Cyclic Ketimines Research Articles

Visible light mediated decarboxylative difluoroalkylations of cyclic N-sulfonyl ketimines: Efficient synthesis of difluoroalkylated Cα-tetrasubstituted α-amino acid derivatives

An efficient decarboxylative difluoroalkylation method of cyclic N-sulfonyl ketimines with difluoroalkyl carboxylates has been developed through visible light-mediated photoredox catalysis process. This protocol provides a straightforward route for the synthesis of difluoroalkylated Cα-tetrasubstituted α-amino acid derivatives in moderate to good yields with excellent functional group tolerance under mild and simple conditions.

Enantioselective Mannich Reaction between Cyclic N-Sulfonyl Ketimines and Isatin-Derived Ketimines.

An enantioselective Mannich reaction with cyclic N-sulfonyl ketimines as the nucleophiles was developed. In the presence of 5 mol % chiral thiourea catalyst C11, the asymmetric Mannich reaction between cyclic N-sulfonyl ketimines and isatin-derived ketimines was achieved in high yields and good-to-excellent enantioselectivities (84-99% yields with 75-99.8% ee). This methodology provided an effective route to construct chiral 3-amino-2-oxindoles containing a cyclic N-sulfonyl ketimine scaffold. The initial biological evaluation of the products in cell-based assays demonstrated that some compounds have excellent antiproliferative activity against human osteosarcoma cells.

Chiral Binaphthol-Catalyzed Enantioselective Conjugate Addition of Alkenyl and Arylboronic Acids to α,β-Unsaturated Cyclic N-Sulfonyl Ketimines.

The chiral binaphthol-catalyzed enantioselective conjugate addition of alkenylboronic acids and heteroarylboronic acids to cyclic N-sulfonyl ketimines is reported, providing the 1,4-addition products in high yields and moderate to excellent enantioselectivities (up to >99% ee). This mild, scalable catalytic system exhibits high efficiency and broad substrate scopes. Additionally, arylboronic acids were viable nucleophiles under more forcing conditions.

Chiral Spirophosphoric-Acid-Catalyzed Divergent Vinylogous Mannich and aza-Friedel-Crafts Reactions of 2-Methoxyfuran.

The first enantioselective vinylogous Mannich reaction is developed using 2-methoxyfuran under chiral spirophosphoric acid catalysis. The strategy involves 4-isoxazoline derivatives as cyclic ketimine surrogates and provides γ-butenolide scaffolds (up to 97% ee and >20:1 dr). The mechanistic investigations suggest that an in situ generated water molecule plays a crucial role in delivering γ-butenolide, while the use of molecular sieves delivers aza-Friedel-Crafts products. The synthetic utility of γ-butenolide is shown toward obtaining piperidone skeleton via a lactone-lactam rearrangement.

Organocatalytic Enantioselective Synthesis of Polycyclic Benzosultams from 2-Amino-β-nitrostyrenes with Cyclic N-Sulfonyl Ketimines.

A highly efficient enantioselective [4 + 2] cycloaddition of 2-amino-β-nitrostyrenes with cyclic N-sulfonyl ketimines has been developed. This reaction utilizes an organocatalytic approach, employing a multiple-hydrogen-bonding bifunctional squaramide-based catalyst. The process allows for the precise synthesis of chiral polycyclic benzosultams, showcasing intricate structures that incorporate chiral quaternary centers. Noteworthy outcomes of this method include high yields with excellent enantioselectivities and diastereoselectivities (up to 97% yield, 96% ee, and >20:1 dr).

Divergent access to polycyclic spiro- and fused-N,O-ketals through Bi(OTf)3-catalyzed [4+2]-annulation of cyclic N-sulfonyl ketimines and alkynols.

Bismuth(III) triflate-catalyzed [4+2]-annulation of cyclic N-sulfonyl ketimines (derived from saccharin) and alkynyl alcohols (4-pentyn-1-ols and 5-hexyn-1-ols) has been reported. This cascade annulation provides a diverse array of polycyclic spiro-and-fused N,O-ketals with excellent substrate scope, good isolated yields, and diastereoselectivities under mild reaction conditions.

Catalytic enantioselective [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones.

A highly efficient asymmetric [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones has been developed. This innovative reaction employs an organocatalytic approach, utilizing a hydrogen-bonding bifunctional squaramide-based catalyst. The process enables precise synthesis of chiral polyheterotricyclic oxazolidines and 1,3-oxazinane derivatives, revealing intricate structures with incorporated chiral quaternary centers. Remarkably, this method delivers high yields and exceptional enantioselectivities and diastereoselectivities, achieving up to 99% yield, >20 : 1 dr, and >99% ee.

