Indium-mediated Allylation Research Articles

Dichotomous Selectivity in Indium-Mediated Aza-Barbier-Type Allylation of 2-N-Acetyl Glycosyl Sulfinylimines in Brine: Convenient Access to Potent Anti-Influenza Agents.

A highly diastereoselective indium-mediated allylation of 2-N-acetyl glycosyl sulfinylimines in brine under mild reaction conditions is reported. The method allows the achievement of a highly remarkable dichotomous selectivity for substrates, providing a single diastereoisomer of the product in 80-98% yield. With chiral (S)-homoallylic sulfinamide (RS)-5 and (RS)-8 formed as key intermediates, two potent anti-influenza agents, zanamivir and zanaphosphor, were synthesized in 50% and 41% overall yields, respectively.

Solvent Effects on Heterogeneous Rate Constants for Indium Mediated Allylations

Indium mediated allylation is a highly selective tool for synthetic chemists to create carbon-carbon bonds, but the first step, heterogeneous reaction of allyl halides at solid indium surfaces, is still poorly understood. For example, the nature of the solvent dramatically affects the rate of reaction, but solvent choice is often based on empirical experiments. Fundamental kinetic studies are the best way to study this effect, but the determination of heterogeneous rate constants is challenging. In an effort to better understand solvent effects, we use optical microscopy to determine heterogeneous rate constants for IMA in aqueous acetonitrile, methanol, ethanol, and 2-propanol. We fit the reaction rate data over a range of mass transport rates using only two adjustable parameters, the heterogeneous rate constant and the mass transport rate. The results emphasize the critical importance of water in determining the rate of reaction. Surprisingly, the polarity of the organic solvent in the mix does not have a major effect on the rate. It is hypothesized that the oxygen atom in water and alcohols is an especially effective Lewis base to stabilize the transition state and the organoindium intermediates, similar to the importance of the oxygen in ethers for the formation of Grignard reagents. This study again demonstrates the power of microscopy for the study of heterogeneous reactions.

Indium-mediated allylation of disaccharides

The indium-mediated allylation followed by ozonolysis has been applied for the elongation of different disaccharides such as cellobiose, lactose and maltose. This reaction sequence and per-O-acetylation produced the expected mixture of α/β-pyranoid as well as α/β-furanoid isomers. The main product in all cases adopted the β-pyranose form and could be isolated and fully characterized with the help of NMR-spin simulations. Thorough investigation of the side products throughout optimization of the conditions for the ozonolysis resulted in the discovery of a novel 12 membered bridged disaccharide.

Indium-mediated C-allylation of melibiose.

The indium-mediated allylation reaction has been applied to melibiose, a disaccharidic substrate. This elongation methodology allows for a short, efficient and diastereoselective approach towards complex glycosylated carbohydrate structures. The stereochemical outcome of the key intermediates, allylated disaccharides, has been determined by X-ray analysis. Ozonolysis of the introduced double bond yielded the unprotected elongated disaccharides in the equilibrium of the pyranoid as well as furanoid isomers in both anomeric forms, respectively. Per-O-acetylation has been performed to facilitate separation of the isomeric mixture for structural identification. The main product revealed to adopt a β-pyranoid form of the elongated unit at the reducing end of the disaccharide.

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

We utilized the indium-mediated allylation reaction for the synthesis of carbohydrate structures containing the 3-deoxy-2-ulose motif, a barely investigated compound class. The stereoselective outcome can be controlled by the presence or absence of a chelating group in α-position to the carbonyl function. By introduction of an UV-active allyl building block, we enabled epimer separation by HPLC towards the synthesis of 3-deoxy-d-glycero-d-galacto-2-nonulose, the carboxyl-reduced analogue of widely distributed 3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn). Ozonolysis of the introduced 2-C-methylidenepropan-1-ol motif provided the desired 3-deoxy-2-uloses.Graphical abstract

A versatile de novo synthesis of legionaminic acid and 4-epi-legionaminic acid starting from d-serine

Legionaminic acid and 4-epi-legionaminic acid are 5,7-diacetamido nonulosonic acids and are assumed to play a crucial role in the virulence of Legionella pneumophila, the causative agent of Legionnaires’ disease. Moreover, they are ideal target motifs for the development of vaccines and pathogen detection. Herein, we present a versatile de novo synthesis of legionaminic acid and 4-epi-legionaminic acid. Starting from simple d-serine, the C9-backbone is built up by two CC-bond formation reactions. First, the protected d-serine motif is elongated utilizing a highly stereoselective nitroaldol reaction to give a C6-precursor of desired d-rhamno configuration. Second, an indium-mediated allylation is employed to further elongate the carbon backbone and introduce a masked α-keto acid function.

