Enantioselective Intramolecular Hydroamination Research Articles

Catalytic enantioselective intramolecular hydroamination of alkenes using chiral aprotic cyclic urea ligand on manganese (II)

Asymmetric catalysis for enantioselective intramolecular hydroamination of alkenes is a critical method in the construction of enantioenriched nitrogen-containing rings, often prevalent in biologically active compounds and natural products. Herein, we demonstrate a facile enantioselective intramolecular hydroamination of alkenes for the synthesis of chiral pyrrolidine, piperidine, and indoline moieties, using a manganese (II) chiral aprotic cyclic urea catalyst. The cyclic ligand hinders the inversion of the N atom of the urea and effectively discriminate between the enantiomers of substrates. High-resolution mass spectrometry, deuterium labeling experiments, and molecular orbital energy analysis clearly reveal the intermediates and mechanism of the transformation. As a key step, oxygen coordination by chiral aprotic urea presents a robust control over the asymmetric intra-HA reaction through the involvement of a convergent assembly of two vital intermediates (Mn-N and C-Mn-Br), providing access to chiral cyclic amine systems in high yields with excellent enantioselectivity.

A chiral pool-derived calcium catalyst for intramolecular hydroamination with enhanced enantioselectivity

The synthesis of (2S,3S)-3-methyl-2-(methyl(pyridin-2-yl-methyl)amino)-1,1-diphenylpentan-1-ol 5 and its use together with [Ca(N(SiMe3)2)2(thf)2] 6 as in situ generated catalytic system in the enantioselective intramolecular hydroamination of 2,2-diphenylpent-4-en-1-amine 7 as benchmark substrate is discussed. Enantiomeric excesses of up to 77 %, the highest yet reported for calcium-based systems, as well as significantly shortened reaction times while only requiring 5 mol-% of catalyst, were achieved.

Computational study on N-triflylphosphoramide-catalyzed enantioselective hydroamination of alkenyl thiourea.

The mechanism of the enantioselective intramolecular hydroamination of alkenyl thiourea catalyzed by chiral binaphthol N-triflylphosphoramide (NPTA) was investigated using density functional theory calculations. This study reveals the details of the hydrogen bonding mode between NPTA and the substrate and indicates the importance of the dual hydrogen binding properties of the thiourea moiety for the reactivity and stereoselectivity of the hydroamination.

Chiral NHC-Iridium Complexes and Their Performance in Enantioselective Intramolecular Hydroamination and Ring-Opening Amination Reactions

A series of chiral N-heterocyclic carbene (NHC)-iridium complexes of general formula [(NHC*)Ir(diene)Cl] bearing TFB (tetrafluorobenzobarrelene), TCB (tetrachlorobenzobarrelene), BB (benzobarrelene), and COD (cyclooctadiene) as diene ligands were synthesized and fully characterized. Chiral NHC ligands used were of the type previously reported from our group, with backbone stereocenters as well as axial chirality present. The cationic NHC-iridium complexes [(NHC*)Ir(diene)][PF6] were obtained via chloride abstraction from [(NHC*)Ir(diene)Cl] with AgPF6. X-ray crystallographic data for some of the neutral and cationic complexes were obtained and analyzed. The topographic steric bulk of the chiral NHC ligands was calculated using the SambVca 2.0 program. While attempting to get a single crystal of the unstable (Ra,Ra,S,S)-[(DiPh-2-SICyoctNap)Ir(BB)][PF6] complex, a decomposition product with an unexpected pincer-type NHC*-diene ligand was obtained. The series of chiral cationic NHC-iridium complexes were eit...

Catalytic Asymmetric Synthesis of α-Arylpyrrolidines and Benzo-fused Nitrogen Heterocycles.

Herein, we report a practical two-step synthetic route to α-arylpyrrolidines through Suzuki-Miyaura cross-coupling and enantioselective copper-catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium-ring dibenzo-fused nitrogen heterocycles.

Developing NHC-Iridium Catalysts for the Highly Efficient Enantioselective Intramolecular Hydroamination Reaction

Chiral, cationic NHC-iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of pyrrolidines, which are accessed with excellent optical purity. Enantiomerically enriched piperidines and indolines are also produced, and various functional groups are tolerated with this LTM system. A reaction mechanism is proposed, and a major deactivation pathway of these catalysts is presented and discussed.