Enantioselective construction of chiral gem-difluorinated C2-quaternary indoline via dual MgSO4–CPA-catalyzed asymmetric Mannich reactions

Herein, the synthesis of 2-(3,3-difluoro-2-phenylindolin-2-yl)-1-phenylethan-1-one scaffolds through asymmetric Mannich reactions between 3,3-difluoro cyclic ketimines and simple ketones is described.

Synthesis of Polycyclic Imidazolidinones via Cascade [3 + 2]-Annulation of β-Oxo-acrylamides with Cyclic N-Sulfonyl Imines.

An Et3N-catalyzed cascade [3 + 2]-annulation of β-oxo-acrylamides with cyclic N-sulfonyl ketimines or sulfamate-derived imines is developed under mild reaction conditions, which provides a concise and efficient route to access valuable sultam- or sulfamidate-fused imidazolidinone derivatives in good to excellent yields (80-95% yields) with excellent diastereoselectivities (>20:1 drs). The current protocol features atom economy, a transition-metal-free process, and broad functional group tolerance. Moreover, the asymmetric variant of the [3 + 2]-cycloaddition reaction was achieved in the presence of diphenylethanediamine or quinine-based bifunctional squaramide organocatalysts C-1 and C-11, giving the corresponding chiral polycyclic imidazolidinones in 68-90% yields with 25-94% ees and >20:1 drs in all cases.

Chiral-Boron-Complex Catalyzed Asymmetric Inverse-Electron-Demand Aza-Diels-Alder Reaction of β-Trifluoromethyl α,β-Unsaturated Ketones with Cyclic N-Sulfonyl Ketimines.

A highly efficient asymmetric inverse-electron-demand aza-Diels-Alder reaction of β-trifluoromethyl α,β-unsaturated ketone with cyclic N-sulfonyl ketimines catalyzed by (R)-3,3'-I2-BINOL-boron-complex was developed. A broad range of fused piperidine derivatives bearing stereogenic carbon containing CF3 motifs were prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and high stereoselectivity.

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.

W-Phos Ligand Enables Copper-Catalyzed Enantioselective Alkylation of N-Sulfonyl Ketimines with Grignard Reagents

Catalytic asymmetric addition of reactive Grignard reagents to ketimines poses a considerable challenge. Herein, a PNP-type W-Phos ligand developed recently by our group showed a unique effect toward this end, paving the way to a Cu(I)-catalyzed asymmetric alkylation reaction of N-sulfonyl ketimines, delivering optically active α-tertiary amines in high enantioselectivities. This catalytic protocol shows an unprecedented substrate scope with more than 80 examples, not only compatible with benzo five- and six-membered cyclic N-sulfonyl ketimines but also suitable for geometrically unstable (E or Z) acyclic N-sulfonyl ketimines. The application potential of the protocol is featured by the extensive presence of α-tertiary amines in natural products and pharmaceutical compounds and also demonstrated by downstream transformations with maintenance of the enantioselectivity.

Rhodium-catalyzed addition reactions of benzylic C–H bonds to cyclic N-sulfonyl ketimines via π-coordination

Mannich-type reactions are a widely used method for the synthesis of amines due to the readily availability of nucleophiles and electrophiles. However, the inclusion of alkylarenes instead of active carbon pronucleophiles such as aldehydes and ketones in these addition reactions has been a challenge due to the inherent difficulty of benzylic deprotonation. In this study, we present a novel approach for the construction of N-sulfonyl amines via rhodium-catalyzed addition of unbiased benzylic CH bonds to cyclic N-sulfonyl ketamines through π-coordination. This strategy enables the synthesis of a diverse range of N-sulfonyl amines, and subsequent diversification of the addition products showcases the synthetic potential of this protocol.

A One‐Pot Approach to Multi‐Substituted Fused Aziridines: Formal Intermolecular [2+1] Cycloaddition Reaction between Saccharin‐Derived Cyclic Ketimines and Sulfur Ylides

AbstractHerein a concise and efficient method for the synthesis of aziridines has been developed. The reaction proceeds through a formal intermolecular [2+1] cycloaddition reaction of saccharin‐derived cyclic ketimines with sulfur ylides. This methodology features high atom‐economy, broad substrate scope and an operationally simple procedure, affording the aziridines with excellent yields and diastereoselectivity (>20 : 1 dr). In the presence of base, the aziridine products could be readily converted to benzothiazines by an unusual rearrangement reaction.

