Highly efficient and diastereoselective gold(I)-catalyzed synthesis of tertiary amines from secondary amines and alkynes: substrate scope and mechanistic insights

An efficient method for the synthesis of tertiary amines through a gold(I)‐catalyzed tandem reaction of alkynes with secondary amines has been developed. In the presence of ethyl Hantzsch ester and [{(tBu)₂(o‐biphenyl)P}AuCl]/AgBF₄ (2 mol %), a variety of secondary amines bearing electron‐deficient and electron‐rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron‐deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99 % yield. For indolines bearing a preexisting chiral center, their reactions with alkynes in the presence of ethyl Hantzsch ester catalyzed by [{(tBu)₂(o‐biphenyl)P}AuCl]/AgBF₄ (2 mol %) afforded tertiary amines in excellent yields and with good to excellent diastereoselectivity. All of these organic transformations can be conducted as a one‐pot reaction from simple and readily available starting materials without the need of isolation of air/moisture‐sensitive enamine intermediates, and under mild reaction conditions (mostly room temperature and mild reducing agents). Mechanistic studies by NMR spectroscopy, ESI‐MS, isotope labeling studies, and DFT calculations on this gold(I)‐catalyzed tandem reaction reveal that the first step involving a monomeric cationic gold(I)–alkyne intermediate is more likely than a gold(I)–amine intermediate, a three‐coordinate gold(I) intermediate, or a dinuclear gold(I)–alkyne intermediate. These studies also support the proposed reaction pathway, which involves a gold(I)‐coordinated enamine complex as a key intermediate for the subsequent transfer hydrogenation with a hydride source, and reveal the intrinsic stereospecific nature of these transformations observed in the experiments.     

Scandium triflate as an efficient and useful catalyst for the synthesis of β-amino alcohols by regioselective ring opening of epoxides with amines under solvent-free conditions

A simple and efficient method has been developed for the synthesis of β-amino alcohols by ring opening of epoxides in the presence of a catalytic amount of Sc(OTf)₃ at room temperature under solvent-free conditions. The reaction works well with both aromatic and aliphatic amines. High regio-, and diastereoselectivity can be considered as a noteworthy advantage of this method.     

Palladium-catalyzed cross-coupling of 2-haloselenophene with terminal alkynes in the absence of additive

We present herein our results of the Sonogashira coupling reaction of 2-haloselenophenes with terminal alkynes catalyzed by PdCl₂(PPh₃)₂, under co-catalyst free conditions and establish a new procedure to prepare (2-alkynyl)-selenophenes in good yields. The reaction proceeded cleanly under mild reaction conditions and was performed with propargylic alcohols, protected propargylic alcohols, propargylic amines, as well as alkyl, and aryl alkynes, in the presence of PdCl₂(PPh₃)₂, Et₃N, DMF, and in the absence of any supplementary additives. In addition, by this protocol (2,5-bis-alkynyl)-selenophenes were also obtained, in a one pot procedure, using 2,5-bis-iodoselenofene with an excess of terminal alkynes.     

Nickel‐catalyzed three‐component coupling reaction of terminal alkynes,dihalomethane and amines to propargylamines

Direct C―H and C―halogen activation is an important and practical task in C―C, C―N bond formation reactions using alkynes. Propargylic amines are synthetically versatile intermediates for the preparation of many nitrogen‐containing biologically active motifs. Herein, a 15 mol% Ni(py)₄Cl₂/bipyridine‐catalyzed three‐component coupling reaction of alkynes, halomethane and amines through C―H and C―halogen activation was developed for the facile synthesis of propargylic amines. Tetramethylguanidine shows excellent basicity in acetonitrile and works under mild conditions. The reaction has very good functional group tolerance to aliphatic and aromatic alkynes. Copyright © 2013 John Wiley & Sons, Ltd.     

A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina

A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina has been developed. β-Aminoalkynes are generated in good yields. The reaction can be extended to include a cyclization, which affords 2-substituted benzo[b]furans. The chemoselectivity of the reaction indicates that terminal alkynes are much more reactive than enolizable ketones under the reaction conditions.     

A convenient rhodium-catalyzed intermolecular hydroamination procedure for terminal alkynes

The first rhodium-catalyzed intermolecular hydroamination of alkynes is presented. Terminal alkynes react efficiently with anilines in the presence of cationic rhodium(I) catalysts under very mild reaction conditions (e.g., base and acid free at room temperature) to yield up to 99% of the corresponding imines. An easy one-pot protocol for the synthesis of secondary amines was developed by combining this alkyne amination reaction with in situ addition of organolithium reagents.     

Asymmetric synthesis of ethoxydienamines in superbasic medium mediated by chiral sulfinyl group

The direct addition of metalated alkoxydiene 2, obtained from α,β-unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure β-keto amines 7.     

Syntheses of substituted 3-methyleneisoindolin-1-ones by a palladium-catalyzed Sonogashira coupling-carbonylation-hydroamination sequence in phosphonium salt-based ionic liquids

Two efficient approaches for the synthesis of isoindolin-1-one derivatives in phosphonium salt ionic liquids are described. The palladium-catalyzed carbonylation-hydroamination reaction of 1-halo-2-alkynylbenzene with amines afforded the substituted 3-methyleneisoindolin-1-ones in good yields and high selectivities in favor of the Z-isomers. The target molecules could also be synthesized by the Sonogashira coupling-carbonylation-hydroamination one-pot reaction of dihalides, alkynes, and amines. Both processes can be conducted under mild conditions and tolerate a wide array of functionalized substrates.     

Gold(I)-catalyzed Conia-ene reaction of beta-ketoesters with alkynes

The intramolecular addition of beta-ketoesters to unactivated alkynes under neutral conditions and at room temperature is described. The method employs triphenylphosphinegold(I) cation as a catalyst for the formation of exo-methylenecycloalkanes. Both monocyclic and bicyclic cyclopentanes and cyclohexanes can be formed in excellent yields and with good diastereoselectivity.     

New coupling reaction of secondary amines, aldehydes, and alkynes catalyzed by an iridium complex

A new reductive coupling reaction of secondary amines, aldehydes, and alkynes using an iridium complex as catalyst has been developed. For example, dibutylamine was allowed to react with butyraldehyde and 1-octyne in 1,4-dioxane at 50 degrees C under the influence of a catalytic amount of [IrCl(cod)](2) to give the corresponding allylamines such as N,N-dibutyl-2-butylideneoctylamine and N,N-2-tributyl-2-octenylamine in excellent yields. [reaction: see text]     

Oxidative amide synthesis and N-terminal alpha-amino group ligation of peptides in aqueous medium

A new method for oxidative synthesis of amides from alkynes and amines in high yields (up to 96%) using [Mn(2,6-Cl2TPP)Cl] 1 as a catalyst and Oxone/H2O2 as an oxidant in aqueous medium has been developed. This method could be used for N-terminal alpha-amino group ligation of unprotected peptides with aryl, aliphatic, and internal alkynes under mild conditions.     

A highly efficient three-component coupling of aldehyde, terminal alkyne, and amine via C-H activation catalyzed by reusable immobilized copper in organic-inorganic hybrid materials under solvent-free reaction conditions

Recycling copper(I) immobilized on organic-inorganic hybrid material behaves as a very efficient heterogeneous catalyst in the three-component Mannich coupling reaction of aldehydes, terminal alkynes, and amines via C-H activation to afford the corresponding products in good to excellent yields under solvent-free reaction conditions.     

Facile synthesis of tetrahydro-1H-isoindolones via a sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction

An interesting sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction, providing a facile synthesis of highly substituted tetrahydro-1H-isoindolones from conjugated vinylic alkynes, imines, and α,β-unsaturated enoic acid chlorides is reported. The most attractive feature of this transformation is that three stereogenic centers could be generated in one step with high diastereoselectivity.     

anti-1,2-Diols via Ni-catalyzed reductive coupling of alkynes and alpha-oxyaldehydes

[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.     

Propargylic amines constructed via copper-catalyzed three-component coupling of terminal alkynes, benzal halides and amines

A method for the synthesis of propargylic amines has been developed via an efficient copper(I)-catalyzed three-component coupling reaction of alkynes, benzal halides and amines through C-H and C-halogen activation. This reaction is conducted under mild conditions and provides an alternative method for the synthesis of propargylic amines.     

An efficient synthesis of propargylamines via three-component coupling of aldehydes, amines and alkynes catalyzed by nanocrystalline copper(II) oxide

An efficient three-component coupling of aldehydes, amines and alkynes to prepare propargylamines, in nearly quantitative yields using nanocrystalline CuO as a catalyst is described. Structurally divergent aldehydes and amines were converted to the corresponding propargylamines. The reaction does not require any co-catalyst. After completion of the reaction, the catalyst was recovered by centrifugation and reused several times with only a slight decrease of activity observed under the same reaction conditions.     

Ind(2)TiMe(2)]: a general catalyst for the intermolecular hydroamination of alkynes

[Ind(2)TiMe(2)] (Ind=indenyl) is a highly active and general catalyst for the intermolecular hydroamination of alkynes. It catalyzes the reaction of primary aryl-, tert-alkyl-, sec-alkyl-, and n-alkylamines with internal and terminal alkynes. In the case of unsymmetrically substituted 1-phenyl-2-alkylalkynes, the reactions occur with modest to excellent regioselectivities, whereby formation of the anti-Markovnikov regioisomers is favored. While the major product of hydroamination reactions of terminal arylalkynes is always the anti-Markovnikov isomer, alkylalkynes react with arylamines to preferably give the Markovnikov products. To achieve reasonable rates for the addition of sterically less hindered n-alkyl- and benzylamines to alkynes, these amines must be added slowly to the reaction mixtures. This behavior is explained by the fact that the catalytic cycle proposed on the basis of an initial kinetic investigation includes the possibility that the rate of the reaction increases with decreasing concentration of the employed amine. Furthermore, no dimerization of the catalytically active imido complex is observed in the hydroamination of 1-phenylpropyne with 4-methylaniline in the presence of [Ind(2)TiMe(2)] as catalyst. In general, a combination of [Ind(2)TiMe(2)]-catalyzed hydroamination of alkynes with subsequent reduction leads to the formation of secondary amines with good to excellent yields. Particularly impressive is that [Ind(2)TiMe(2)] makes it possible for the first time to perform the reactions of n-alkyl- and benzylamines with 1-phenylpropyne in a highly regioselective fashion.     

Intermolecular Hydroamination of Alkynes Catalyzed by Dimethyltitanocene

A completely new application of dimethyltitanocene as catalyst for the intermolecular hydroamination of alkynes is presented. With this inexpensive and readily available catalyst, alkynes can be easily converted into imines, amines, and ketones (see reaction scheme).     

A convenient and efficient route for the allylation of aromatic amines and alpha-aryl aldehydes with alkynes in the presence of a Pd(0)/PhCOOH combined catalyst system

The allylation of aromatic amines with alkynes proceeded smoothly in the presence of catalytic amounts of Pd(PPh(3))(4) and benzoic acid. The allylation products were obtained in high yields in a regio- and stereoselective manner. The effect of various groups on the nitrogen atom of anilines was studied. Regardless of the substituent (electron withdrawing or electron donating) on the aromatic ring, the reaction proceeded well. Various functionalities, including -CH(3), -OMe, -Cl, -CN, -COOMe, -NO(2) and -COCH(3) were tolerated under the reaction conditions. Similarly, the allylation of alpha-aryl aldehydes proceeded well with the same level of regio- and stereoselectivity as the allylation of aromatic amines. This reaction provides the second example of the transition metal catalyzed direct alpha-allylation of aldehydes.     

Stereoselective [3+2+2] cycloaddition utilizing optically active binuclear Fischer carbene complexes with alkynes

The reaction of optically active α,β-unsaturated binuclear Fischer carbene complexes with alkynes gave planar chiral cycloheptatriene chromium complexes via [3+2+2] cycloaddition with high diastereoselectivity.