ChemInform Abstract: Enantioselective Intramolecular Hydroamination of Unactivated Alkenes Catalyzed by Mono‐ and Bis(gold) Phosphine Complexes.

AbstractThe title process allows the cyclization of unactivated alkenes with carbamates and ureas to form pyrrolidine derivatives with enantioselectivities up to 85%.

Enantioselective Intramolecular Hydroamination of Unactivated Alkenes Catalyzed by Mono‐ and Bis(gold) Phosphine Complexes

AbstractA 1:2 mixture of (P1)(AuCl)2 [P1=(S)‐DTBM‐MeO‐BIPHEP] and silver tetrafluoroborate (AgBF4) in methanol catalyzes the intramolecular hydroamination of unactivated alkenes with carbamates and ureas to form pyrrolidine derivatives with up to 85% ee.magnified image

ChemInform Abstract: Catalytic, Enantioselective Intramolecular Hydroamination of Primary Amines Tethered to Di‐ and Trisubstituted Alkenes.

AbstractThe new complexes generated form Li(thf)4[Y(CH2SiMe3)4] and the diamines (I) effectively promote the asymmetric cyclization of amine substrates.

Enantioselective Intramolecular Hydroamination of N-Alkenyl Ureas [nl]Catalyzed by tropos BIPHEP-Gold(I) Complexes with Au-Au Interaction

Correction to: Enantioselective Intramolecular Hydroamination of N-Alkenyl Ureas Catalyzed by tropos BIPHEP-Gold(I) Complexes with Au-Au InteractionSynlett 2012; 2012(01): 57-61DOI: 10.1055/s-0031-1289875

Catalytic, Enantioselective Intramolecular Hydroamination of Primary Amines Tethered to Di- and Trisubstituted Alkenes

The in situ preparation of chiral amido alkyl ate yttrium complexes from an array of chiral N-benzyl-like-substituted binaphthyldiamines is reported. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of primary amines tethered to sterically demanding alkenes at high reaction temperatures. Fine tuning of their chiral environment allowed up to 77% ee to be reached for the cyclization of aminoalkenes bearing 1,2-dialkyl-substituted carbon-carbon double bonds. These chiral complexes also demonstrate the ability to promote the cyclization of amine-tethered trisubstituted alkenes in up to 55% ee, as the first report of the formation of enantioenriched quaternary centers by an hydroamination reaction.

Enantioselective Intramolecular Hydroamination of N-Alkenyl Ureas Catalyzed by tropos BIPHEP-Gold(I) Complexes with Au-Au Interaction

Corrected by: Enantioselective Intramolecular Hydroamination of N-Alkenyl Ureas Catalyzed by tropos BIPHEP-Gold(I) Complexes with Au-Au InteractionSynlett 2012; 2012(01): e1-e1DOI: 10.1055/s-0031-1290122

Enantioselective Intramolecular Hydroamination of Secondary Amines Catalyzed by Easily Accessible Ate and Neutral Rare‐Earth Complexes

Enantioselective Intramolecular Hydroamination of Secondary Amines Catalyzed by Easily Accessible Ate and Neutral Rare‐Earth Complexes

Gold(I)-catalyzed enantioselective intramolecular hydroamination of allenes with ureas

Enantioselective intramolecular hydroamination of N-allenyl ureas catalyzed by an enantiomerically enriched bis(gold) phosphine complex forms pyrrolidine derivatives in good yield with up to 93% ee.

Amidate ligand design effects in zirconium-catalyzed enantioselective hydroamination of aminoalkenes

In situ generated axially chiral zirconium biphenyl amidate complexes are efficient precatalysts for the enantioselective intramolecular hydroamination of aminoalkenes, generating α-substituted pyrrolidines and piperidine with up to 74% ee. Five new chelating amide proligands and three new zirconium amidate complexes have been prepared and fully characterized in this investigation of ligand structure/catalyst function. Solid-state molecular structures of the complexes suggest that the observed moderate and highly variable enantioselectivities are a consequence of the multiple isomers accessible to this family of complexes, including a κ 2-( O, O)-bonding motif. Thermal stability studies of the complexes further revealed the tendency of these complexes to undergo diastereoselective dimerization to afford homochiral dimers. These dimeric precatalysts are less efficient when used for the cyclization of aminoalkenes in comparison to their monomeric precursors. These results illustrate the variable coordination modes accessible to amidate ligands and suggest steric factors that must be considered in advanced ligand design.

