Catalytic enantioselective conjugate addition of indoles to simple α,β-unsaturated ketones

Chiral [Al(salen)Cl] complex (10 mol%) in the presence of 2,6-lutidine (10 mol%) was found to be effective in catalysing the enantioselective Friedel-Crafts-type conjugate addition of indoles (3) to (E)-arylcrotyl ketones (2), furnishing the corresponding β-indolyl ketones in excellent yield and high enantioselectivity (ee up to 89%).     

Cobalt-catalyzed conjugate addition of silylacetylenes to α,β-unsaturated ketones

Catalytic addition of silylacetylenes to α,β-unsaturated ketones proceeded in the presence of a cobalt complex coordinated with a bisphosphine ligand to give high yields of β-alkynylketones.     

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides took place in good yields to give products exclusively with cis-β,γ-olefinic bond.     

Green, efficient and practical Michael addition of arylamines to α,β-unsaturated ketones

The aza-Michael addition of aromatic amines to α,β-unsaturated ketones was carried out effectively at room temperature in good to excellent yields without any catalyst or solvent. It was significant that part of adducts could be collected in almost quantitative yield without column chromatography. This procedure offered a green, efficient, and practical approach for the synthesis of β-amino ketones.     

Organocatalyzed enantioselective michael addition of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonatesθ

By employing a cinchonine-based thiourea as catalyst, highly enantioselective Michael addition reactions of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonates were realized. The reaction afforded the corresponding β-substituted carboxylates in excellent yields with high levels of enantioselectivities (94->99% ee) upon quenching the generated parent structures with DBU and MeOH as a second nucleophile.     

Rhodium-catalyzed conjugate addition of arylindium reagents to α,β-unsaturated carbonyl compounds

A novel rhodium-catalyzed conjugate addition of indium reagents to electron deficient olefins is reported. The reaction takes place in THF/MeOH at 110 °C using arylindium dichlorides, a rhodium(I)-binap complex as catalyst, and α,β-unsaturated ketones and lactones in good yields (45–94%). The addition of MeOH is crucial for an efficient transformation and NMR studies seem to indicate that promotes the catalytic cycle leaving the indium organometallic unaltered. The use of chiral non-racemic ligands allows performing the reaction with moderate enantioselectivities.     

Rhodium-catalyzed asymmetric 1,4-addition of arylboron reagents to α,β-unsaturated esters

Reaction of arylboron reagents, arylboronic acids or arylborates, which are readily accessible by lithiation of aryl bromides followed by treatment with trimethoxyborane, with α,β-unsaturated esters in the presence of rhodium/(S)-binap catalyst proceeded with high enantioselectivity to give high yields of optically active β-aryl esters of up to 98% ee. The enantioselectivity depends on the steric bulkiness of the ester moiety.     

Copper-catalyzed conjugate additions of alkylboranes to imidazolyl α,β-unsaturated ketones: formal reductive conjugate addition of terminal alkenes

Conjugate addition of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl α,β-unsaturated ketones proceeded in the presence of a catalytic amount (10 mol %) of CuCl, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), and t-BuOK. The alkylboranes are available through alkene hydroboration, and thus the overall process represents a reductive conjugate addition of alkenes to enone derivatives. A variety of functional groups are tolerated in both the alkenes and the α,β-unsaturated ketones. The 2-acylimidazole moiety can easily be converted into the corresponding carboxylic acid, ester, and amide derivatives.     

Sc(III)-catalyzed enantioselective addition of thiols to α,β-unsaturated ketones in neutral water

This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)(3)/bipyridine 1 catalytic system. It is noteworthy that the protocol presented employs water as a reaction medium and allows us to obtain very high stereoselectivity and satisfactory yields for β-keto sulphides deriving from aliphatic thiols. The recovery and reuse of both the aqueous medium and the catalytic system is also reported.     

Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral δ-keto nitroalkanes and δ-keto esters.     

Highly enantioselective Cu(I)-Tol-BINAP-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-unsaturated esters

The copper-catalyzed conjugate addition (CA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the construction of C-C bonds. Interestingly, the application of Grignard reagents, which are among the most widely used of organometallic compounds, in asymmetric conjugate addition (CA) reactions has received less attention. Therefore, our group and others have been exploring better catalytic systems to effect the asymmetric 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters. It is only in the past decade that significant breakthroughs have been made in this field. In our studies, we found that CuI-Tol-BINAP could catalyze the asymmetric conjugate addition (CA) reactions of Grignard reagents, including the addition of MeMgBr to α,β-unsaturated esters to afford the β-methylated esters in good yields with excellent regio- and enantioselectivities. Both enantiomers of the products could be obtained by either using the enantiomers of the chiral Tol-BINAP or by using the geometrical isomer of the starting material. This method is also suitable for other Michael acceptors. In this article, we describe the development of the asymmetric Cu(I)-Tol-BINAP catalyzed 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters and applications of this chemistry. This method provides a convenient method to synthesize β-alkyl esters with high enantioselectivity or diastereoselectivity using CuI and the inexpensive chiral ligand, Tol-BINAP.     

Conjugate addition to α,β-unsaturated ketones with mixed lithium triorganozincates

Lithium Triorganozincates of the type RR′₂ZnLi, where R′ = Me and R = n-Bu or sec-Bu, efficiently transfer the R group in a 1,4 fashion to α,β-unsaturated ketones.     

Recyclable graphite oxide catalyzed Friedel-Crafts addition of indoles to α,β-unsaturated ketones

The Friedel-Crafts addition of indoles to α,β-unsaturated ketones, and nitro styrenes was studied with graphite oxide as catalyst. Various indole derivatives were synthesized in good to excellent yields. The preparation of graphite oxide catalyst from simple and readily available starting materials makes this method more affordable. The heterogeneous graphite oxide can be easily recovered and recycled up to five cycles without loss of activity.     

Highly enantioselective conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Asymmetric conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones was studied using chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient catalyst for the transformation. 4-Bromo-4-nitroketones were obtained with excellent enantioselectivities (97-99% ee) and good yields (61-99%) for a variety of alkyl vinyl ketones. The product could be further debrominated with Bu₃SnH/AIBN to provide chiral 4-nitroketones in good yield and without loss of the optical purity.     

Enantioselective sulfa-Michael addition of thioacids to α,β-unsaturated ketones with bifunctional organocatalyst

Organocatalytic conjugate addition of thioacids to α,β-unsaturated ketones has been studied in the presence of cinchona alkaloid derived urea catalyst. Both the enantiomers of products are accessible with the same level of enantioselectivity using pseudoenantiomeric quinine/quinidine derived catalysts. The catalytic process provides optically active thioesters with high chemical yields (up to 99%) and useful enantioselectivity (up to 83% ee). The reaction was performed with 1 mol % of catalyst in toluene at room temperature. A transition state model has been proposed to explain the stereochemical outcome of the reaction.     

1,4-Conjugate addition of 2-hydroxynaphthazarins to acyclic and cyclic α,β-unsaturated ketones. Prototropic ring-chain tautomerism of the adducts

TsOH-Catalyzed reactions of 6,7-disubstituted 2-hydroxynaphthazarins and acyclic or cyclic α,β-enones afforded the corresponding Michael-type adducts, viz., 3-substituted naphthazarins in 17–78% yields. ¹H and ¹³C NMR and IR spectroscopy showed that the adducts with cyclohexenone and methyl vinyl ketone exist in CDCl₃ solutions as mixtures of open-chain and cyclic tautomers, whereas the adducts with cyclopentenones exist only as the open-chain forms.     

Two-carbon homologation of aldehydes and ketones to α,β-unsaturated aldehydes

Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched α,β-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.     

Modular approach to saturated and α,β-unsaturated ketones

2-Fluoro-6-pyridinyloxy derivatives of 2-ethoxyvinyl carbinols react with radicals derived from xanthates by an addition-fragmentation pathway to give highly functionalized ketones after acid hydrolysis. 1,4-Diketones are readily accessible by this approach. α,β-Unsaturated ketones can be obtained by starting with geminal acetoxy xanthates prepared by addition of a simpler xanthate to vinyl acetate.     

NHC–copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones

N-Heterocyclic carbene–copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones was developed for the synthesis of chiral phosphorus derivatives in high yields with moderate enantioselectivity under mild conditions.