Catalytic Addition Research Articles

Organocatalytic Enantioselective Nucleophilic Addition of Indole Imine 5-Methides.

Despite the enormous developments in the asymmetric transformations of indole imine methides (IIMs), the remote asymmetric induction involving IIMs remains challenging due to the spatial interaction requirement between the substrate and catalyst. Herein we report the first catalytic asymmetric nucleophilic addition to indole imine 5-methide (5-IIM), the only topological isomer of IIMs whose asymmetric addition remains unknown. Despite the challenging remote stereocontrol, high efficiency and respectable enantioselectivity were achieved to provide access to a range of enantioenriched indole-containing triaryl alkanes.

Catalytic asymmetric conjugate addition of coumarins to unsaturated ketones catalyzed by a chiral-at-metal Rh(III) complex.

The first catalytic asymmetric vinylogous Michael addition of coumarins to unsaturated ketones catalyzed by chiral rhodium catalysts has been established. This strategy allowed the synthesis of a variety of highly enantioenriched compounds containing coumarin skeletons in 41-99% yields and 84-99% ee. The developed reaction enriches the chemistry of catalytic asymmetric vinylogous Michael additions of 3-cyano-4-methylcoumarins. Furthermore, the protocol showed obvious advantages in reaction enantioselectivity. When the chiral rhodium catalyst was reduced to 0.06 mol%, a Gram-level reaction was still achieved to provide the desired products with 99% ee.

A de novo synthesis of the bisindole alkaloid geissolosimine: collective synthesis of geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids

Collective synthesis of geissolosimine, geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids was achieved based on a catalytic asymmetric double Michael addition.

Amide-Directed, Rhodium-Catalyzed Regio- and Enantioselective Hydroacylation of Internal Alkenes with Unfunctionalized Aldehydes.

Despite the current progress achieved in asymmetric hydroacylations, highly enantioselective catalytic addition of unfunctionalized aldehydes to internal alkenes remains an unsolved challenge. Here, using a coordination-assisted strategy, we developed a rhodium-catalyzed regio- and enantioselective addition of unfunctionalized aldehydes to internal alkenes such as enamides and β,γ-unsaturated amides. Valuable α-amino ketones and 1,4-dicarbonyl compounds were directly obtained with high enantioselectivity from readily available materials.

Synthesis of α,β-diamino acid derivatives by acid-catalyzed Aza-Michael addition of N-phthalyldehydroalanine with different amine

A series of α,β-diamino acid derivatives were synthesized from N-phthalyldehydroalanine with different amines by acetic acid catalytic Aza-Michael additions. This reaction achieves C–N bond formation with good functional group tolerance. Under optimized conditions, the desired products of most aromatic and secondary aliphatic amines were obtained in moderate to good yields under mild conditions. The electronic effect and steric effect play the important roles to the reactivity of amines.

Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Chiral Macrocyclic Catalysts for the Enantioselective Addition of Lithium Acetylides to Ketones.

Alkynyl addition to carbonyl compounds is a valuable synthetic method for the preparation of versatile chiral alcohols that are widely found in pharmaceuticals and natural products. Although a variety of enantioselective variations have been reported, alkynyl addition to simple ketones remains an unmet challenge due to their low reactivity and difficult enantiofacial discrimination. Here, we report a method for the catalytic enantioselective addition of lithium acetylide to a variety of ketones using macrocyclic lithium binaphtholates as catalysts. These reactions generally suffer from facile aggregation of lithium species, which leads to less active and selective catalysts. The macrocyclic structure designed in this study prevents such aggregation, affording a monomeric and highly active catalyst that can furnish enantioenriched tertiary alcohols from a variety of ketones within 5-30 min. Moreover, the confined cavity and lipophilicity of the macrocycle confer substrate specificity on the system, demonstrating a multiselectivity similar to that of enzymatic reactions. Thus, these findings offer new insights into the rational design of small-molecule artificial enzymes that exhibit high levels of reactivity and multiselectivity.

