Chelation Control Research Articles

Insights into the Two-Electron Reductive Process of [FeFe]H2 ase Biomimetics: Cyclic Voltammetry and DFT Investigation on Chelate Control of Redox Properties of [Fe2 (CO)4 (κ2 -Chelate)(μ-Dithiolate)

The electrochemical reduction of complexes [Fe2 (CO)4 (κ2 -phen)(μ-xdt)] (phen=1,10-phenanthroline; xdt=pdt (1), adtiPr (2)) in MeCN-[Bu4 N][PF6 ] 0.2 m is described as a two-reduction process. DFT calculations show that 1 and its monoreduced form 1- display metal- and phenanthroline-centered frontier orbitals (LUMO and SOMO) indicating the non-innocence of the phenanthroline ligand. Two energetically close geometries were found for the doubly reduced species suggesting an intriguing influence of the phenanthroline ligand leading to the cleavage of a Fe-S bond as proposed generally for this type of complex or retaining the electron density and avoiding Fe-S cleavage. Extension of calculations to other complexes with edt, adtiPr bridge and even virtual species [Fe2 (CO)4 (κ2 -phen)(μ-adtR )] (R=CH(CF3 )2 , H) or [Fe2 (CO)4 (κ2 -phen)(μ-pdtR )] (R=CH(CF3 )2 , iPr) showed that the relative stability between both two-electron-reduced isomers depends on the nature of the bridge and the possibility to establish a remote anagostic interaction between the iron center {Fe(CO)3 } and the group carried by the bridged-head atom of the dithiolate group.

Internal Chelation within Functionalized Organoindium Reagents: Prospects for Regio- and Stereocontrol in the Allylation, Propargylation and Allenylation of Carbonyl Compounds

The low basicity, selective nucleophilicity, and mildness of organoindium compounds allow for the incorporation of many important yet sensitive functional groups into their structure, including examples capable of intramolecularly chelating the indium center within these reagents. The specific nature of such chelated organoindiums causes the reactions involving them to proceed in a unique manner, often with regio- and stereoselectivity inaccessible with simple organometallic reagents. This review covers the rare examples of regio- and stereoselective allylation, propargylation, and allenylation of carbonyl compounds with chelated organoindiums, including brief descriptions of the applications of the resulting adducts in the asymmetric synthesis of natural products and synthetic targets of biological and medicinal interest.1 Introduction2 Internal Chelation Control in the Allylation Processes2.1 Allylindiums with a Chelating Center at the γ-Position2.2 Allylindiums with a chelating Center at the δ-Position2.3 Allylindiums with a Chelating Center at ε- and ζ-Positions2.4 Allylindiums with a Chelating Center at γ′- and δ′-Positions3 Internal Chelation Control in Propargylation and Allenylation Processes­3.1 Additions of Chelated Allenylindiums3.2 Additions of Chelated Propargylindiums4 Conclusion

Stereodivergence in the Ireland-Claisen Rearrangement of α-Alkoxy Esters.

A systematic investigation into the Ireland-Claisen rearrangement of α-alkoxy esters is reported. In all cases, the use of KN(SiMe3)2 in toluene gave rearrangement products corresponding to a Z-enolate intermediate with excellent diastereoselectivity, presumably because of chelation control. On the other hand, chelation-controlled enolate formation could be overcome for most substrates through the use of lithium diisopropylamide (LDA) in tetrahydrofuran (THF).

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds.

The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR3 moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and -trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation-control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral α- and β-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation-controlled additions. α-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to α-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C═C bonds can play the role of chelating groups in additions to β,γ-unsaturated ketones. The results outlined in this Account redefine the commonly held idea that chiral silyloxy- and halo-substituted carbonyl compounds only give Felkin addition products. The key to achieving chelation control in these reactions is the use of weakly coordinating solvents (dichloromethane and toluene) that do not readily bind to the zinc Lewis acids RZnX.

ChemInform Abstract: Ligand‐Assisted Palladium(II)/(IV) Oxidation for sp3 C—H Fluorination.

AbstractThe palladium‐catalyzed fluorination of 3‐phenyl‐N‐(quinolin‐8‐yl)propanamide (I) proceeds readily in the presence of quinoxaline as a ligand.

