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.     

Rhodium-catalyzed anti-Markovnikov hydroamination of vinylarenes

The transition metal-catalyzed anti-Markovnikov hydroamination of unactivated vinylarenes with a rhodium complex of DPEphos is reported. The reaction of electron-neutral or electron-rich vinylarenes with a variety of secondary amines in the presence of catalyst forms the products from anti-Markovnikov hydroamination in high yields. Reactions of morpholine, N-phenylpiperazine, N-Boc-piperazine, piperidine, 2,5-dimethylmorpholine, and perhydroisoquinoline reacted with styrene to form the amine product in 51-71% yield. Reactions of a variety of vinylarenes with morpholine generated amine as the major product. Reactions of morpholine with electron-poor vinylarenes gave lower amine:enamine ratios than reactions of electron-rich vinylarenes at the same concentration of vinylarene, but conditions were developed with lower concentrations of electron-poor vinylarene to maintain formation of the amine as the major product. Reactions of dimethylamine with vinylarenes were fast and formed amine as the major product. Mechanistic studies on the hydroamination process showed that the amine:enamine ratio was lower for reactions conducted with higher concentrations of vinylarene and that one vinylarene influences the selectivity for reaction of another. A mechanism proceeding through a metallacyclic intermediate that opens in the presence of a second vinylarene accounts for these and other mechanistic observations.     

A redox-enabled strategy for intramolecular hydroamination

Metal- or acid-catalyzed intramolecular hydroamination and Cope-type intramolecular hydroamination, a distinct concerted approach using hydroxylamines, typically suffer from significant synthetic limitations. Herein we report a process for intramolecular hydroamination that uses a redox-enabled strategy relying on efficient in situ generation of hydroxylamines by oxidation, followed by Cope-type hydroamination, then reduction of the resulting pyrrolidine N-oxide. The steps are performed sequentially in a single pot, no catalyst is required, the conditions are mild, the process is highly functional group tolerant, and no chromatography is generally required for isolation. A robustness screen and a gram-scale example further support the practicality of this approach.

A redox strategy enables hydroaminations: mild conditions allows efficient hydroxylamine formation & cyclization, then B₂(OH)₄ as reductant also facilitates isolation!     

Copper-catalyzed hydroamination of propargyl imidates

Propargyl imidates derived from aromatic and aliphatic nitriles cyclize at room temperature in high yields when treated with a catalytic amount of copper (I) iodide. This 5-exo-dig process affords dihydrooxazoles which do not aromatize under the reaction conditions, and which are isolated without chromatography. Investigations of the reaction scope, subsequent functionalization of the reaction products, and preliminary mechanistic data are presented.     

Asymmetric hydroamination of non-activated carbon-carbon multiple bonds

The catalysed enantioselective formation of carbon-nitrogen bonds by the hydroamination reaction is reviewed. All examples deal with substrates containing non-activated carbon-carbon multiple bonds which are transformed either via intramolecular or intermolecular reactions. Structurally different complexes already provided nitrogen containing compounds/heterocycles with high enantioselectivities.     

Aminotroponiminate zinc complexes as catalysts for the intramolecular hydroamination

This review deals with the synthesis of aminotroponiminate and aminotroponate zinc complexes. The main focus is on their application as catalysts for the intramolecular hydroamination, in which good activity, particularly high functional group tolerance and a relatively high stability towards moisture and air were observed. In addition, a heterogeneous zinc catalyst was reported in order to increase the stability and the recyclability of the catalytic system.     

Rhodium-catalyzed intramolecular, anti-Markovnikov hydroamination. Synthesis of 3-arylpiperidines

The intramolecular anti-Markovnikov hydroamination of 1-(3-aminopropyl)vinylarenes in the presence of a readily available rhodium catalyst to form 3-arylpiperidines is reported. In contrast to intermolecular hydroamination of vinylarenes, which occurred in high yields in the presence of rhodium catalysts containing DPEphos, the intramolecular reaction occurred in high yield in the presence of [Rh(COD)(DPPB)]BF4 as catalyst. Reactants with substituents beta to the nitrogen occurred in high yield, and these reactions formed 3,5-disubstituted piperidines with high diastereomeric excess. The regiochemistry of these cyclizations contrasts with the regiochemistry of intramolecular hydroaminations catalyzed by lanthanide complexes, group III metal complexes, and platinum complexes, all of which have been reported to form cyclization products from Markovnikov addition.     

Intramolecular hydroamination of conjugated enynes

An intramolecular hydroamination of conjugated enyne was developed using commercially available n-BuLi as a precatalyst. This hydroamination reaction led to products with allene and pyrrolidine functional groups. One of the enyne hydroamination products was successfully converted to natural products irniine and irnidine in three steps. The scope and mechanism of the enyne hydroamination are also discussed.     

Inorganic base-mediated stereoselective hydroamination of arylalkynes with imidazole: An efficient access to N-vinylimidazoles

A metal-free inorganic base-mediated highly stereoselective hydroamination of arylalkynes with imidazoles has been developed, and the corresponding N-vinylimidazoles were obtained in good yields and with moderate to excellent stereoselectivities (up to 99:1). For the electron rich alkynes, the reaction system of CsOH·H₂O/NMP/140?°C led to the predominant formation of E-addition products, while the reaction system of KOH/NMP/90?°C afforded the Z-isomers as the major product. The electron deficient alkynes furnished predominantly the E-addition products in both reaction systems. This study essentially provides a general and an efficient protocol for the synthesis of E-isomer of the N-vinylimidazoles.     

Catalytic asymmetric hydroamination of non-activated olefins

Hydroamination is a highly atom-economical process in which an amine N-H functionality is added to an unsaturated carbon-carbon linkage. This potentially highly useful process gives access to various nitrogen-containing basic and fine chemicals as well as naturally occurring alkaloid skeletons. Asymmetric hydroamination reactions promoted by chiral catalysts are particularly attractive. This review highlights recent progress in the development of early transition metal catalysts for the asymmetric hydroamination of non-activated alkenes.     

Ruthenium-catalyzed anti-Markovnikov hydroamination of vinylarenes

A ruthenium-catalyzed intermolecular, anti-Markovnikov hydroamination of vinylarenes with secondary aliphatic and benzylic amines is reported. The combination of Ru(cod)(2-methylallyl)2, 1,5-bis(diphenylphosphino)pentane, and triflic acid was the most effective catalyst of those tested. Control reactions conducted without ligand or acid did not form the amine. The reaction of morpholine, piperidine, 4-phenylpiperazine, 4-BOC-piperazine, 4-piperidone ethylene ketal, and tetrahydroisoquinoline with styrene in the presence of 5 mol % of this catalyst formed the corresponding beta-phenethylamine products in 64-96% yield, with 99% regioselectivity, and without enamine side products. Acyclic amines such as n-hexylmethylamine and N-benzylmethylamine reacted with styrene in 63 and 50% yields, respectively. Alkyl-, methoxy-, and trifluoromethyl-substituted styrenes reacted with morpholine in the presence of this catalyst or a related one containing 1,1'-bis(diisopropylphosphino)ferrocene as ligand to give the products in 51-91%. Further, the hydroamination of alpha-methyl styrene was observed for the first time with a homogeneous transition metal catalyst. Preliminary mechanistic studies showed that the reaction occurred by direct, irreversible, anti-Markovnikov hydroamination and that the mechanism of the ruthenium-catalyzed hydroamination is likely to be distinct from that of the recently reported rhodium-catalyzed reaction.     

