Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

A new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/Zn^II complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.     

Upgrading CO2 by Incorporation into Urethanes through Silver‐Catalyzed One‐Pot Stepwise Amidation Reaction

One‐pot two‐step stepwise reaction of terminal propargylic alcohols, carbon dioxide, and primary/secondary amines for the effective synthesis of various urethanes through robust silver‐catalysed C‐O/C‐N bond formation is reported. Catalytic activities were investigated by controlling catalyst loading, reaction pressure and time, and very high turnover number (turnover frequency) was obtained: 3350 (35 h⁻¹) with 0.01 mol% silver catalyst under 0.1 MPa, and up to 13360 (139 h⁻¹) with 0.005 mol% silver catalyst under 2.0 MPa at room temperature. The strategy was ingeniously regulated, and synchronously afforded a wide range of β‐oxopropylcarbamate and 1,3‐oxazolidin‐2‐one motifs in excellent yields and selectivity together with unprecedented high turnover number (TON) and turnover frequency (TOF) value.     

Functionalized Ionic Liquid Promoted Aza‐Michael Addition of Aromatic Amines

A functionalized ionic liquid, 3‐(N,N‐dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO₄]) has been used as catalyst for the aza‐Michael reactions of aromatic amines with α,β‐unsaturated compounds at room temperature to produce β‐amino compounds in good yields. The catalyst can be reused for several times without obvious loss of the catalytic activity.     

Byproduct‐Catalyzed Four‐Component Reactions of Aldehydes with Hexamethyldisilazane,Chloroformates, and Nucleophiles in Acetonitrile Leading to Protected Primary Amines, β‐Amino Esters,and β‐Amino Ketones

Multicomponent reactions are a very powerful tool for the construction of complex organic molecules by using readily available starting materials. While most of the multicomponent reactions discovered so far consist of three components, the reactions with four or more components remain sparse. We have successfully developed several four‐component reactions using a catalytic amount of water as a hydrolyzing agent to decompose byproduct chlorotrimethylsilane (TMSCl) to yield secondary byproduct HCl that serves as a catalyst. In the presence of 40 mol % of water, the four‐component reaction of aldehydes with hexamethyldisilazane (HMDS), chloroformates, and silylated nucleophiles proceeds smoothly at room temperature to give a range of protected primary amines in moderate to excellent yields. Importantly, a wide variety of protic carbon nucleophiles, such as β‐keto esters, β‐diketones, and ketones, have further been explored as suitable substrates for the synthesis of protected β‐amino esters and β‐amino ketones that are useful building blocks for various pharmaceuticals and natural products. These four‐component reactions proceed through a pathway of tandem nitrogen protection/imine formation/imine addition, and the decomposition of byproduct TMSCl, generated in the first step of nitrogen protection, with water results in the formation of secondary byproduct HCl, a strong Brønsted acid that catalyzes the following imine formation/imine addition. Taking advantage of the fact that alcohols or phenols are also able to decompose byproduct TMSCl to yield secondary byproduct HCl, no catalyst is needed at all for the four‐component reactions with aldehydes bearing hydroxy groups.     

Chemoselective hydrogenation of nitriles to primary amines catalyzed by water‐soluble transition metal catalysts

The water‐soluble rhodium complex generated in situ from [Rh (COD)Cl]₂ in aqueous ammonia has been revealed as a highly efficient catalyst for the hydrogenation of aromatic nitriles, to primary amines with excellent yields. The catalyst is also highly selective towards primary amines in the case of sterically hindered aliphatic nitriles. The catalytic system can also be recycled and re‐used with no significant loss of activity.     

Chemical Kinetic Resolution of Unprotected β‐Substituted β‐Amino Acids Using Recyclable Chiral Ligands

The first chemical method for resolution of N,C‐unprotected β‐amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target β‐substituted‐β‐amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including β‐aryl, β‐heteroaryl, and β‐alkyl‐derived β‐amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti‐diabetic drug sitagliptin.     

Chromium‐Catalyzed Alkylation of Amines by Alcohols

The alkylation of amines by alcohols is a broadly applicable, sustainable, and selective method for the synthesis of alkyl amines, which are important bulk and fine chemicals, pharmaceuticals, and agrochemicals. We show that Cr complexes can catalyze this C?N bond formation reaction. We synthesized and isolated 35 examples of alkylated amines, including 13 previously undisclosed products, and the use of amino alcohols as alkylating agents was demonstrated. The catalyst tolerates numerous functional groups, including hydrogenation‐sensitive examples. Compared to many other alcohol‐based amine alkylation methods, where a stoichiometric amount of base is required, our Cr‐based catalyst system gives yields higher than 90 % for various alkyl amines with a catalytic amount of base. Our study indicates that Cr complexes can catalyze borrowing hydrogen or hydrogen autotransfer reactions and could thus be an alternative to Fe, Co, and Mn, or noble metals in (de)hydrogenation catalysis.     

