Chiral Propargylamines Research Articles

Copper(I)‐Catalyzed Enantioselective Synthesis of Chiral Cyclohexenylallenes and Transfer of Axial to Center Chirality by Ytterbium (III) Catalyzed [4+2] Cycloaddition

AbstractChiral cyclohexenylallenes are readily accessed from 1‐enynes, aldehydes and chiral secondary amines in good yields (up to 79 % yield) with excellent enantioselectivities (up to 99 % ee), through CuI catalyzed the formation of chiral propargylamine intermediates. Subsequent Yb(OTf)3 catalyzed [4+2] cycloaddition reaction of cyclohexylallenes with the dienophiles tetracyanoethylene and diethyl acetylenedicarboxylate afforded the corresponding bicyclic products in 69–75 % yield and 84–90 % ee.

Catalytic Enantioselective Alkyne Addition to Nitrones Enabled by Tunable Axially Chiral Imidazole-Based P,N-Ligands.

Although catalytic enantioselective alkyne addition is an established method for the synthesis of chiral propargylic alcohols and amines, addition to nitrones presents unique challenges, and no general chiral catalyst system has been developed. In this manuscript, we report the first Cu-catalyzed enantioselective alkyne addition to nitrones utilizing tunable axially chiral imidazole-based P,N-ligands. Our approach effectively overcomes difficulties in both reactivity and selectivity, resulting in a simple Cu-catalyzed protocol. The reaction accommodates a wide range of nitrones and alkynes, enabling the streamlined synthesis of chiral propargyl N-hydroxylamines via the enantioselective C-C bond formation. A diverse array of optically active nitrogen-containing compounds, including chiral hydroxylamines, can be accessed directly through facile transformations of the reaction products.

Enantioselective Synthesis of C2-Quaternary Indolin-3-ones by Pt-Catalyzed Alkynylation of 2-Aryl-3H-indol-3-one with Alkynylsilanes.

An efficient method for the synthesis of five-membered chiral propargylic amines from 2-aryl-3H-indol-3-one and alkynylsilanes has been developed. The reaction proceeded under the catalytic system of PtCl4, oxazoline-based ligand L11, Zn(CF3COO)2, and AcOH in DCE at 95 °C via in situ desilylation of TMS-alkynes. This methodology also highlights a new protocol for the in situ desilylation of alkynylsilanes. The reaction showed a broad substrate scope with good yields and enantioselectivity.

Cu‐Catalyzed Cross‐Coupling Reactions of Enamines and Terminal Alkynes: Access of Propargylamines as Neurodegenerative Disorder Agents

AbstractReactions between enamine analogues and terminal alkynes were explored. Copper(I) complex of 1,10‐phenanthroline catalyzed these reactions to generate a diastereoselective propargylamines via C−C bond formation. In the presence of Zn2+, the chiral propargylamines converted into the β‐allenoates with an excellent yield and enantioselectivity achieved up to 99 %. Models of synthesized propargylamines were used for molecular docking and dynamic simulations, which indicate that this class of molecules shows promise for anti‐neurodegenerative activity.

Enantioselective Alkynylation of 2-Aryl-3H-indol-3-ones via Cooperative Catalysis of Copper/Chiral Phosphoric Acid.

A facile enantioselective alkynylation of cyclic ketimines attached to a neutral functional group utilizing the dual Cu(I)-CPA catalysis is described. The strategy of the alkynylation of 2-aryl-3H-indol-3-one directly to chiral propargylic amines containing indolin-3-one moiety in good yields and enantioselectivities. Moreover, gram-scale synthesis of chiral propargylamines based C2-quaternary indolin-3-ones was performed. The synthetic applications were confirmed by transformations of the products with no decrease in the yield and enantioselectivity.

A chiral covalent-organic framework for asymmetric photooxidation in water

In a recent issue of Journal of the American Chemical Society , Dong and co-workers described a chiral covalent-organic framework assembled from porphyrin photosensitizers, chiral propargylamine linkers, and ammonium bromide phase-transfer groups for enantioselective photooxidation of sulfides to sulfoxides, including photocatalytic synthesis of ( R )-modafinil for treating excessive sleepiness. In a recent issue of Journal of the American Chemical Society , Dong and co-workers described a chiral covalent-organic framework assembled from porphyrin photosensitizers, chiral propargylamine linkers, and ammonium bromide phase-transfer groups for enantioselective photooxidation of sulfides to sulfoxides, including photocatalytic synthesis of ( R )-modafinil for treating excessive sleepiness.