Ligand‐Assisted Palladium(II)/(IV) Oxidation for sp3 CH Fluorination

AbstractThe direct functionalization of inert sp3 CH bonds is limited to a few bond types. Although the activation of sp3 CH bonds can be accomplished under mild conditions using palladium catalysts, the subsequent functionalization is not trivial due to the high energy required to convert palladium(II) to palladium(IV). We have systematically studied the palladium oxidation using computation‐guided experiments for reactions involving strong chelation control. We find that a mild external ligand could significantly accelerate the oxidation of palladium(II) to palladium(IV) for strong bidentate directing groups. The acceleration is believed to be a result of ligand stabilization of both the palladium(II) and palladium(IV) intermediates.magnified image

Sustainable Electrochemistry: From Lignin Processing to Paired Electrolysis Reactions

When evaluating the sustainability of an electrochemical synthesis, the source and efficient use of electricity, the generation of waste byproducts, and the source of chemicals used should be considered in the development of a greener process. Constant current electrochemical oxidation reactions increase functionality of a molecule but are limited in scope based on oxidation potential. This shortcoming disappears when using a chemical oxidant, which can select based on steric hindrance, chirality, chelation control, and other factors. However, a major pitfall of any stoichiometric chemical oxidation reaction is the generation of a stoichiometric reduction byproduct, oftentimes a metal waste product. To circumvent this problem, chemical oxidants can be recycled directly at the anode while generating only H­2 gas at the cathode and can be powered by a simple photovoltaic power supply.1,2 From a green chemistry standpoint, the substrates used in anodic oxidations should have their origins from renewable feedstocks. Lignin, a biopolymer found in wood, has been disassembled into small monomers and converted into substrates for synthesis of heterocyles and quinones.3 Ideally, to maximize efficiency of these and other electrochemical processes, one wants to perform a useful oxidation at the anode simultaneously with a useful reduction at the cathode. Using this idea of a paired electrolysis, electrochemical oxidation of lignin-derived substrates has been coupled with CO2 reduction. In this presentation, the recycling of a variety of chemical oxidants at an electrode using simple photovoltaics as the source of electricity will be discussed. Furthermore, breakdown of lignocellulosic biomass into chemical building blocks for use in paired electrolyses will be explored (Figure 1).

A useful methoxyvinyl cation equivalent: α-t-butyldimethylsilyl-α-methoxyacetaldehyde

Described are the synthesis and application of α-t-butyldimethylsilyl-α-methoxyacetaldehyde as a formal methoxyvinyl cation equivalent. Addition of Grignard reagents to the title aldehyde, followed by treatment of the intermediate β-hydroxysilanes with KH, gives good yields of largely Z-methoxyvinylated products. Assuming a Peterson-like elimination mechanism, one can infer that the Grignard addition proceeds with high syn selectivity. These results are consistent with a chelation control model involving coordination to the α-methoxy group in the title aldehyde rather than an alternative stereoelectronic Felkin–Anh-type model. It must be noted that a steric Felkin–Anh model also accounts for the observed stereochemistry. All told, the title reagent can be employed to efficiently append a Z-configured methoxyvinyl group to an appropriate R–M species, in two steps.

ChemInform Abstract: Diastereoselection During 1,2‐Addition of 3‐Bromomethyl‐5H‐furan‐2‐one to α‐Chiral Aldehydes Mediated by Indium in Aqueous and Organic Solvent Systems: Direct Route to Obtain Optically Active α‐Methylene‐γ‐butyrolactones.

The stereochemical course of indium-promoted allylations to α-chiral aldehydes with 3-bromomethyl-5H-furan-2-one was investigated in anhydrous THF and pure H2O. High levels of 3,4-syn;4,5-syn diastereomers were produced with free hydroxyl derivatives whether in THF or pure H2O, reflecting the promising synthetic potential of this chemistry. This stereo-differentiation was attributed to the strong geometric bias exercised by our allylindium reagent and adherence to a chelation control transition-state alignment. Meanwhile, heightened levels of 3,4-anti;4,5-anti diastereomers were obtained with the rigid aldehydes 1h and 1i.