Allylation of isatin-derived N-Boc-hydrazones followed by Pd-catalyzed carboamination reaction: an entry to 3-spiro-pyrazolidyl-oxindoles.

The indium-mediated allylation of novel 3-(2-Boc-hydrazono)indolin-2-one derivatives, followed by a palladium-catalysed carboamination reaction, is described to afford unprecedented spirocyclic oxindoles in good yields. The method provides an efficient access to both cis and trans diastereoisomers of highly functionalized compounds, bearing an N-Boc, 5-substituted pyrazolidine ring at the C3-oxindole spiro junction. The versatility of the method is fully demonstrated starting from a series of substituted isatins and employing a variety of aryl halides in the key cyclization step.

Indium-Mediated Allylation of Carbonyl Compounds in Ionic Liquids: Effect of Salts in Ionic Liquids.

The In-mediated allylation of carbonyl compounds can be performed in various types of solvents including ionic liquids. However, we have found that in [bmim][BF4] (where bmim = 1-butyl-3-methylimidazolium), the In-mediated coupling of crotyl bromide with benzaldehyde gives a complex mixture, and some additives, such as halides and amines, are crucial for the successful conversion to the corresponding γ-adduct. Instead, the addition of alcohols or water promotes the formation of the α-adduct. An asymmetric induction with up to 62% enantiomeric excess (ee) was observed employing cinchonidine as an additive in a binary solvent consisting of an ionic liquid and dichloromethane.

A concise route to access C-glycosidic tetrazolyl analogues of Kdo as bioisosteres

Ulosonic acids are an important class of carbohydrates, including well-known representatives as 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo), 3-deoxy-d-glycero-d-galacto-non-2-ulosonic acid (Kdn) and N-Acetylneuraminic acid (Neu5Ac). As part of the lipopolysaccharides (LPS) and capsular polysaccharides (CPS, K-antigen), these carbohydrates can be found on the surfaces of, both, Gram-positive and Gram-negative bacteria. We developed a synthetic approach to access tetrazole-derivatives of these compounds. Tetrazoles have shown to be ideal analogues for the bioisosteric replacement of carboxylic acids in several drugs, improving biological activity and pharmacokinetic properties. The presented route features indium-mediated allylation with subsequent [2 + 3]-cycloaddition as key steps, leading to tetrazole-derivative of Kdo and its corresponding C-4 epimer. The route is flexible enough to be adapted to the preparation of further tetrazole ulosonic acids.

ChemInform Abstract: Indium‐Mediated Stereoselective Allylation

AbstractReview: 55 refs.

Indium-Mediated Stereoselective Allylation

Stereoselective indium-mediated organic reactions have enjoyed tremendous growth in the last 25 years. This is in part due to the insensitivity of allylindium to moisture, affording facile and practical reaction conditions coupled with outstanding functional group tolerance and minimal side reactions. Despite the plethora of articles about allylindium, there is much yet to be discovered and exploited for efficient and sustainable synthesis. In this Account, we describe indium-mediated synthetic methods for the preparation of chiral amines with the aim to present a balance of practical method development, novel asymmetric chemistry, and mechanistic understanding that impact multiple chemical and materials science disciplines. In 2005, we demonstrated the indium-mediated allylation of chiral hydrazones with complete diastereoselectivity (>99:1) and quantitative yields. Further, we revealed the first example of enantioselective indium-mediated allylation of hydrazones using catalytic (R)-3,3'-bis(trifluoromethyl)-BINOL ligands to afford homoallylic amines with high enantioselectivity. The use of enantiopure perfluoroalkylsulfonate BINOLs greatly improved the indium-mediated allylation of N-acylhydrazones with exquisite enantiocontrol (99% yield, 99% ee). This laboratory has also investigated indium-mediated asymmetric intramolecular cyclization in the presence of amino acid additives to deliver biologically relevant chromanes with excellent diastereoselectivity (dr >99:1). The effect of amino acid additives (N-Boc-glycine) was further investigated during the indium-mediated allylation of isatins with allyl bromide to yield homoallylic alcohols in excellent yields in a short time with a wide range of functional group tolerance. Critical mechanistic insight was gained, and evidence suggests that the additive plays two roles: (1) to increase the rate of formation of allylindium from allyl bromide and In(0) and (2) to increase the nucleophilicity of the allylindium reagent, probably through disruption of aggregates and coordination to the metal. We recently reported the palladium-catalyzed umpolung allylation of hydrazones with allyl acetates in the presence of indium(I) iodide (InI) with excellent diastereoselectivity (up to 99:1). The conversion was found to be inversely proportional to the phosphine concentration, providing insight into the mechanism of the critical redox transmetalation process that has implications for other Pd-catalyzed umpolung-type allylation processes. A detailed overview of the work in our lab is presented with the intention of stimulating further research interest in organoindium chemistry and its application in organic synthesis.