Asymmetric Deoxygenative Alkynylation of Tertiary Amides Enabled by Iridium/Copper Bimetallic Relay Catalysis.

A variety of inert tertiary amides have been successfully transformed into synthetically important chiral propargylamines in high yields with good to excellent enantioselectivities via a relayed sequence of Ir catalyzed partial reduction and Cu/GARPHOS catalyzed asymmetric alkynylation with terminal alkynes. The reaction was readily extended to some drug molecules and the transformations of representative products have been demonstrated, thus attesting the practical utilities and the robust nature of the protocol.

Asymmetric Deoxygenative Alkynylation of Tertiary Amides Enabled by Iridium/Copper Bimetallic Relay Catalysis

AbstractA variety of inert tertiary amides have been successfully transformed into synthetically important chiral propargylamines in high yields with good to excellent enantioselectivities via a relayed sequence of Ir catalyzed partial reduction and Cu/GARPHOS catalyzed asymmetric alkynylation with terminal alkynes. The reaction was readily extended to some drug molecules and the transformations of representative products have been demonstrated, thus attesting the practical utilities and the robust nature of the protocol.

Synthesis of Chiral Propargylamines, Chiral 1,2-Dihydronaphtho[2,1-b]furans and Naphtho[2,1-b]furans with C-Alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals and β-Naphthols.

Chiral phosphoric acid-catalyzed couplings of C-alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals with β-naphthols led to chiral propargylamines in moderate to high yields with high to excellent enantioselectivity, in which the reactions underwent sequential chiral phosphoric acid-catalyzed in situ formation of N-(tert-butoxycarbonyl)-imines (N-Boc-imines) from the aminals, and 1,2-addition of β-naphthols to the N-Boc-imines. Chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans were prepared with satisfactory results when 10 mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the resulting chiral propargylamines solution, respectively.

Cobalt-Catalyzed Chemo- and Enantioselective Hydrogenation of Conjugated Enynes.

Asymmetric hydrogenation is one of the most powerful methods for the preparation of single enantiomer compounds. However, the chemo- and enantioselective hydrogenation of the relatively inert unsaturated group in substrates possessing multiple unsaturated bonds remains a challenge. We herein report a protocol for the highly chemo- and enantioselective hydrogenation of conjugated enynes while keeping the alkynyl bond intact. Mechanism studies indicate that the accompanying Zn2+ generated from zinc reduction of the CoII complex plays a critical role to initiate a plausible CoI /CoIII catalytic cycle. This approach allows for the highly efficient generation of chiral propargylamines (up to 99.9 % ee and 2000 S/C) and further useful chemical transformations.

Cobalt‐Catalyzed Chemo‐ and Enantioselective Hydrogenation of Conjugated Enynes

AbstractAsymmetric hydrogenation is one of the most powerful methods for the preparation of single enantiomer compounds. However, the chemo‐ and enantioselective hydrogenation of the relatively inert unsaturated group in substrates possessing multiple unsaturated bonds remains a challenge. We herein report a protocol for the highly chemo‐ and enantioselective hydrogenation of conjugated enynes while keeping the alkynyl bond intact. Mechanism studies indicate that the accompanying Zn2+ generated from zinc reduction of the CoII complex plays a critical role to initiate a plausible CoI/CoIII catalytic cycle. This approach allows for the highly efficient generation of chiral propargylamines (up to 99.9 % ee and 2000 S/C) and further useful chemical transformations.

Nickel-catalyzed Asymmetric Propargylic Amination of Propargylic Carbonates with Aniline Derivatives

A study for the development of the nickel-catalyzed highly enantioselective propargylic amination of propargylic carbonates with aniline derivatives is described. The reaction of internal alkyne-substituted propargylic carbonates with a series of aniline derivatives smoothly proceeded in DMSO using a combination of Ni(cod)2 and (R)-SEGPHOS as the catalyst to give the corresponding chiral propargylic amines in 61–93% yields with 91–97% ee (24 examples).