Magnesium-Coordinated Chelation Control in 1,3-Dipolar Cycloaddition of Chiral α-Alkoxymethyl Ether Nitrile Oxide: Application to the Synthesis of (–)/(–)-cis-Clausenamide

A facile regio- and diastereoselective nitrile oxide cycloaddition method using magnesium-coordinated chelation control of chiral α-alkoxymethyl ether nitrile oxide is reported. This reaction could be successfully applied as a key step in both the formal total synthesis of (–)-clausenamide and the total synthesis of (–)-<i>cis</i>-clausenamide.

ChemInform Abstract: C—H Activation by Amide Chelation Control: Ruthenium‐Catalyzed Direct Synthesis of 2‐Aryl‐3‐furanamides.

AbstractAn efficient base‐free one‐step method is presented for the synthesis of heterobiaryls through highly regioselective directed C—H activation/arylation reaction of furan amides with aryl boroneopentylates.

Stereocontrol in synthesis of homoallylic amines. Syn selective direct allylation of hydrazones with allylboronic acids.

Allylboronic acids directly react with acyl hydrazones, affording homoallylic amine derivatives. The reaction proceeds with very high syn selectivity, which is the opposite of the stereochemistry observed for allylboration of imines. The reaction can be carried out with both aromatic and aliphatic acyl hydrazones. Based on our studies the excellent syn stereochemistry can be explained by chelation control of the acyl hydrazone and the B(OH)(2) moiety.

ChemInform Abstract: 2‐Aminobenzaldehydes as Versatile Substrates for Rhodium‐Catalyzed Alkyne Hydroacylation: Application to Dihydroquinolone Synthesis.

Alkene and alkyne hydroacylation reactions are archetypal examples of simple addition processes that display excellent atom economy.1 Both reactions result in the formation of a new C–C bond and deliver synthetically useful carbonyl-containing products.2 In recent years, there has been considerable interest in converting these processes into synthetically useful transformations. Transition-metal-catalyzed variants represent the largest class of hydroacylation reactions, and amongst these, processes that involve some form of chelation control dominate. The need to employ a chelating substrate stems from the fact that the majority of the metal-catalyzed examples proceed through an inherently unstable acyl metal intermediate 1 (Scheme 1), which can lead to the formation of unwanted side products formed by decarbonylation. A limitation of the chelation-controlled strategy is that the coordinating group, which is present to stabilize the metal–acyl intermediate 2, will also be present in the product. If this group is not needed in the final product, then it must be removed or converted into an alternative functional group.3 Despite this limitation, the advantages of this chelation-controlled process, such as mild reaction conditions, control of enantio- and regioselectivity,4, 5 and broad substrate scope, have resulted in widespread applications of this approach. One strategy to overcome the innate limitation of a chelation-controlled approach is to develop catalytic methods that function without the need for such coordinating groups; although there are notable examples of success with this approach,2c, 6 significant limitations with regard to substrate scope and enantio- and regioselectivity remain. An alternative strategy is to consider the need for a chelating unit as an opportunity, and to expand the range of effective coordinating groups, so that a large variety of useful functional groups can act as the crucial chelating motif. As synthetic chemistry is generally concerned with the preparation of functionalized molecules, an approach that is tolerant of, or indeed benefits from, as many useful functional groups as possible should find wide application. Herein, we demonstrate that simple and readily available 2-aminobenzaldehydes are excellent substrates for intermolecular Rh-catalyzed alkyne hydroacylation, and in doing so add to the motifs available for use in these valuable processes. Furthermore, the products of these reactions, amino-substituted enones, were directly converted into a series of useful dihydroquinolone heterocycles.

ChemInform Abstract: The Chelation‐Controlled Mukaiyama Aldol Reaction of Chiral α‐ and β‐Alkoxy Aldehydes

AbstractReview: [49 refs.