Enantioselective Michael Addition of Malononitrile to Unsaturated Ketones Catalyzed by Rare-Earth Metal Amides RE[N(SiMe3)2]3 with Phenoxy-Functionalized TsDPEN Ligands.

The catalytic enantioselective Michael addition of α,β-unsaturated ketones with malononitrile was well established using rare-earth metal amides RE[N(SiMe3)2]3 (RE = Y, Eu, Sm, Nd, La) with chiral phenoxy-functionalized TsDPEN ligands. The combination of lanthanum amide La[N(SiMe3)2]3 and chiral TsDPEN ligand H3L1 [H3L1 = N-((1R,2R)-2-((3,5-di-tert-butyl-2-hydroxybenzyl)amino)-1,2-diphenylethyl)-4-methylbenzenesulfonamide] in a 1:1.5 molar ratio was proved to be the optimal partner in THF, which provided the desired β-carbonyl dinitriles in excellent yields and good to high enantioselectivities after 12 h at -15 °C.

Chiral Lewis Acid-Catalyzed Asymmetric Multicomponent Michael Reaction through [1,2]-Phospha-Brook Rearrangement.

The multicomponent catalytic asymmetric Pudovik addition/[1,2]-phospha-Brook rearrangement/Michael reaction sequence of isatins, phosphites, and 4-oxobutenoates was realized. A series of oxindole derivatives containing two contiguous stereocenters was obtained in high yields and excellent stereoselectivities (up to >99% yield, >95:5 dr, >99% ee) using a chiral Lewis acid catalyst. A possible catalytic model is presented to illustrate the stereocontrol.

Carbene-Catalyzed Regioselective Addition of Oxindoles to Ynals for Quick Access to Allenes

AbstractA catalytic regioselective addition reaction of oxindoles with ynals is developed. Allene-containing derivatives bearing various substituents and substitution patterns are afforded as the products in generally moderate to good yields with moderate diastereoselectivities. Several of allenes obtained from this protocol are valuable in the development of novel bactericides for plant protection.

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.

Formal Addition of β‐Acylalkenyl Anions to Ketones Utilizing [1,2]‐Phospha‐Brook Rearrangement under Brønsted Base Catalysis

AbstractA methodology for the formal addition of β‐acylalkenyl anions was developed by utilizing the [1,2]‐phospha‐Brook rearrangement under Brønsted base catalysis. The two‐step reaction involves the catalytic addition of α‐oxygenated propargyl anions generated via [1,2]‐phospha‐Brook rearrangement to electron‐deficient ketones and subsequent alcoholysis to afford tertiary alcohols having an enone moiety. This is a rare example of a catalytic carbon‐carbon bond forming reaction of β‐acylalkenyl anion equivalents, providing synthetic building blocks that are otherwise difficult to access.

Confronting the Challenge of Asymmetric Carbonyl Addition to Sterically Bulky Isatins: Upgrading Dirhodium(II)/Biphosphine Catalytic System

Catalytic asymmetric addition of arylboronic acids to ketones is a powerful transformation for directly delivering chiral tertiary alcohols. However, there is no successful example of enantioselective addition to steric bulky isatins, which contain bulky substituent at the 4-position. To confront this challenge, in this work a dirhodium/(BTFM-Garphos) system was developed that showed extremely high activity and stereoselectivity, and the reactions were usually finished within a few minutes.

Catalytic Asymmetric Cyclopropanations with Nonstabilized Carbenes.