Copper mediated A3-coupling reaction for the preparation of enantioselective deoxy sugar based chiral propargylamines using bifunctional ligand l-proline

An efficient three component coupling of aromatic aldehyde, deoxy sugar based alkyne (α-2-deoxy propargyl glycoside) and heterocyclic amine have been refluxed to synthesize stereoselective chiral propargylamines with good to excellent yield using only CuI catalyst along with bifunctional ligand l-proline. This method has proved to be applicable in wide range of substrates and found highly enantioselective with respect to earlier reported methods. In addition, l-proline was found as a chiral source which demonstrated that it could be developed as a highly enantioselective method for the construction of deoxy sugar based chiral propargylamines. The ligand l-proline was used for the first time in enantioselective A3-coupling reaction of α-2-deoxy propargyl glycosides involving substituted aromatic aldehyde and heterocyclic amines. Herein, we have synthesized 15 novel compounds based on A3-coupling reaction and structures of all the enantioselective compounds were characterised by TLC and NMR spectroscopy.

Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir-Catalyzed Hydroalkynylation.

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β-disubstituted enamides to afford propargyl amides in a highly regio-, diastereo-, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.

Synthesis of Propargylamines by Cross-Dehydrogenative Coupling

Propargylamines are versatile compounds for heterocyclic synthesis, some of which are current drugs prescribed to treat patients with Parkinson’s disease. There are different methods to synthesize propargylamines, however, modern chemistry has moved progressively to rely on new strategies that meet the principles of Green Chemistry. In this context, propargylamines are readily accessible by the cross-dehydrogenative coupling (CDC) of two C-H bonds (i.e., NCsp3-H and Csp-H bonds); surely, CDC can be considered the most atom-economic and efficient manner to form C-C bonds. The aim of this review is to provide a comprehensive survey on the synthesis of propargylamines by the CDC of amines and terminal alkynes from three fronts: (a) transition-metal homogeneous catalysis, (b) transition-metal heterogeneous catalysis and (c) photoredox catalysis. A section dealing with the asymmetric synthesis of chiral propargylamines is also included. Special attention is also devoted to the proposed reaction mechanisms.

The Asymmetric A³(Aldehyde⁻Alkyne⁻Amine) Coupling: Highly Enantioselective Access to Propargylamines.

The recent developments in asymmetric A3 (aldehyde–alkyne–amine) coupling has been summarized in this review. Several interesting modifications of the ligands enabled the highly enantioselective synthesis of chiral propargylamines, which are further used in the construction of nitrogen-containing chiral building blocks.

Rh(II)/Brønsted Acid Catalyzed General and Highly Diastereo- and Enantioselective Propargylation of in Situ Generated Oxonium Ylides and C-Alkynyl N-Boc N,O-Acetals: Synthesis of Polyfunctional Propargylamines.

The first metal/organo cooperatively catalyzed asymmetric reaction of C-alkynyl N-Boc-protected N,O-acetals with in situ generated oxonium ylides has been developed. This new type of propargylation allows for the efficient synthesis of structurally diverse unreported chiral propargylamines bearing oxa-quaternary stereocenters. The reaction features unprecedented substrate scope and high diastereo- and enantioselectivity. Theoretical studies suggest a novel cooperative catalysis model and the unique transfer of R2OH.

Development of and recent advances in asymmetric A3 coupling.

Asymmetric A3 coupling has emerged as an important class of reactions to synthesise chiral propargylamines. In this tutorial review, an up to date progress of this reaction, with significant recent advancements in terms of ligand development, is presented. Applications of asymmetric A3 coupling in natural product synthesis and in tandem processes are also discussed.

Nickel-Catalyzed Asymmetric Propargylic Amination of Propargylic Carbonates Bearing an Internal Alkyne Group.

We have achieved the nickel-catalyzed asymmetric propargylic amination of propargylic carbonates bearing an internal alkyne group. A wide variety of propargylic carbonates and N-methylaniline derivatives were tolerated under the reaction conditions, providing the corresponding chiral propargylic amines in up to 97% yield with up to 97% ee.

Rhodium‐Catalyzed Chemo‐ and Enantioselective Hydrogenation of Alkynyl‐Aryl Hydrazones

AbstractAs an update of our continuous interest in the hydrogenation of hydrazones, a chemo‐ and enantioselective hydrogenation of alkynyl‐aryl hydrazones was developed using a rhodium complex [Rh((R,Sp)‐JosiPhos)(cod)]SbF6 as the catalyst and benzoic acid as an additive. Directed by a p‐nitrobenzamido group, the chiral propargyl hydrazines, which can be easily converted to chiral propargylamines of significant importance and potential use, were obtained with good yields, excellent chemoselectivities and good to excellent enantioselectivities. Although the enantioselectivity of the reaction and the substrate/catalyst ratio require further refinement, the reported methodology provides an alternative route for the efficient preparation of chiral propargylamines.magnified image