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Chiral Amido Alkyl Rare Earth Complexes: A New Family of Asymmetric Intramolecular Hydroamination Catalysts

New chiral binaphthylamido alkyl ate and neutral yttrium and ytterbium complexes have been synthesized and characterized. X-ray structures have been obtained for ate alkyl complexes [(R)-C20H12(NC5H9)2]Y[(μ-Me)2Li(THF)2(μ-Me)Li(THF)] and [(R)-C20H12(NC5H9)2]Ln[(μ-Me)2Li(TMEDA)(μ-Me)Li(OEt2)] (Ln = Y, Yb) and for the neutral complex [(R)-C20H12(NC5H9)2]YCH2SiMe3(DME). Both types of complexes can be easily prepared in a one-pot procedure starting from yttrium and ytterbium chlorides and used in situ. They proved to be very efficient catalysts for enantioselective intramolecular hydroamination of aminopentenes or aminohexene at room temperature with enantiomeric excesses up to 83%.

New Chiral Lanthanide Amide Ate Complexes for the Catalysed Synthesis of Scalemic Nitrogen‐Containing Heterocycles

New chiral binaphthylamido yttrium and ytterbium ate complexes with lithium and potassium counterions have been synthesised and characterised. X-ray structures have been obtained for [Li(thf)4][Ln{(R)-C20H12(NC5H9)2}2] (Ln=Yb, Y) and [K(thf)5][Yb{(R)-C20H12(NCH2CMe3)2}2] as isostructural complexes. The efficiency of these complexes for the enantioselective intramolecular hydroamination was examined. [Li(thf)4][Yb{(R)-C20H12(NC5H9)2}2] afforded the highest enantiomeric excess (up to 87 %) for the synthesis of a spiropyrrolidine, while [Li(thf)4][Y{(R)-C20H12(NC5H9)2}2] proved to be slightly more active. The role of the counter cation in the active catalytic species was evidenced by the comparison between lithium and potassium ate complexes. The most active catalyst of this series, [Li(thf)4][Yb{(R)-C20H12(NCH2CMe3)2}2], was successfully used for the cyclisation of aminopentenes with internal double bonds.

A Study on Chiral Organocalcium Complexes: Attempts in Enantioselective Catalytic Hydrosilylation and Intramolecular Hydroamination of Alkenes

The chiral β -diketimine ligand [(S)-Ph(Me)CH-N=C(Me)]CH2 was prepared by condensation of acetylacetone with the commercially available chiral building block (S)-Ph(Me)CH-NH2. Reaction of bis(o-Me2N-α-Me3Si-benzyl)calcium with this β -diketimine led to double deprotonation. Reaction of bis(o-Me2N-α-Me3Si-benzyl)calcium with the commercially available chiral bis-oxazoline (S)-Ph-BOX gave diastereopure [(S)-Ph-BOX](o-Me2N-α-Me3Si-benzyl)calcium which in solution slowly decomposed with formation of o-Me2N-α-Me3Si-toluene. The corresponding amide complex [(S)-Ph-BOX]CaN(SiMe3)2·(THF)2 is stable and the crystal structure has been determined. In solution, this heteroleptic amide is in Schlenk equilibrium with the homoleptic species [(S)-Ph-BOX]2Ca and Ca[N(SiMe3)2]2·(THF)2. This Schlenk equilibrium can be steered to the heteroleptic side. Use of the enantiopure calcium amide catalyst for the hydrosilylation of styrene with PhSiH3 or in the intramolecular hydroamination of aminoalkenes gave good product yields, but only small ee-values were observed (5 - 10%). From stoichiometric reactions of the catalyst with the substrates it is concluded that the “true” catalytically active species is mainly present as a homoleptic calcium complex, which explains the poor enantioselectivities