Straightforward α-Amino Nitrile Synthesis Through Mo(CO)6 -Catalyzed Reductive Functionalization of Carboxamides.

The selective reduction of amides into an intermediate hemiaminal catalyzed by Mo(CO)6 together with the inexpensive and easy to handle TMDS (1,1,3,3-tetramethyldisiloxane) as reducing agent, followed by subsequent trapping of the hemiaminal with a cyanide source, allows for the straightforward synthesis of α-amino nitriles. The methodology presented here, displays high levels of chemoselectivity allowing for the reduction of amides in the presence of functional groups such as ketones, imines, aldehydes, and acids, which affords a simple route for the synthesis of α-amino nitriles with a broad scope of functionalities in high yields. Furthermore, the applicability of this methodology is demonstrated by scale up experiments and by derivatization of the target compounds into synthetically interesting products. The selective cyanation is successfully applied in late stage functionalizations of amide containing drugs and prolinol derivatives.

Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation.

The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η2-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.

Chemoselective reduction of carboxamides.

The reduction of amides gives access to a wide variety of important compounds such as amines, imines, enamines, nitriles, aldehydes and alcohols. The chemoselective transformation into these functional groups is challenging due to the intrinsic stability of the amide bond; nevertheless, the ability to reduce highly stable carboxamides selectively in the presence of sensitive functional groups is of high synthetic value for academic and industrial chemists. Hydride-based reagents such as LiAlH4 or diboranes are today the most commonly used compounds for amide reductions, and apart from the substantial amount of waste generated using these methods, they lack tolerance to most other functional groups. This tutorial review provides an overview of the recent progress made in the development of chemoselective protocols for amide reduction and gives an insight to their advantages and drawbacks.

Chemoselective Reduction of Tertiary Amides under Thermal Control: Formation of either Aldehydes or Amines.

The chemoselective reduction of amides in the presence of other more reactive reducible functional groups is a highly challenging transformation, and successful examples thereof are most valuable in synthetic organic chemistry. Only a limited number of systems have demonstrated the chemoselective reduction of amides over ketones. Until now, the aldehyde functionality has not been shown to be compatible in any catalytic reduction protocol. Described herein is a [Mo(CO)6 ]-catalyzed protocol with an unprecedented chemoselectivity and allows for the reduction of amides in the presence of aldehydes and imines. Furthermore, the system proved to be tunable by variation of the temperature, which enabled for either C-O or C-N bond cleavage that ultimately led to the isolation of both amines and aldehydes, respectively, in high chemical yields.

Highly efficient and chemoselective zinc-catalyzed hydrosilylation of esters under mild conditions.

A mild and highly efficient catalytic hydrosilylation protocol for room-temperature ester reductions has been developed using diethylzinc as the catalyst. The methodology is operationally simple, displays high functional group tolerance and provides for a facile access to a broad range of different alcohols in excellent yields.

Catalytic amide formation from non-activated carboxylic acids and amines.

The amide functionality is found in a wide variety of biological and synthetic structures such as proteins, polymers, pesticides and pharmaceuticals. Due to the fact that synthetic amides are still mainly produced by the aid of coupling reagents with poor atom-economy, the direct catalytic formation of amides from carboxylic acids and amines has become a field of emerging importance. A general, efficient and selective catalytic method for this transformation would meet well with the increasing demands for green chemistry procedures. This review covers catalytic and synthetically relevant methods for direct condensation of carboxylic acids and amines. A comprehensive overview of homogeneous and heterogeneous catalytic methods is presented, covering biocatalysts, Lewis acid catalysts based on boron and metals as well an assortment of other types of catalysts.

Mild deoxygenation of aromatic ketones and aldehydes over Pd/C using polymethylhydrosiloxane as the reducing agent.

Herein, a practical and mild method for the deoxygenation of a wide range of benzylic aldehydes and ketones is described, which utilizes heterogeneous Pd/C as the catalyst together with the green hydride source, polymethylhydrosiloxane. The developed catalytic protocol is scalable and robust, as exemplified by the deoxygenation of ethyl vanillin, which was performed on a 30 mmol scale in an open-to-air setup using only 0.085 mol % Pd/C catalyst to furnish the corresponding deoxygenated product in 93 % yield within 3 hours at room temperature. Furthermore, the Pd/C catalyst was shown to be recyclable up to 6 times without any observable decrease in efficiency and it exhibited low metal leaching under the reaction conditions.

Ruthenium-catalyzed tandem-isomerization/asymmetric transfer hydrogenation of allylic alcohols.

A one-pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem-isomerization/asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p-cymene)Cl2 }2 ] in combination with the α-amino acid hydroxyamide ligand 1, and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93 %.

Efficient palladium-catalyzed aminocarbonylation of aryl iodides using palladium nanoparticles dispersed on siliceous mesocellular foam.

A highly dispersed nanopalladium catalyst supported on mesocellular foam (MCF), was successfully used in the heterogeneous catalysis of aminocarbonylation reactions. During the preliminary evaluation of this catalyst it was discovered that the supported palladium nanoparticles exhibited a "release and catch" effect, meaning that a minor amount of the heterogeneous palladium became soluble and catalyzed the reaction, after which it re-deposited onto the support.

Asymmetric transfer hydrogenation of ketones catalyzed by rhodium complexes containing amino acid triazole ligands.

Active and selective catalysts for the asymmetric reduction of ketones, under transfer hydrogenation conditions, were obtained by combining [RhCl(2)Cp*](2), with a series of l-amino acid thioamide ligands functionalized with 1,2,3-triazoles. The obtained secondary alcohol products were formed with up to 93% ee.

Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core.

In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

Mechanistic investigations into the asymmetric transfer hydrogenation of ketones catalyzed by pseudo-dipeptide ruthenium complexes.

The combination of N-Boc-protected alpha-amino acid hydroxyamides (pseudo-dipeptides) and [{Ru(p-cymene)Cl(2)}(2)] resulted in the formation of superior catalysts for the asymmetric transfer hydrogenation (ATH) of non-activated aryl alkyl ketones in propan-2-ol. The overall kinetics of the ATH of acetophenone to form 1-phenylethanol in the presence of ruthenium pseudo-dipeptide catalysts were studied, and the individual rate constants for the processes were determined. Addition of lithium chloride to the reaction mixtures had a strong influence on the rates and selectivities of the processes. Kinetic isotope effects (KIEs) for the reduction were determined and the results clearly show that the hydride transfer is rate-determining, whereas no KIEs were detected for the proton transfer. From these observations a novel bimetallic outer-sphere-type mechanism for these ATH process is proposed, in which the bifunctional catalysts mediate the transfer of a hydride and an alkali metal ion between the hydrogen donor and the substrate. Furthermore, the use of a mixture of propan-2-ol and THF (1:1) proved to enhance the rates of the ATH reactions. A series of aryl alkyl ketones were reduced under these conditions in the presence of 0.5 mol % of catalyst, and the corresponding secondary alcohols were formed in high yields and with excellent enantioselectivities (>99% ee) in short reaction times.

Asymmetric transfer hydrogenation of ketones catalyzed by amino acid derived rhodium complexes: on the origin of enantioselectivity and enantioswitchability.

Amino acid based thioamides, hydroxamic acids, and hydrazides have been evaluated as ligands in the rhodium-catalyzed asymmetric transfer hydrogenation of ketones in 2-propanol. Catalysts containing thioamide ligands derived from L-valine were found to selectively generate the product with an R configuration (95 % ee), whereas the corresponding L-valine-based hydroxamic acids or hydrazides facilitated the formation of the (S)-alcohols (97 and 91 % ee, respectively). The catalytic reduction was examined by performing a structure-activity correlation investigation with differently functionalized or substituted ligands and the results obtained indicate that the major difference between the thioamide and hydroxamic acid based catalysts is the coordination mode of the ligands. Kinetic experiments were performed and the rate constants for the reduction reactions were determined by using rhodium-arene catalysts derived from amino acid thioamide and hydroxamic acid ligands. The data obtained show that the thioamide-based catalyst systems demonstrate a pseudo-first-order dependence on the substrate, whereas pseudo-zero-order dependence was observed for the hydroxamic acid containing catalysts. Furthermore, the kinetic experiments revealed that the rate-limiting steps of the two catalytic systems differ. From the data obtained in the structure-activity correlation investigation and along with the kinetic investigation it was concluded that the enantioswitchable nature of the catalysts studied originates from different ligand coordination, which affects the rate-limiting step of the catalytic reduction reaction.

Facile preparation of pyrimidinediones and thioacrylamides via reductive functionalization of amides.

The development of an efficient protocol for the reductive functionalization of amides into pyrimidinediones and amino-substituted thioacrylamides is presented. Enamines are generated in a highly chemoselective amide hydrosilylation reaction catalyzed by molybdenum hexacarbonyl in combination with 1,1,3,3-tetramethyldisiloxane. The direct addition of either isocyanate or isothiocyanate generates the corresponding pyrimidinediones and 3-aminothioacrylamides in high yields.

Mild Reductive Functionalization of Amides into N-Sulfonylformamidines.

The development of a protocol for the reductive functionalization of amides into N-sulfonylformamidines is reported. The one-pot procedure is based on a mild catalytic reduction of tertiary amides into the corresponding enamines by the use of Mo(CO)6 (molybdenum hexacarbonyl) and TMDS (1,1,3,3-tetramethyldisiloxane). The formed enamines were allowed to react with sulfonyl azides to give the target compounds in moderate to good yields.

Enantioswitchable catalysts for the asymmetric transfer hydrogenation of aryl alkyl ketones.

A subtle change in the ligand structure, replacing the carbonyl oxygen with sulfur in simple alpha-amino acid amides, resulted in a dramatic activity and selectivity improvement in the rhodium- or ruthenium-catalyzed reduction of ketones under hydrogen transfer conditions. In addition, in most cases, a switch of the product's absolute configuration was observed on going from amides to the corresponding thioamides. Under optimized conditions, we obtained the secondary alcohol products in high yield and enantioselectivity (up to 97% ee) using only 0.25 mol % catalyst loading. [structure: see text]

In situ formation of ligand and catalyst--application in ruthenium-catalyzed enantioselective reduction of ketones.

The direct in situ formation of highly efficient ruthenium-catalysts for the asymmetric reduction of ketones was obtained by combining chiral ligand building blocks with a ruthenium precursor.

Mild and selective Et2Zn-catalyzed reduction of tertiary amides under hydrosilylation conditions.

Diethylzinc (Et2Zn) can be used as an efficient and chemoselective catalyst for the reduction of tertiary amides under mild reaction conditions employing cost-effective polymeric silane (PMHS) as the hydride source. Crucial for the catalytic activity was the addition of a substoichiometric amount of lithium chloride to the reaction mixture. A series of amides containing different additional functional groups were reduced to their corresponding amines, and the products were isolated in good-to-excellent yields.

Metal-free N-arylation of secondary amides at room temperature.

The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties, and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.