CH Activation by Amide Chelation Control: Ruthenium‐ Catalyzed Direct Synthesis of 2‐Aryl‐3‐furanamides

AbstractA new, catalytic methodology for the synthesis of heterobiaryls by the ruthenium‐catalyzed CH activation/cross‐coupling of heterocyclic amides with aryl boroneopentylates is surveyed. From this survey, the highly regioselective reaction of furan‐3‐carboxamide to give 2‐aryl‐3‐furanamides is optimized and generalized in scope with respect to the aryl boroneopentylate coupling partners. Established thereby is a one‐step synthetic method which may supercede the broadly applied two‐step directed ortho metalation (DoM)–cross coupling reaction involving cryogenic and strong base conditions and which has potential for further ortho and remote metalation chemistry.magnified image

Diastereoselection during 1,2-addition of 3-bromomethyl-5H-furan-2-one to α-chiral aldehydes mediated by indium in aqueous and organic solvent systems: direct route to obtain optically active α-methylene-γ-butyrolactones

High chelation control or Felkin–Ahn selective allylic addition of2to α-hydroxyaldehydes or α-rigid aldehydes mediated by indium.

2‐Aminobenzaldehydes as Versatile Substrates for Rhodium‐Catalyzed Alkyne Hydroacylation: Application to Dihydroquinolone Synthesis

2‐Aminobenzaldehydes as Versatile Substrates for Rhodium‐Catalyzed Alkyne Hydroacylation: Application to Dihydroquinolone Synthesis

The Chelation-controlled Mukaiyama Aldol Reaction of Chiral α- and β-Alkoxy Aldehydes

Abstract The concept of treating chiral α- and β-alkoxy aldehydes with bicoordinate Lewis acids such as TiCl4, SnCl4, or MgBr2 followed by the addition of carbon nucleophiles for achieving chelation control with 1,2- and 1,3-asymmetric induction, respectively, was introduced three decades ago and has since evolved into a general method. In the case of enol silanes, the chelation-controlled Mukaiyama aldol reaction is involved, which has been used in recent natural products syntheses.

Chelation-Controlled Addition of Organozincs to α-Chloro Aldimines

Nucleophilic additions to α-chiral α-halo carbonyl derivatives are well-known to generate Cornforth-Evans products via a nonchelation pathway. What was unprecedented before this report is C-X bonds reversing the diastereoselectivity through coordination to metals during C-C bond-forming reactions (chelation control). Herein we describe chelation control involving C-X bonds in highly diastereoselective additions of organozinc reagents to a variety of α-chloro aldimines. The unique ability of alkylzinc halide Lewis acids to coordinate to the Cl, N, and O of α-chloro sulfonyl imine substrates is supported by computational studies.

Rhodium catalyzed chelation-assisted C-H bond functionalization reactions.

Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a paradigm shift in chemical synthesis, and today synthetic chemists can readily access carbon-carbon and carbon-heteroatom bonds from a vast array of starting compounds. Although we cannot understate the importance of these methods, the required prefunctionalization to carry out these reactions adds cost and reduces the availability of the starting reagents. The use of C-H bond activation in lieu of prefunctionalization has presented a tantalizing alternative to classical cross-coupling reactions. Researchers have met the challenges of selectivity and reactivity associated with the development of C-H bond functionalization reactions with an explosion of creative advances in substrate and catalyst design. Literature reports on selectivity based on steric effects, acidity, and electronic and directing group effects are now numerous. Our group has developed an array of C-H bond functionalization reactions that take advantage of a chelating directing group, and this Account surveys our progress in this area. The use of chelation control in C-H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. The predictability and decreased dependence on the inherent stereoelectronics of the substrate generally result in selective and high yielding transformations with broad applicability. The nature of the chelating moiety can be chosen to serve as a functional handle in subsequent elaborations. Our work began with the use of Rh(I) catalysts in intramolecular aromatic C-H annulations, which we further developed to include enantioselective transformations. The application of this chemistry to the simple olefinic C-H bonds found in α,β-unsaturated imines allowed access to highly substituted olefins, pyridines, and piperidines. We observed complementary reactivity with Rh(III) catalysts and developed an oxidative coupling with unactivated alkenes. Further studies on the Rh(III) catalysts led us to develop methods for the coupling of C-H bonds to polarized π bonds such as those in imines and isocyanates. In several cases the methods that we have developed for chelation-controlled C-H bond functionalization have been applied to the total synthesis of complex molecules such as natural products, highlighting the utility of these methods in organic synthesis.