvent- and catalyst-free synthesis of enaminones and their conversion into 1,3,5-trisubstituted benzenes as well as 3-aroyl-6-substituted pyridines

Enaminones were obtained in good yields via condensing methyl ketones with ( N , N -dimethylformamide dimethyl acetal) DMF-DMA under microwave irradiation in absence of solvent. These enaminones were readily converted into 1,3,5-trisubstituted benzenes. Reacting enaminones in presence of ammonium acetate has afforded pyridine derivatives.

Cycloaddition of Alkynes: Atom-Economic Protocols for Constructing Six-Membered Cycles

Recent advances on the synthesis of six-membered carbo- and heterocyclic compounds including functionalized benzenes, 1,3- cyclohexadienes, pyridines, pyridones, pyranones, coumarins and isocoumarins via the cycloaddition reaction of alkynes are reviewed. Special attention is paid to atom-economic controllable chemo- and regioselective reactions, which are currently extremely attractive methodologies in organic synthesis.

ChemInform Abstract: Organic Electrosynthesis: A Promising Green Methodology in Organic Chemistry

AbstractReview: 153 refs.

A versatile supported cobalt(ii) complex for heterogeneously catalysed processes: conventional vs. microwave irradiation protocols

A highly active and reusable Co(II) complex supported on SBA-15 has been employed as a versatile heterogeneous catalyst in a range of processes including the synthesis of 1,1-diacetates, the acetalisation of aldehydes and the selective oxidation of various alcohols. The results obtained by using conventional protocols have been compared to the use of microwave irradiation as an alternative reaction media. The highly active catalyst was successfully utilised in such heterogeneously catalysed processes, in which the improved rates of reactions (from hours to minutes), yields and even selectivities in some cases, demonstrated the usefulness of microwave-assisted protocols as alternative methodologies in organic synthesis. The reported catalyst is believed to be a potentially versatile option that can be extended to further catalytic systems.

Nickel-catalyzed cross coupling of non-activated alkyl halides: a mechanistic perspective

Cross coupling of non-activated alkyl halides is a potentially transformative methodology in organic synthesis. Herein we review the recent development of nickel-catalyzed coupling of non-activated alkyl halides. The current understanding of the mechanism of these coupling reactions is highlighted. As the mechanism is ligand-dependant, the perspective is organized according to the types of ligands employed in the catalysis.

ChemInform Abstract: Heterogeneous Catalytic Synthesis Using Microreactor Technology

AbstractReview: 100 refs.

ChemInform Abstract: Development of Novel Methodology in Organic Synthesis Using Cobalt(II) Catalyst

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Alternatives to Organoboron Reagents in Rhodium‐Catalyzed Conjugate Additions

The rhodium-catalyzed conjugate addition of organoboron reagents to alkene acceptors has emerged as an important methodology in organic synthesis. The process results in the formation of new carbon-carbon bonds, and in principle, can create new stereocenters at both the alpha and beta carbon atoms of the acceptor. Other organometallics are known to participate in the key transmetalation to rhodium and are becoming more established in stereoselective synthesis (notably arylzinc reagents). This Focus Review will describe recent developments in the use of alternative organometallic donors to organoboron reagents in rhodium-catalyzed conjugate addition reactions and their growing applications in synthesis.

Unravelling the olefin cross metathesis on solid support. Factors affecting the reaction outcome

Olefin cross metathesis on solid support under a variety of conditions is described. A comprehensive analysis considering diverse factors governing the reaction outcome gives a series of patterns for the application of this useful methodology in organic synthesis. If the intrasite reaction is not possible, homodimerization of the soluble olefin is crucial. When the homodimer is less reactive than its monomer, reaction outcome depends on the homodimerization rate, which, in turn, depends on the precatalyst used and the reaction conditions. If the site-site interaction is a feasible process, the cross metathesis product is obtained exclusively when the newly-formed double bond is resilient to further metathetic events. Taking into account these considerations, we have demonstrated that excellent results in terms of cross metathesis coupling can be obtained under the optimized conditions, and that microwave irradiation is also an interesting alternative for the development of a practical and energy-efficient cross metathesis on solid support.

Heterogeneous catalytic synthesis using microreactor technology

The application of heterogeneous catalysis in conjunction with microreactor technology can facilitate a cleaner and scalable flow methodology for organic synthesis. In this tutorial review we present recent advances in the design of supported catalysts for emerging synthetic applications within microreactor technology. Specifically, transition metal catalysts such as palladium, copper, ruthenium, and nickel are described on silica, monolithic, magnetic nanoparticles and polymer supports. These catalysts have been utilised to promote a range of reactions including Heck, Sonogashira, Suzuki, Kumada, olefin metathesis, hydrogenation and benzannulation reactions.