Cyclopropanes are common building blocks in pharmaceuticals, agrochemicals, and organic materials. The most general methods for the synthesis of chiral cyclopropanes are catalytic additions of diazoalkanes to alkenes. However, a limitation of this approach is that diazoalkanes can only be safely handled on preparative scales if they possess stabilizing substituents. Here we show that gem-dichloroalkanes can serve as precursors to nonstabilized carbenes for asymmetric cyclopropanation reactions of alkenes. The process uses a cobalt catalyst and is proposed to involve the formation of a cationic carbenoid species bearing structural resemblance to the Simmons-Smith reagent. High levels of enantioselectivity are observed for monosubstituted, 1,1-disubstituted, and internal alkenes. The reaction is compatible with alkyl-substituted carbenes, which are susceptible to undergoing competing 1,2-hydride shifts.

Enantioselective Transformations from Nitriles to NH2 -α-Tertiary Amines.

Organic molecules, containing one or more amine chiral centers, are very common to see in natural products and medicines. Although a large number of methods have been developed to afford enantiopure amines, most of the known approaches are limited with various reasons. For example, many methodologies start from nitrogen protected and activated substrates, which usually need multistep operations and seriously decrease the atom economy. Here we disclose a new catalytic strategy from commercial nitriles to high enantioselective α-tertiary primary amines in up to 90 % yield and 95 % enantiomeric excess. This transformation firstly undergoes an addition process of organolithium reagents to nitriles to generate the imine intermediates in situ. Subsequently, the most challenging step is by employing copper catalytic enantioselective addition of AllylBpin to the imine intermediates to form the final amines in one pot.

Catalytic Asymmetric Conjugate Addition of 1,4-Dienes to β-Substituted Alkenyl Azaarenes

Key words asymmetric conjugate addition - azaarenes - copper catalysis - 1,4-dienes

Directing Group Repositioning Strategy Enabled Site- and Enantioselective Addition of Heteroaromatic C-H Bonds to Acyclic Internal Alkenes.

Despite the notable advances achieved in the Murai-type hydroarylations, highly enantioselective catalytic addition of native (hetero)arenes to internal alkenes remains a prominent challenge. Herein, we report a directing group repositioning strategy, which enables the iridium-catalyzed enantioselective addition of heteroarenes including furan, benzofuran, and thiophene to internal enamides. The C-H bond at the C2 position of the heteroarene is site-selectively cleaved and added regioselectively to the β-position of an enamide, affording a valuable β-heteroaryl amide with high enantioselectivity. Mechanistic studies indicate that the rate and the enantioselectivity are determined by separate elementary steps.

Enantioselective Catalytic Addition of N‐Acyl Radicals: In Batch and In Flow Organophotoredox α‐Amination of Aldehydes

AbstractThe organophotoredox catalytic enantioselective addition of N‐acyl radicals to aldehydes, to afford enantioenriched N‐acyl 1,2 aminoalcohols was studied. Under the best conditions, in batch, the product was isolated in up to 52 % yield and 85 % e.e., using a low cost and commercially available chiral imidazolidinone as organocatalyst. The reaction was then studied in flow, exploring different experimental setups and photoreactors. Although modest yields were obtained, the in‐flow process afforded the product in higher productivities (up to 60 times higher) and improved space time yields (increased up to 113 times) compared to the batch reaction, with no loss of stereoselectivity.

Recent Advances in Catalytic and Technology-Driven Radical Addition to N,N-Disubstituted Iminium Species.

Recently, radical chemistry has grown exponentially in the toolbox of organic synthetic chemists. Upon the (re)introduction of modern catalytic and technology-driven strategies, the implementation of highly reactive radical species is currently facilitated while expanding the scope of numerous synthetic methodologies. In this context, this review intends to cover the recent advances in radical-based transformations of N,N-disubstituted iminium substrates that encompass unique reactivities with respect to imines or protonated iminium salts. In particular, we have focused on the literature concerning the dipole type substrates, such as nitrones or azomethine imines, together with the chemistry of N+-X- (X = O, NR) azaarenium dipoles, which proved to be very versatile platforms in that field of research. The N-alkylazaarenium salts were been considered, which demonstrated specific reactivity profiles in radical chemistry.