Asymmetric aza-Friedel-Crafts Reaction of Cyclic Ketimines with 5-Aminopyrazole Derivatives: Expedient Access to Pyrazole-Based C2-quaternary Indolin-3-Ones.

A chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of 5-aminopyrazole derivatives with cyclic ketimines attached to a neutral functional group is reported. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 5-aminopyrazole-based C2-quaternary indolin-3-ones was performed, with no decrease in the yield and enantioselectivity.

Copper-Catalyzed Highly Enantioselective Addition of a Silicon Nucleophile to 3-Substituted 2H-Azirines Using an Si-B Reagent.

3-Substituted 2H-azirines can be considered strained cyclic ketimines, and highly enantioselective addition reactions of silicon nucleophiles to either acyclic or cyclic ketimines have been elusive so far. The present work closes this gap for those azirines by means of a copper-catalyzed silylation using a silyl boronic ester as a latent silicon nucleophile. The resulting C-silylated, unprotected (N-H) aziridines are obtained in high yields and with excellent enantioselectivities and can be further converted into valuable compounds with hardly any erosion of the enantiomeric excess.

Cooperative NHC and nickel-catalyzed asymmetric reductive coupling of nitrobenzyl bromides and cyclic ketiminesviaSET process

A synergistic NHC/Ni catalyzed asymmetric reductive coupling of nitrobenzyl bromides with cyclic ketiminesviaSET process was realized.

Rh-Catalyzed [3+2] Annulation of Cyclic Ketimines and Alkynyl Chloride: A Strategy for Accessing Unsymmetrically Substituted and Highly Functionalizable Indenes.

Alkynyl chlorides were found to be extraordinarily novel electrophiles, which could afford a single regioisomer of the [3+2] annulation adducts with cyclic ketimines by rhodium catalysis. The alkenyl chloride moiety in the products provided a valuable functional handle for further diverse transformations. Therefore, this research provided not only a synthetic protocol for accessing unsymmetrically substituted indenyl amines but also a highly divergent solution for decorating the substituting group by postmanipulation of the chloride.

Regio- and Diastereoselective [3 + 2]-Spiroannulation of Benzoxazines with Chalcones: A Rh(III)-Catalyzed Redox-Neutral Approach to α-Aroyl Spiro-Indanamines

We report an atom-economic Rh(III)-catalyzed [3 + 2]-spiroannulation reaction between cyclic ketimines and α,β-unsaturated carbonyl compounds, allowing the synthesis of novel spirocycles with concomitant generation of three stereogenic centers in one pot. The reaction does not require any silver additives or external oxidants and is believed to proceed in a redox-neutral manner. A broad substrate scope with good functional group tolerance permitted the synthesis of a vast spectrum of spirocyclic 1,4-benzoxazine derivatives containing polysubstituted α-aroyl-indanamines in good to excellent yields with high diastereoselectivity.

Theoretical Insights into Enantioselective [3 + 2] Cycloaddition between Cinnamaldehyde and Cyclic N-Sulfonyl Trifluoromethylated Ketimine Catalyzed by N-Heterocyclic Carbene.

The density functional theory (DFT) method was used to investigate the mechanism and the origin of stereoselectivity of N-heterocyclic carbene (NHC)-catalyzed [3 + 2] cycloaddition between enals and cyclic imine N-sulfonyl trifluoromethyl ketimines at the M06-2X/SMD/6-311+G(d,p)//M06-2X/SMD/6-31G (d,p) level. The results show that the favorable reaction path consists of five steps: nucleophilic attack, proton transfer, the formation of the C-C bond, the tautomerism of the enol intermediate, the formation of the five-membered ring, and the regeneration of the catalyst. For the process of proton transfer, the base-assisted reaction can reduce the activation free energy and make the reaction easier to occur compared with the direct proton transfer process. The formation of the C-C bond is the crucial step of stereoselectivity, in which two chiral centers and four configurations of intermediates (RR/RS/SR/SS) were generated. The free energy barriers obtained and the noncovalent interaction analysis confirm that the dominant configuration is SS, becoming the final trans-type product observed in experiment. Furthermore, through the analyses of the conceptual DFT and natural atomic charges, it is revealed that NHC acts as a double catalyst, which can not only increase the nucleophilicity of reactants by Lewis base but also activate the C-H bond and promote the proton transfer process. The understanding of the mechanism obtained in this study should be helpful to the other organic catalytic reactions with high stereoselectivity.