Indium-mediated diastereoselective allylation of N-tert-butanesulfinyl imines derived from α-ketoesters

The indium-mediated allylation of α-aldimino and -ketimino esters 3 with allylic bromides proceeds with high diastereoselectivity to yield homoallylic α-amino ester derivatives 5, in both THF and water as solvents. The reactions are diastereospecific, the stereochemical outcome depending on the configuration of both the sulfur atom of the sulfinyl group and the CN double bond. Of particular interest are the reaction products using ethyl bromomethylacrylate as allylating reagent because amino diesters are obtained, which can be easily transformed into enantiomerically pure α-methylidene-γ-butyrolactams 6 with an alkoxycarbonyl group on the ring bearing the nitrogen atom.

ChemInform Abstract: Highly Diastereoselective Palladium‐Catalyzed Indium‐Mediated Allylation of Chiral Hydrazones.

The general and efficient palladium-catalyzed indium-mediated allylation of chiral hydrazones was accomplished with excellent yield (72-92%) and diastereoselectivity (up to 99:1). The development of this reaction and the substrate scope are described. The conversion was found to be proportional to the phosphine concentration, which provided insight into the mechanism and competing pathways of the redox transmetalation process.

N-Boc-glycine-assisted indium-mediated allylation reaction: a sustainable approach

An unprecedent improvement in the reaction rate (from hours to minutes) was observed during the In-mediated allylation of isatins with allyl bromide in the presence of N-Boc-glycine. The observed phenomena were generalized as a general protocol for the allylation of differently substituted isatins with excellent yields in a short time and with a wide range of functional group tolerance. Evidence suggests the unique role of the N-Boc-glycine additive was to increase the rate of formation and increase the nucleophilicity of the allylindium organometallic reagent.

Highly diastereoselective palladium-catalyzed indium-mediated allylation of chiral hydrazones.

The general and efficient palladium-catalyzed indium-mediated allylation of chiral hydrazones was accomplished with excellent yield (72-92%) and diastereoselectivity (up to 99:1). The development of this reaction and the substrate scope are described. The conversion was found to be proportional to the phosphine concentration, which provided insight into the mechanism and competing pathways of the redox transmetalation process.

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars.

Higher aminosugars are interesting targets in carbohydrate synthesis since these compounds play important roles in biological systems. However, their availability from natural sources is limited. Thus, in order to investigate their biological function, the development of facile and adaptable routes to this class of compounds is of fundamental importance. Our synthetic route towards these target molecules makes use of readily accessible pentoses and hexoses, which are subjected to indium-mediated two-carbon chain elongation. Subsequent ozonolysis and treatment with base yields α,β-unsaturated aldehydes, which are stereoselectively epoxidized using Jørgenson’s protocol. After Wittig chain elongation the obtained allylic epoxides were regio- and stereoselectively opened with trimethylsilyl azide under palladium catalysis. Finally, a suitable deprotection protocol, starting with acidic acetate cleavage and ozonolysis was established. Peracetylation of the products simplifies purification and subsequent azide reduction followed by final deacetylation using methanolic sodium methoxide furnishes the title compounds.

Retraction of "Indium-mediated catalytic enantioselective allylation of N-benzoylhydrazones using a protonated chiral amine".

A catalytic enantioselective indium-mediated allylation of N-benzoylhydrazones in conjunction with a protonated chiral amine affording enantioenriched homoallylic amines with an extremely high level of enantioselectivity and chemical yield was developed.