Intermolecular, markovnikov hydroamination of vinylarenes with alkylamines

A transition metal-catalyzed intermolecular hydroamination of vinylarenes with alkylamines is reported. The combination of Pd(O2CCF3)4, DPPF, and TfOH was the most effective catalyst of those tested. Control experiments without palladium, acid, or ligand all occurred in low yield. The reaction of various vinylarenes with cyclic and acyclic alkylamines in the presence of 5 mol % of this catalyst formed the corresponding arylethylamine products in moderate to high yields. For example, reactions of morpholine, 4-phenylpiperazine, 4-Boc-piperazine, isoindoline, and tetrahydroisoquinoline with styrene all occurred in 58-75% yield. Acyclic amines such as N-benzylmethylamine and n-hexylmethylamine reacted with 2-vinylnaphthalene in 63% and 53% yields, respectively. Mechanistic investigations showed that the reaction occurred through an eta3-arylethyl palladium complex. The reactions of this complex with alkylamines generated product in combination with regenerating free vinylarene, Pd(0), and ammonium salt. Thus, one hurdle to developing hydroamination of vinylarenes with palladium complexes is the faster elimination of free vinylarene from the eta3-arylethyl complex than addition to form the C-N bond. The feasibility of conducting enantioselective hydroaminations with alkylamines was also examined. The product from addition of N-benzylmethylamine to 2-vinylnaphthalene was generated in 63% ee and 36% yield in the presence of Pd(OCOCF3)2, a ferrotane ligand, and TfOH cocatalyst.     

Metal-ligand cooperation in catalytic intramolecular hydroamination: a computational study of iridium-pyrazolato cooperative activation of aminoalkenes

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2-dimethyl-4-penten-1-amine by Cp*Ir chloropyrazole (1; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2?S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C=C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium-olefin linkage; 2) Ir-C bond protonolysis via stepwise transfer of the ammonium N-H proton at the zwitterionic [Cp*IrPz-alkyl] intermediate onto the metal that is linked to turnover-limiting, reductive, cycloamine elimination commencing from a high-energy, metastable [Cp*IrPz-hydrido-alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine-iridium bound 2?a?S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen-bonded network involving suitably aligned β-basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β- or γ-basic pyrazolato unit. As far as the route that involves amine N-H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N-H concurrent with N-C ring closure is disclosed as a favourable scenario. Although not practicable in the present system, this pathway describes a novel mechanistic variant in late transition metal-ligand bifunctional hydroamination catalysis that can perhaps be viable for tailored catalyst designs. The insights revealed herein concerning the operative mechanism and the structure-reactivity relationships will likely govern the rational design of late transition metal-ligand bifunctional catalysts and facilitate further conceptual advances in the area.     

The catalytic hydroamination of alkynes

The direct addition of ammonia or primary and secondary amines to non-activated alkenes and alkynes is potentially the most efficient approach towards the synthesis of higher substituted nitrogen-containing products. It represents the most atom economic process for the formation of amines, enamines and imines, which are important bulk and fine chemicals or building blocks in organic synthesis. While the hydroamination of alkenes is still limited to more or less activated alkenes, great progress has been achieved in the case of alkynes over the last three years. To illustrate this progress, the review will mostly focus on recent developments in the field of intermolecular hydroamination of alkynes. However, if it is necessary for the discussion, older results and intramolecular reactions, which can be achieved more easily, will be mentioned as well.     

Regio- and enantioselective hydroamination of dienes by gold(i)/menthol cooperative catalysis

Alcohol is key: Regio- and enantioselective hydroamination of 1,3-dienes has been achieved with the dinuclear catalyst (R)-DTBM-SEGPHOS. The rate and selectivity of the reaction are enhanced by alcohol additives like menthol, which coordinates the cationic gold(I) to generate a Br?nsted acid that can participate in catalysis. Mbs=p-methoxybenzenesulfonyl.     