Organic electrosynthesis: a promising green methodology in organic chemistry

Over the last decade, organic electrosynthesis has become recognized as one of the methodologies that can fulfill several important criteria that are needed if society is to develop environmentally compatible processes. It can be used to replace toxic or dangerous oxidizing or reducing reagents, reduce energy consumption, and can be used for the in situ production of unstable and hazardous reagents. These are just a few of the most important attributes that render electrochemistry environmentally useful. In this review the main characteristics of electrochemistry as a promising green methodology for organic synthesis are described and exemplified. Herein we provide basic information concerning the nature of electrosynthetic processes, paired electrochemical reactions, electrocatalytic reactions, reactions carried out in ionic liquids, electrogeneration of reactants, electrochemical reactions that use renewable starting materials (biomass), green organic electrosynthesis in micro- and nano-emulsions, the synthesis of complex molecules using an electrosynthetic key step, and conclude with some insights concerning the future. Throughout the review the “green aspects” of these topics are highlighted and their relationship with the twelve green chemistry principles is described.

Kinetic Resolution of 2,3-Dihydro-2-substituted 4-Quinolones by Palladium-Catalyzed Asymmetric Allylic Alkylation

The kinetic resolution of a carbon nucleophile is realized for the first time via Pd-catalyzed asymmetric allylic alkylation with "unstabilized" ketone enolates as the nucleophile, providing both allylated 2,3-disubstituted 2,3-dihydro-4-quinolones and recovered substrates in high yields and high ee (S-factor is 40-145). The application of the methodology in organic synthesis is demonstrated by the ready transformation of an allylated adduct into pyrrolo[3,2-c]quinoline, which features a core structure of biologically active Martinella alkaloids.

Highly Selective Synthetic Reactions by the Combined Use of Organometallic Reagents and Radical Species

Abstract During these thirty years, we have pursued new methodologies in organic synthesis and developed many synthetically useful reactions. Among them, four topics are described in this article. (1) Regio- and stereoselective silylmetalation of acetylenes has been examined. Whereas platinum- or copper-catalyzed silylmagnesation of terminal acetylenes afforded (E)-1-silyl-1-alkene exclusively, palladium-catalyzed silylalumination with PhMe2Si-AlEt2 provided 2-silyl-1-alkenes with high regioselectivity. (2) Triethylborane induced radical addition of Ph3SnH to acetylenes gave 1-triphenylstannyl-1-alkenes in the presence of small amount of oxygen. The reaction has two distinguishing characteristics. One feature is that Et3B can initiate the radical reaction at low temperature, such as −78 °C. (3) The other distinctive feature of Et3B-induced radical reaction is that many solvents could be used for the reaction. Thus, water was chosen as a solvent, and Et3B-induced atom-transfer radical cyclization of iodo acetals and iodoacetates in water was examined. (4) Three types of organometallic ate complexes, R3MnMgBr, R3MgLi, and R3Co(L2)MgBr, were prepared and used for organic synthesis. Treatment of gem-dibromocyclopropane with trialkylmanganate provided alkylated cyclopropane after aqueous workup. Aryl and alkenyl halides could be converted into the corresponding magnesium reagents by the action of trialkylmagnesate via halogen–magnesium exchange. Finally, synthetic reactions catalyzed by cobalt complexes are described. Without suffering from β-elimination, cobalt complexes allow cross-coupling reactions of alkyl halides with Grignard reagents.

Onium Salt Supported Organic Synthesis in Water: Application to Ugi’s 4-Components Reaction

The utilization of the Onium Salt Supported Organic Synthesis methodology for Ugi's 4 components reaction in water is presented. An easy preparation of substrates followed by quantitative reactions led to peptidic moieties which are subsequently easily isolated in good yields and purities. Advantages of the OSSOS strategy including extreme simplification of purification and monitoring of the reaction are presented.

Photochemical Route to the Synthesis of Thiolane 1-Oxides

The preparation of thiolane 1-oxide 10 by photochemically mediated rearrangement of sulfoxide 9 in high yield is described. The efficient construction of quaternary carbon centers underscores the utility of this methodology in organic synthesis. Further manipulation of photoadduct 10 leads to the formation of diverse heterocyclic structures.