An Eficient One‐Pot Synthesis of 1,4‐Dihydropyridines Catalyzed by Magnetic Nanocrystalline Fe3O4

An efficient approach for one‐pot three‐component reaction of aromatic amines, α,β‐unsaturated aldehydes and β‐keto esters using magnetic nanocrystalline Fe₃O₄ as a catalyst has been described. The corresponding 1,4‐dihydropyridines are obtained in good yields under mild conditions. In addition, the catalyst can be recovered with a magnet and reused at least five consecutive cycles without appreciable loss of its catalytic activity.     

Development of a General Non‐Noble Metal Catalyst for the Benign Amination of Alcohols with Amines and Ammonia

The N‐alkylation of amines or ammonia with alcohols is a valuable route for the synthesis of N‐alkyl amines. However, as a potentially clean and economic choice for N‐alkyl amine synthesis, non‐noble metal catalysts with high activity and good selectivity are rarely reported. Normally, they are severely limited due to low activity and poor generality. Herein, a simple NiCuFeO_x catalyst was designed and prepared for the N‐alkylation of ammonia or amines with alcohol or primary amines. N‐alkyl amines with various structures were successfully synthesized in moderate to excellent yields in the absence of organic ligands and bases. Typically, primary amines could be efficiently transformed into secondary amines and N‐heterocyclic compounds, and secondary amines could be N‐alkylated to synthesize tertiary amines. Note that primary and secondary amines could be produced through a one‐pot reaction of ammonia and alcohols. In addition to excellent catalytic performance, the catalyst itself possesses outstanding superiority, that is, it is air and moisture stable. Moreover, the magnetic property of this catalyst makes it easily separable from the reaction mixture and it could be recovered and reused for several runs without obvious deactivation.     

A versatile Ru catalyst for the asymmetric transfer hydrogenation of both aromatic and aliphatic sulfinylimines

A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alcohol ligand (2‐amino‐2‐methylpropan‐1‐ol) has been developed for the asymmetric transfer hydrogenation (ATH) of chiral N‐(tert‐butylsulfinyl)imines. This complex is able to catalyze the ATH of both aromatic and the most challenging aliphatic sulfinylimines by using isopropyl alcohol as the hydrogen source. The diastereoselective reduction of aromatic, heteroaromatic, and aliphatic sulfinylketimines, including sterically congested cases, over short reaction times (1–4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99 %) α‐branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)‐ and (S)‐amines by using the appropriate absolute configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen‐transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized.     

Synthesis and Characterization of Silica@Copper Core–Shell Nanoparticles: Application for Conjugate Addition Reactions

Silica@copper (SiO₂@Cu) core–shell nanoparticles were synthesized and well characterized by XRD, TEM, AFM, XPS, UV/Vis, TGA–MS, and ICP–AES techniques. The synthesized SiO₂@Cu core–shell nanoparticles were employed as catalysts for the conjugate addition of amines to α,β‐unsaturated compounds in water to obtain β‐amino carbonyl compounds in excellent yields in shorter reaction times. Furthermore, the catalyst works well for hetero‐Michael addition reactions of heteroatom nucleophiles such as thiols to α,β‐unsaturated compounds. As the reaction is performed in water, it allows for easy recycling of the catalyst with consistent activity.     

Amide Synthesis from Alcohols and Amines Catalyzed by Ruthenium N‐Heterocyclic Carbene Complexes

The direct synthesis of amides from alcohols and amines is described with the simultaneous liberation of dihydrogen. The reaction does not require any stoichiometric additives or hydrogen acceptors and is catalyzed by ruthenium N‐heterocyclic carbene complexes. Three different catalyst systems are presented that all employ 1,3‐diisopropylimidazol‐2‐ylidene (IiPr) as the carbene ligand. In addition, potassium tert‐butoxide and a tricycloalkylphosphine are required for the amidation to proceed. In the first system, the active catalyst is generated in situ from [RuCl₂(cod)] (cod=1,5‐cyclooctadiene), 1,3‐diisopropylimidazolium chloride, tricyclopentylphosphonium tetrafluoroborate, and base. The second system uses the complex [RuCl₂(IiPr)(p‐cymene)] together with tricyclohexylphosphine and base, whereas the third system employs the Hoveyda–Grubbs 1st‐generation metathesis catalyst together with 1,3‐diisopropylimidazolium chloride and base. A range of different primary alcohols and amines have been coupled in the presence of the three catalyst systems to afford the corresponding amides in moderate to excellent yields. The best results are obtained with sterically unhindered alcohols and amines. The three catalyst systems do not show any significant differences in reactivity, which indicates that the same catalytically active species is operating. The reaction is believed to proceed by initial dehydrogenation of the primary alcohol to the aldehyde that stays coordinated to ruthenium and is not released into the reaction mixture. Addition of the amine forms the hemiaminal that undergoes dehydrogenation to the amide. A catalytic cycle is proposed with the {(IiPr)Ru^II} species as the catalytically active components.     

Efficient Synthesis of β‐Amino Alcohols Catalyzed by Niobium Pentachloride: Regioselective Ring Opening of Epoxides with Aromatic Amines

Epoxides undergo a rapid ring‐opening reaction with aromatic amines catalyzed by niobium pentachloride under mild reaction conditions. All the reactions were carried out at room temperature to afford the corresponding β‐amino alcohols in excellent yields and with high regioselectivity.     

Sulfamic Acid as a Cost‐Effective and Recyclable Catalyst for β‐Amino Carbonyl Compounds Synthesis

Sulfamic acid was used as a catalyst in the synthesis of β‐amino carbonyl compounds from amines, acetophenone and aldehyde. The reaction was carried out at room temperature. High selectivity, mild reaction temperature, cost‐effective catalyst, simple product separation and catalyst recycle were notable achievements in the reaction. Another feature was that the reaction could be performed on a relatively larger scale to the model reaction (50 times), which also gave good yields. In particular, the first preparation of β, β'‐diamino diketone derivatives via the direct coupling of amines, acetophenone and isophthalic aldehyde promoted by sulfamic acid has been developed.     

Radical Arylation of Phenols,Phenyl Ethers,and Furans

Radical arylations of para‐substituted phenols and phenyl ethers proceeded with good regioselectivity at the ortho position with respect to the hydroxy or alkoxy group. The reactions were conducted with arenediazonium salts as the aryl radical source, titanium(III) chloride as the reductant, and diluted hydrochloric acid as the solvent. Substituted biaryls were obtained from hydroxy‐ and alkoxy‐substituted benzylamines, phenethylamines, and aromatic amino acids. The methodology described offers a fast, efficient, and cost‐effective new access to diversely functionalized biphenyl alcohols and ethers. Free phenolic hydroxy groups, aromatic and aliphatic amines, as well as amino acid substructures, are well tolerated. Two examples for the applicability of the methodology are the partial synthesis of a β‐secretase inhibitor and the synthesis of a calcium‐channel modulator.     

Rice husk: Introduction of a green,cheap and reusable catalyst for the protection of alcohols,phenols, amines and thiols

A mild, efficient and eco-friendly protocol for the chemoselective protection of benzylic and primary and less hindered secondary aliphatic alcohols and phenols as trimethylsilyl ethers and different types of amines as N-tert-butylcarbamates is developed using rice husk (RiH) as the catalyst. This reagent is also able to catalyze the acetylation of alcohols, phenols, thiols and amines with acetic anhydride. Easy work-up, relatively short reaction times, excellent yields and low cost, availability and reusability of the catalyst are the striking features of this methodology, which can be considered to be one of the best and general methods for the protection of alcohols, phenols, thiols and amines. In addition, the use of a green reagent in the above-mentioned reactions results in a reduction of environmental pollution and of the cost of the applied methods.     

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

A new catalytic system has been developed for the asymmetric hydrogenation of β‐secondary‐amino ketones using a highly efficient P‐chiral bisphosphine–rhodium complex in combination with ZnCl₂ as the activator of the catalyst. The chiral γ‐secondary‐amino alcohols were obtained in 90–94 % yields, 90–99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl₂ on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)‐duloxetine, (R)‐fluoxetine, and (R)‐atomoxetine, in high yields and with excellent enantioselectivities.     

Nickel‐Catalyzed Asymmetric Hydrogenation of 2‐Amidoacrylates

Earth‐abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2‐amidoacrylates, affording the chiral α‐amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α‐amino acids, β‐amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium‐labeling experiments and computational calculations.     

O‐Alkylation of Pyridine Aldo‐ and Ketoximes with Dihalohydrins under Phase‐Transfer Conditions

Phase‐transfer‐catalyzed alkylation of (E)‐pyridine aldo‐ and (E)‐ketoximes with dihalohydrins in the benzene (or DMSO)/10% aq. NaOH system in the presence of tetradecylammonium bromide proceeds regiospecifically to afford the corresponding O‐halohydrins in good yields. In this study, first O‐halohydrin derivatives were converted into glycidyl ether derivatives, and then a new series of amino alcohols were synthesized by the condensation of amines with these glycidyl ethers.     

Highly efficient iron‐catalyzed allylation of aromatic aldehydes with allyltriethoxysilane: one‐pot and practical synthesis of homoallyl ethers

FeCl₃ was found to be an active catalyst for the one‐pot allylation reaction of aromatic aldehydes with allyltriethoxysilane under mild and simple conditions, which resulted in the direct synthesis of homoallyl ethers with very high chemoselectivity and yields. Various types of homoallyl ethers were obtained in excellent yields (up to 99%). Copyright © 2008 John Wiley & Sons, Ltd.