Currier Reaction Research Articles

Concise Synthesis of Tetrasubstituted 1,6-Dihydropyridazine and Pyridazine Derivatives

AbstractA novel one-pot three-steps process has been developed, including phosphine-catalyzed Rauhut–Currier reaction of γ-alkyl allenoates, Diels–Alder reaction with di-tert-butyl azodicarboxylate, followed by deprotection of Boc group to prepare tetra-substituted 1,6-dihydropyridazines in good yields. The 1,6-dihydropyridazines were easily converted to pyridazine derivatives via oxidative aromatization by DDQ.

Chiral Aziridine Phosphines as Highly Effective Promoters of Asymmetric Rauhut–Currier Reaction

A series of chiral enantiomerically pure aziridines containing a phosphine moiety were synthesized and successfully applied as organocatalysts in asymmetric intramolecular Rauhut–Currier reactions of p-quinone derivatives. The desired chiral phenols were achieved in high chemical yields and with satisfactory values of enantiomeric excess (up to 98% ee, in some cases). The stereochemical course of the title reaction may be controlled by the use of an appropriate enantiomer of the catalyst. The individual enantiomers of the organocatalyst led to the formation of specific enantiomers of the chiral product.

Identification and Characterization of the First Biological Rauhut–Currier Reaction

Identification and Characterization of the First Biological Rauhut–Currier Reaction

An isatin aldol adduct as a precursor to α,α’-difunctionalized methyl vinyl ketones

Isatin-methyl vinyl ketone aldol adducts underwent efficient Morita–Baylis–Hillman (MBH) and Rauhut–Currier (RC) reactions under mild conditions to bring about a functionalization of the olefinic α-carbon, and thereby α,α’-difunctionalization of methyl vinyl ketone in the process. The MBH adducts were characterized by the presence of a 2-methylene-1,3,5-trioxygenated system, whereas the RC dimerization of the substrate furnished compounds that bore two oxindole moieties, each adorned with a tetrasubstituted carbon and a hydroxyl group.

Asymmetric cross Rauhut–Currier reactions of vinyl ketones with carbonylpara-quinone methidesviaphosphine catalysis

Novel cross Rauhut–Currier reactions, involving chiral phosphine catalysis, between vinyl ketones and terminal-carbonyl-substitutedpara-quinone methides are presented.

Evidence for an Enzyme-Catalyzed Rauhut-Currier Reaction during the Biosynthesis of Spinosyn A.

The catalog of enzymes known to catalyze the nucleophile-assisted formation of C-C bonds is extremely small, and there is presently no definitive example of a biological Rauhut-Currier reaction. Biosynthesis of the polyketide insecticide spinosyn A in Saccharopolyspora spinosa involves a [4 + 2]-cycloaddition and a subsequent intramolecular C-C bond formation catalyzed by SpnF and SpnL, respectively. Isotope tracer experiments and kinetic isotope effects, however, imply that the SpnL-catalyzed reaction proceeds without initial deprotonation of the substrate. The crystal structure of SpnL exhibits high similarity to SAM-dependent methyltransferases as well as SpnF. The residue Cys60 is also shown to reside in the SpnL active site, and the Cys60Ala SpnL mutant is found to be devoid of activity. Moreover, SpnL is covalently modified at Cys60 and irreversibly inactivated when it is coincubated with a fluorinated substrate analogue designed as a suicide inactivator of nucleophile-assisted C-C bond formation. These results suggest that SpnL catalyzes a biological Rauhut-Currier reaction.

DMAP Catalyzed Domino Rauhut-Currier Cyclization Reaction between Alkylidene Pyrazolones and Nitro-olefins: Access to Tetrahydropyrano[2,3-c]pyrazoles.

Herein, we employ unsaturated pyrazolones in the Rauhut-Currier reaction for the first time. A domino Rauhut-Currier cyclization reaction has been developed between unsaturated pyrazolones and nitro-olefins. The trisubstituted tetrahydropyrano[2,3-c]pyrazoles were obtained in moderate to high yields with excellent diastereoselectivities. A few applications including a synthesis of disubstituted tetrahydropyrano[2,3-c]pyrazole have been demonstrated. A preliminary catalytic asymmetric version of this process was also studied with chiral DMAP catalysts.

Chemoselective synthesis of multifunctional ferrocene-containing derivatives by the cross Rauhut-Currier reaction.

A simple protocol has been developed for the chemoselective synthesis of ferrocene-containing Rauhut–Currier adducts from 1-ferrocenyl-2-nitroethene and vinyl ketones using 20 mol% of triphenylphosphine. Multifunctional ferrocene derivatives were obtained in moderate to high yields (51–92%) by the coupling between the α-position of vinyl ketones and the β-position of the nitroalkene. The study of the Rauhut–Currier reaction under the described conditions showed that the strong electron-donating group at the β-position of nitroalkenes plays a significant role in the reaction outcome due to prevention of polymerization and stabilization of the zwitterionic intermediate. Additionally, a preparative synthesis of 4-ferrocenyl-3-methylene-5-nitropentan-2-one was carried out and its synthetic transformations showed easy conversion to other useful building blocks.