Direct carboxylation of allylic halides with carbon dioxide in the presence of indium

A highly regioselective indium-mediated allylation of carbon dioxide starting from simple allylic halides (X = I, Br, Cl) has been developed. No transition metal catalyst is needed and an inert atmosphere is not necessary. The reaction tolerates a wide range of synthetically attractive functional groups with a very high branched regioselectivity.

ChemInform Abstract: Formation of Homoallylic Bromohydrins in Indium‐Mediated Allylation Reactions of Phenacyl Bromides in Aqueous Solution.

Abstract A method is described for carrying out indium-mediated allylation reactions of phenacyl bromides in aqueous solution that form homoallylic bromohydrins. By employing subsequent base treatment, the homoallylic bromohydrins were converted to allylic epoxides. Finally, the process has been used as a key step in a concise sequence for the synthesis of 3-allylbenzofuran.

A One-Pot Asymmetric Synthesis of Homoallylic Amines via Indium-Mediated Allylation of Hydrazones

Homoallylic amines are an important structural element of natural products and valuable synthetic building blocks in organic syntheses. The nucleophilic addition of organometallic reagents to the C=N bond is a straightforward method for the synthesis of homoallylic amines. However, due to the low reactivity of imines toward nucleophiles, more reactive nucleophiles are required for the addition reaction. Thus, there are some drawbacks to such methods including aza-enolization and competitive formation of side products. Some organometallic reagents such as allylsilanes and allylboronates have been successfully employed for the formation of homoallylic amines. Employing allylindium reagents for the synthesis of homoallylic amines is attractive as indium reagents have low toxicity and low basicity and are stable to moisture and air. Recently, various methodologies for the enantioselective allylation of imines in the presence of chiral ligands have been developed. However, the synthesis of chiral ligands is frequently difficult and requires multi-step synthesis. Diastereoselective allylation of imines bearing a chiral auxiliary is a reliable and efficient method for the synthesis of optically pure homoallylic amines. Several chiral imines have been developed for indium-mediated allylations. Since Loh and co-workers’ report, chiral N-aliphatic imines, which are derived from amino acid derivatives such as (S)-valinol and (R)-phenylglycinol, have been used for diastereoselective allylations. Yus and co-workers developed a method for the synthesis of optically pure homoallylic amines via chiral Nsulfinyl imines. Chiral imines have also been widely employed. Among the chiral imine derivatives, chiral hydrazones are the choice of chiral auxiliary due to advantages that include ease of preparation, high reactivity, and high selectivity. Although (S)-1-amino-2-methoxymethylpyrrolidine and (S)-4-phenylmethyl-oxazolidin-2-one-derived hydrazones have been employed for indium-mediated diastereoselective allylations, these auxiliaries have some drawbacks such as the use of expensive and toxic reagents and multiple steps for their synthesis. Herein, we wish to report a one-pot stereoselective allylation of aldimines bearing an L-proline moiety to afford chiral homoallylic amine derivatives in a highly stereoselective manner. A one-pot asymmetric reaction that involves aldehydes, chiral hydrazides, and an allyindium species is attractive since the reaction is simple and easy to perform as well as being both eco-friendly and rapid. Benzaldehyde was chosen as a model substrate, and Zn(ClO4)2·6H2O was chosen as the catalyst since it is known to be an efficient promoter for the formation of hydrazones. We examined the one-pot allylation with benzaldehyde, a chiral L-proline-derived hydrazide, allyl bromide and indium in the presence of 1 mol % Zn(ClO4)2 in methanol at room temperature. The reaction proceeded smoothly and was complete in 2 h affording 87% of the allylated product with a 60:40 dr (Table 1, entry 1). The reaction rate was much faster than that of the reaction performed without a catalyst (15 h). This result suggests that Zn(ClO4)2·6H2O promotes the formation of hydrazone as well as assists in the allylation of the resulting hydrazone. The same reaction performed using allyl iodide instead of allyl bromide at room temperature gave an 85% chemical yield of the product with no stereoselectivity (entry 3). However, the reaction time was shortened. As the reaction temperature was lowered, the stereoselectivity increased. When performed at −20 C, the reaction was complete in 10 h with high diastereoselectivity (entry 5). Upon changing from methanol, a polar solvent, to nonpolar solvents such as toluene, dichloromethane, or chloroform, the reaction did not proceed at −20 C. With optimized reaction conditions in hand, we investigated the scope of the reaction with various aldehydes. The results are presented in Table 2. The reaction with aromatic aldehydes that were substituted with an electron-donating