The catalytic hydroamination of alkynes

Catalytic additions of ammonia or primary and secondary amines to non-activated alkenes and alkynes are called hydroaminations. These reactions of fundamental simplicity represent the most atom efficient processes for the formation of amines, enamines and imines, which are important bulk and fine chemicals or building blocks in organic synthesis. Consequently, the development of corresponding hydroamination reactions has received much attention and great progress has been achieved in the case of catalytic hydroaminations of alkynes over the past four years. To illustrate this progress, this tutorial review will mostly focus on recent developments in the field of intermolecular hydroamination of alkynes that appeared in the literature between the end of 2002 and October 31, 2006.     

Platinum-catalyzed intermolecular hydroamination of terminal alkynes

The hydroamination of terminal alkyl- and arylacetylenes with aniline is catalyzed by platinum(II) bromide, yielding the corresponding imines. Contrary to what has been previously demonstrated for the platinum(II)-catalyzed hydroamination of -olefins, the presence of n-Bu₄PBr has a detrimental effect on the course of the reaction. The hydroamination of 1-hexyne is highly regioselective (Markovnikov) at 60 °C, but the regioselectivity decreases upon increasing the temperature. The hydroamination of phenylacetylene is fully regioselective (Markovnikov) at 100 °C. TON up to 146 were obtained in the presence of a catalytic source of protons.     

Palladium-catalyzed intramolecular asymmetric hydroamination of alkynes

The Pd-catalyzed reaction of internal alkynes with tethered amino groups in the presence of PhCO2H and RENORPHOS as chiral phosphine ligand is reported. Various five- and six-membered nitrogen-containing heterocycles were obtained in good to high yield with moderate to high ee.     

Intermolecular Cope-type hydroamination of alkynes using hydrazines

Metal-free, intermolecular hydroaminations are performed upon heating aryl acetylenes and MeNHNH(2) at 140 degrees C, with preferential formation of the linear, "anti-Markovnikov" hydrazones.     

Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes

The first direct intermolecular hydroamination/hydroalkylation of terminal alkynes catalyzed by In(OTf)(3) under one-pot conditions leading to the formation of conjugated ketimines in good yields is described.     

Heterogeneous intermolecular hydroamination of terminal alkynes with aromatic amines

Heterogeneous intermolecular hydroamination of alkynes with aromatic amines using inexpensive transition metal-exchanged clay catalysts was investigated. Reaction of terminal alkynes with aromatic amines gave higher yields of imines.     

Isoindoles and dihydroisoquinolines by gold-catalyzed intramolecular hydroamination of alkynes

The title compounds are enantioselectively synthesized in just two preparative steps, making use of the Ugi-four-component reaction with an amino acid as chiral component, followed by a gold-catalyzed hydroamination.     

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.     

Controlling selectivity: from Markovnikov to anti-Markovnikov hydroamination of alkynes

Depending on the catalyst a remarkable control of regioselectivity is achieved for the titanium-catalyzed intermolecular hydroamination of various alkynes. Proper choice of sterically hindered phenol ligands such as 1 and 4 enables a selectivity switch from the Markovnikov to the anti-Markovnikov products from M:anti-M = > 90:10 to > 10:90.     

Stereo- and regioselective gold-catalyzed hydroamination of internal alkynes with dialkylamines

We report the use of a P,N-ligand to support a gold complex as a state-of-the-art precatalyst for the stereoselective hydroamination of internal aryl alkynes with dialkylamines to afford E-enamine products. Substrates featuring a diverse range of functional groups on both the amine (ether, sulfide, N-Boc amine, fluoro, nitrile, nitro, alcohol, N-heterocycles, amide, ester, and carboxylic acid) and alkyne (ether, N-heterocycles, N-phthalimide amines, and silyl ethers) are accommodated with synthetically useful regioselectivity.     

Au(I)-catalyzed highly efficient intermolecular hydroamination of alkynes

[reaction: see text] Addition of aniline derivatives to aromatic and aliphatic alkynes proceeds efficiently in the presence of a gold(I) catalyst (0.01-1.0 mol %) to afford ketimines in good yields     

Convenient synthesis of tryptophols and tryptophol homologues by hydroamination of alkynes

A novel method is presented for the one-pot synthesis of substituted 3-(2-hydroxyethyl)- and 3-(3-hydroxypropyl)indoles (tryptophols and homotryptophols) from aryl hydrazines and silyl-protected ω-(hydroxyoalkyl)alkynes. Various tryptophol derivatives were prepared directly in good yield with excellent regioselectivity via a domino reaction sequence consisting of a titanium-catalyzed hydroamination of the alkyne, [3+3]-rearrangement of the resulting aryl hydrazone, and subsequent deprotection of the hydroxy group.     

Palladium-catalyzed intramolecular asymmetric hydroamination, hydroalkoxylation, and hydrocarbonation of alkynes

A conceptually novel approach for asymmetric intramolecular hydroamination, hydroalkoxylation and hydrocarbonation of alkynes using chiral palladium catalysts are described. The reactions of the aminoalkynes 5, alkynols 7, and alkynylmethines 9 in the presence of Pd2(dba)3 x CHCl3/PhCOOH/renorphos 4 in benzene (or benzene-hexane) at 100 degrees C gave the corresponding cyclization products (nitrogen heterocycles 6, oxygen heterocycles 8, and carbocycles 10) in good yields with good enantioselectivities. The origins of enantioselectivities in the hydroamination reaction are discussed based on DFT computations.