Asymmetric Intramolecular Rauhut-Currier Reaction and Its Desymmetric Version via Double Thiol/Phase-Transfer Catalysis.

An asymmetric intramolecular Rauhut-Currier reaction of linear bis(enones) has been achieved via double activation catalysis of thiols and phase transfer substances, furnishing both enantioenriched cyclohexene and cyclopentene derivatives (up to 95% ee). Furthermore, the desymmetric version of prochiral substrates was developed under similar catalysis, producing the frameworks bearing an additional tertiary or even quaternary stereogenic center with moderate to excellent diastereo- and enantioselectivity (up to 95% ee, >19:1 dr).

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Organocatalyzed Rauhut–Currier and [3+2] Annulation Domino Reaction under Flow Conditions

Key words organocatalysis - Rauhut–Currier reaction - [3+2] annulation - domino reaction - spirooxindoles - artificial intelligence

The Intramolecular Rauhut−Currier Reaction between Nitroalkenes and Acrylates: An Approach to 3‐Methylene‐3,4‐Dihydrocoumarin Scaffold

AbstractThe intramolecular Rauhut−Currier reaction between nitroalkene and acrylate has been successfully carried out. The reaction proceeds in the presence of a sulfinamide based bifunctional phosphine in dichloromethane to provide the biologically relevant 3‐methylene‐3,4‐dihydrocoumarin in acceptable yields. Unlike with other nitroalkenes participated cross R−C reactions, in this reaction, nitroalkenes work as electrophiles rather than nucleophiles. The nature of the substituent plays an important role on the chemoselectivity of this reaction. Normal Rauhut−Currier reaction products were obtained for substrates with electron‐donating substituent on the benzene ring, whereas isomerized coumarin products were obtained for those bearing halogen substituent.

Mechanistic insights can resolve the low reactivity and selectivity issues in intermolecular Rauhut–Currier (RC) reaction of γ-hydroxyenone

Low reactivity of Rauhut–Currier reaction can be resolved by shifting the equilibrium of the enone/enolate of the substrate towards enolate.

Halide Anion Triggered Reactions of Michael Acceptors with Tropylium Ion

AbstractTropylium bromide undergoes noncatalyzed, regioselective additions to a large variety of Michael acceptors. In this way, acrylic esters are converted into β‐bromo‐α‐cycloheptatrienylpropionic esters. The reactions are interpreted as nucleophilic attack of bromide ions at the electron‐deficient olefins and the approach of the tropylium ion to the incipient carbanion. Quantum chemical calculations were performed to elucidate the analogy to the amine‐ or phosphine‐catalyzed Rauhut–Currier reactions. Subsequent synthetic transformations of the bromo‐cycloheptatrienylated adducts are reported.

Asymmetric NHC-Catalyzed Rauhut–Currier Reaction of Weakly Electrophilic Bisenoates

Asymmetric NHC-Catalyzed Rauhut–Currier Reaction of Weakly Electrophilic Bisenoates

Double Thiol-Chiral Brønsted Base Catalysis: Asymmetric Cross Rauhut-Currier Reaction and Sequential [4 + 2] Annulation for Assembly of Different Activated Olefins.

A double catalytic system combining 2-mercaptobenzoic acid and a chiral phase transfer substance was disclosed for the intermolecular cross Rauhut-Currier reaction of 2-cyclopentenone and isatin-based alkylidene malononitriles. The resulting chiral adducts were sequentially assembled with diverse electron-deficient olefins to furnish highly enantioenriched cyclohexane derivatives (up to 96:4 er, >19:1 dr). A similar catalytic system of 2-mercaptobenzoic acid and quinine was further developed for the reaction of 2-cyclopentenone and α-cyano chalcones (up to 96.5:3.5 er).

Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

AbstractWhile the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high‐nucleophilicity N‐heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

Enantioselective N-Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut-Currier Reaction.

While the enantioselective Rauhut-Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high-nucleophilicity N-heterocyclic carbenes, it is possible to achieve Rauhut-Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

Ferrocene-based bifunctional organocatalyst for highly enantioselective intramolecular Rauhut–Currier reaction

Three series of novel ferrocene-based bifunctional chiral phosphines have been designed and synthesized. Thethiourea-phosphine A7 showed good performance in enantioselective intramolecular Rauhut–Currier reaction of bis(enones), giving the corresponding products in good yield with up to 98% ee. Moreover, with amino acid derived amide-phosphine B3, optically active α-methylene-δ-valerolactone was obtained in 88% yield and > 99.9% ee utilizing the enantioselective intramolecular Rauhut-Currier reaction of chalcone derivative.

Sulfinate and Carbene Co‐catalyzed Rauhut–Currier Reaction for Enantioselective Access to Azepino[1,2‐a]indoles

AbstractA carbene and sulfinate co‐catalyzed intermolecular Rauhut–Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co‐catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst‐bound intermediates. The dual catalytic reaction affords azepino[1,2‐a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron‐deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions.