Michael addition-electrophilic quenching chemistry of maleimides using dialkylzinc reagents

Michael addition-electrophilic quench reactions of N-alkyl maleimides are possible using dialkylzincs in combination with a copper catalyst and a phosphoramidite ligand. Up to 55% ee has been achieved for one example (E = H) using a chiral ligand.     

Chiral squaramides catalyzed diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides

An efficient diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides catalyzed by quinine or cyclohexane-1,2-diamine derived squaramide catalysts has been disclosed, affording the corresponding adducts in good yields (up to 99%), high diastereoselectivities (up to >20:1 dr) and good to excellent enantioselectivities (up to 94% ee) under mild conditions.     

Enantio- and diastereoselective construction of vicinal quaternary and tertiary carbon centers by catalytic Michael reaction of α-substituted β-keto esters to cyclic enones

A catalytic enantio- and diastereoselective Michael reaction was achieved to construct vicinal quaternary and tertiary carbon centers in one step. Using 5 mol % of La(O-i-Pr)₃ and 10 mol % of a new N-linked-BINOL type ligand, the reaction of α-substituted β-keto esters to cyclic enones provided the corresponding Michael adducts in up to quantitative yield with a diastereomeric ratio up to 86/14 and enantiomeric excess up to 86% for the major isomer. An alternative catalyst preparation method using La(OTf)₃ instead of La(O-i-Pr)₃ was also examined.     

Solvent-dependent enantioswitching in the Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-diamines

Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. Using a single enantiomer of the organocatalyst, both enantiomeric forms of the resulting Michael adducts bearing a new quaternary stereocenter are obtained in high yields, by only changing the reaction solvent from chloroform (up to 86% ee) to aqueous DMF (up to 84% ee).     

Chiral Co(II) complex catalyzed asymmetric Michael reactions of β-ketoamides to nitroolefins and alkynones

The catalytic enantioselective Michael additions of cyclic β-ketoamides to nitroolefins and alkynones were accomplished in the presence of chiral N,N′-dioxide–Co(II) complexes. The desired adducts were obtained in high yields (up to 98%) with excellent enantioselectivities (up to 97% ee).     

Calixarene-based chiral primary amine thiourea promoted highly enantioselective asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides

Calix[4]arene based chiral bifunctional thiourea-primary amines have been shown to act as effective catalysts for the Michael addition of aldehydes to maleimides for the first time. The corresponding adducts were generally obtained preferentially in (R)- or (S)-forms with high yields (up to 99%) and with high to excellent enantioselectivities (up to 98% ee).     

A new type of organocatalyst for highly stereoselective Michael addition of ketones to nitroolefins on water

(S)-2-((Naphthalen-2-ylsulfonyl)methyl)pyrrolidine, prepared in three steps from (S)-N-Boc-2-[((4-toluenesulfonyl)oxy)methyl]pyrrolidine in 62% overall yield, was used as a new type of organocatalyst bearing a pyrrolidine and a sulfone moiety. It shows very high catalytic activity toward the direct asymmetric Michael reaction of cyclohexanone and nitroolefins. All the corresponding adducts can be furnished in 90-99% yields and with up to 98% ee and over 99:1 dr on water in the presence of this catalyst (15 mol %) without any additive.     

Catalytic asymmetric Michael reactions of dibenzyl malonate to α,β-unsaturated N-acylpyrroles using a La(O-iPr)3/Ph-linked-BINOL complex

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)₃/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)₃/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee).     

Highly enantioselective Michael addition of isobutyraldehyde to nitroalkenes

The asymmetric catalytic Michael reaction between isobutyraldehyde and nitroalkanes with chiral primary amine thiourea organocatalysts was described. In the presence of 10 mol % of 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-benzylthiourea, the desired products were achieved in excellent enantioselectivity (up to>99% ee) with up to 98% yield.     

On the reactivity of isoindolo[2,1-a]quinazoline-5-ones

Base- and acid-catalyzed nucleophilic addition of 11H-isoindolo[2,1-a]quinazoline-5-one to aromatic aldehydes and maleimides was investigated. The aldol adducts and condensation products were obtained stereoselectively. Main diastereomers of the Michael adducts were isolated in 74-89% yield, and converted by N-methylation to new stable α-substituted isoindole derivatives, for which 6-methylisoindolo[2,1-a]]quinazoline-5-one stands as the unsubstituted reference. The stability of the latter was monitored in moist aerated CDCl₃ solution, and one of the oxidative hydrolysis product was characterized by X-ray diffraction analysis as the corresponding N-arylphthalimide. The reactivity of the unsubstituted 6-methylisoindolo[2,1-a]]quinazoline-5-one was also investigated with acetylenic Michael acceptors. Fully conjugated isoindole derivatives possessing an original pull-push-pull structure were obtained. The conformations and molecular orbitals of the dibenzoylacetylene adduct were studied at the DFT level of theory. Its static quadratic hyperpolarizabilty β₀ was also calculated at the ZINDO level.     

Aromatic l-prolinamide-catalyzed asymmetric Michael addition of aldehydes to nitroalkenes

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr).     

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors is described. A Sm(O-i-Pr)₃/(R)-H₈-BINOL complex promoted the epoxidation reaction to afford products in high yield (up to quant) and high enantiomeric excess (up to >99.5% ee). Reaction proceeded smoothly using cumene hydroperoxide (CMHP) with low explosive hazard, and completed within 0.2-0.5 h with 5 mol % catalyst. Catalyst loading was successfully reduced to as little as 0.02 mol %. The N-acylpyrrole properties as well as efficient synthesis of α,β-unsaturated N-acylpyrroles are also described.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. The corresponding Michael adducts bearing a new stereocenter were generally obtained in high or quantitative yields and with good enantioselectivities (up to 93% ee).     

Fast, easy, solvent-free, microwave-promoted Michael addition of anilines to α,β-unsaturated alkenes: synthesis of N-aryl functionalized β-amino esters and acids

The rapid, simple, microwave-promoted synthesis of N-aryl functionalized β-amino esters using Michael addition reactions is presented. Reactions are performed neat at 200 °C for 20 min and are catalyzed by acetic acid. The esters can be easily hydrolyzed to the corresponding N-aryl functionalized β-amino acids.     

New chiral ferrocenyl amidophosphine ligand for remarkable improvement of enantioselectivities in copper-catalyzed addition of diethylzinc to N-sulfonylimines

(S)-N-Ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 3 was conveniently prepared from commercially available l-proline and ferrocenecarboxylic acid. In the presence of a catalytic amount of chiral ligand 3 (4 mol %) and Cu(OTf)₂ (3 mol %), the asymmetric addition of diethylzinc to N-sulfonylimines was achieved in 57-99% yield with up to 88% ee.     

Asymmetric Michael addition promoted by (R,R)-trans-1,2-diaminocyclohexane in ionic liquids

In tetrafluoroborate based ionic liquids fair yields and enantiomeric excesses up to 91% were obtained in the Michael addition of ethyl cyclohexanone-2-carboxylate to methyl vinyl ketone, using (R,R)-trans-1,2-diaminocyclohexane as chiral auxiliary (37% mol/mol with respect to the donor). The presence of catalytic amounts of metal sources [Ni(OAc)₂ · 4H₂O, Co(acac)₂, FeCl₃ · 6H₂O, LaCl₃, Cu(OAc)₂ · H₂O] did not improve the activity, and, in some instances, caused a drop of enantioselectivity. Reactions carried out in the absence of any metal and with a Michael donor/diamine molar ratio of 20 allowed us to ascertain that the reaction can be performed catalytically.     

Titrimetric determination of maleinimide and acrylate groups in organic compounds

A simple procedure is proposed for determining the concentration of maleimide and acrylate groups in organic compounds based on the addition of morpholine to the activated double bond by the Michael reaction, followed by the potentiometric titration of the reaction mixture with 1 M HCl in ethanol. The applicability of the method to N-substituted maleimides with aromatic, aliphatic, and oligomeric substituents, as well as to acrylates and acrylonitrile, is verified. It is demonstrated that maleimides and acrylates can be determined simultaneously.     

Highly sensitive method for determination of N-nitrosamines using high-performance liquid chromatography with online UV irradiation and luminol chemiluminescence detection

A new method for the measurement of N-nitrosamines in part-per-trillion concentrations from water samples without preconcentration steps has been developed. This method is based on online UV irradiation after high-performance liquid chromatographic separation and subsequent luminol chemiluminescence detection without addition of an oxidant. It was confirmed that N-nitrosamines in basic aqueous solution were transformed to peroxynitrite by UV irradiation. The detection limits for this method were 1.5 ng/L, 2.9 ng/L, 3.0 ng/L, and 2.7 ng/L for N-nitrosodimethylamine, N-nitrosomorpholine, N-nitrosomethylethylamine, and N-nitrosopyrrolidine, respectively, at a signal-to-noise ratio of 3. The calibration graphs were linear in the range of 5–1000 ng/L for these N-nitrosamines. This method was used for the determination of N-nitrosamines in tap water, river water, and industrial plant effluent samples. The recoveries of N-nitrosodimethylamine, N-nitrosomorpholine, N-nitrosomethylethylamine, and N-nitrosopyrrolidine present in tap water sample at a concentration of 10 ng/L (mean ± standard deviation, n = 4) were (94.8 ± 2.7)%, (102.0 ± 6.9)%, (99.3 ± 3.9)%, and (102.8 ± 2.5)%, respectively. These results indicate that our proposed method can be applied satisfactorily to the determination of N-nitrosamines in water samples.     

Organocatalytic asymmetric synthesis of 3(2H)-furanones with adjacent quaternary and tertiary stereocenters

An efficient stereoselective Michael addition of simple 3(2H)-furanones to α,β-unsaturated ketones has been described. The protocol provides a facile and efficient access to complex 3(2H)-furanones containing adjacent quaternary and tertiary stereocenters in high yields (up to 99%) with good diastereoselectivities (up to 86:14) and excellent enantioselectivities (up to 98% ee) under mild conditions.     

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20-100 °C, 10-60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77-83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59-63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.