Phenalenyl-based organozinc catalysts for intramolecular hydroamination reactions: a combined catalytic, kinetic, and mechanistic investigation of the catalytic cycle

Herein, we report the synthesis and characterization of two organozinc complexes that contain symmetrical phenalenyl (PLY)-based N,N-ligands. The reactions of phenalenyl-based ligands with ZnMe(2) led to the formation of organozinc complexes [N(Me),N(Me)-PLY]ZnMe (1) and [N(iPr),N(iPr)-PLY]ZnMe (2) under the evolution of methane. Both complexes (1 and 2) were characterized by NMR spectroscopy and elemental analysis. The solid-state structures of complexes 1 and 2 were determined by single-crystal X-ray crystallography. Complexes 1 and 2 were used as catalysts for the intramolecular hydroamination of unactivated primary and secondary aminoalkenes. A combined approach of NMR spectroscopy and DFT calculations was utilized to obtain better insight into the mechanistic features of the zinc-catalyzed hydroamination reactions. The progress of the catalysis for primary and secondary aminoalkene substrates with catalyst 2 was investigated by detailed kinetic studies, including kinetic isotope effect measurements. These results suggested pseudo-first-order kinetics for both primary and secondary aminoalkene activation processes. Eyring and Arrhenius analyses for the cyclization of a model secondary aminoalkene substrate afforded ΔH(≠) =11.3?kcal?mol(-1) , ΔS(≠) =-35.75?cal?K(-1) mol(-1) , and E(a) =11.68?kcal?mol(-1) . Complex 2 exhibited much-higher catalytic activity than complex 1 under identical reaction conditions. The in situ NMR experiments supported the formation of a catalytically active zinc cation and the DFT calculations showed that more active catalyst 2 generated a more stable cation. The stability of the catalytically active zinc cation was further supported by an in situ recycling procedure, thereby confirming the retention of catalytic activity of compound 2 for successive catalytic cycles. The DFT calculations showed that the preferred pathway for the zinc-catalyzed hydroamination reactions is alkene activation rather than the alternative amine-activation pathway. A detailed investigation with DFT methods emphasized that the remarkably higher catalytic efficiency of catalyst 2 originated from its superior stability and the facile formation of its cation compared to that derived from catalyst 1.     

Liquid-phase hydroamination of cyclohexanone

Activity and selectivity of supported Ni, Pt, and Pd catalysts were studied in the liquidphase reductive amination of cyclohexanone at temperatures ranging from 100 to 150 °C. The catalyst 20% Ni/SiO₂ is most active and selective providing a maximum yield of cyclohexylamine. The influence of the reaction conditions on the parameters of the catalytic process was studied. A detailed analysis of the reaction products was carried out using ¹³C NMR spectroscopy and gas chromatography coupled with mass spectrometry (GC-MS). This made it possible to refine the reaction mechanism and to identify a new by-product earlier unknown in the literature.     

Base-catalyzed intramolecular hydroamination of conjugated enynes

A de novo intramolecular hydroamination of conjugated enynes was developed using commercially available n-BuLi as a precatalyst. This hydroamination reaction successfully afforded allenyl-substituted pyrrolidines with up to 95% yield. One of the resulting allenyl pyrrolidines was converted to the natural products irniine and irnidine in three steps.     

Kinetic resolution of chiral aminoalkenes via asymmetric hydroamination/cyclisation using binaphtholate yttrium complexes

Chiral binaphtholate yttrium aryl complexes are highly active and enantioselective catalysts for the asymmetric hydroamination of aminoalkenes, as well as the kinetic resolution of alpha-substituted 1-aminopent-4-enes to give trans-2,5-disubstituted pyrrolidines with good enantiomeric excess and high k(rel).     

Palladium-catalyzed hydrocarbonation and hydroamination of 3,3-dihexylcyclopropene with pronucleophiles

The reaction of 3,3-dihexylcyclopropene 1 with carbon and amine pronucleophiles 2 in the presence of palladium catalysts proceeded smoothly to give the corresponding hydrocarbonation products 3, allylated nucleophiles, in good to high yields. For example, in the presence of catalytic amounts of Pd(PPh(3))(4) and dppf, the reaction of 3,3-dihexylcyclopropene with ethyl 2-cyanopropionate and ethyl 2-cyanophenylacetate gave ethyl 2-cyano-2-methyl-4-undecenoate and ethyl 2-cyano-2-phenyl-4-undecenoate in 82 and 86% yield, respectively.