Asymmetric Synthesis of 2,3,4‐Trisubstituted Functionalised Tetrahydrofurans via an Organocatalytic Michael Addition as Key Step

The organocatalytic Michael addition of various aldehydes to (2E,4E)‐ethyl 5‐nitropenta‐2,4‐dienoate has been achieved under the catalysis of diphenylprolinol trimethylsilyl ether furnishing the products in good to excellent yields (61–94%) and high stereoselectivities (dr up to >98:2, ee=97 to >99%). Starting from these Michael adducts, 2,3,4‐trisubstituted functionalized tetrahydrofurans are available in two steps by reduction of the aldehyde followed by an intramolecular oxa‐Michael addition in good yields (54–76%) and stereoselectivities (dr up to >95:5, ee=97 to >99%).     

Control of Six Contiguous Stereocenters in an Asymmetric Organocatalytic One‐Pot Michael/Michael/Aldol Addition Sequence

The asymmetric organocatalytic one‐pot synthesis of polyfunctionalized cyclohexanes is described. Starting from β‐keto esters, nitroalkenes and α,β‐unstaturated aldehydes and employing a bifunctional norephedrine‐based thiourea catalyst, six contiguous stereocenters including one quarternary center are generated. The one‐pot protocol follows a Michael/Michael/aldol addition sequence and affords the highly substituted cyclohexanes in moderate to very good yields (22–70%), diastereomeric ratios of dr>95:5 and excellent enantioselectivities of 91–99% ee.     

A Novel Enantioselective Catalytic Tandem Oxa‐Michael–Henry Reaction: One‐Pot Organocatalytic Asymmetric Synthesis of 3‐Nitro‐2H‐chromenes

An enantioselective oxa‐Michael–Henry reaction of substituted salicylaldehydes with nitroolefins that proceeds though an aromatic iminium activation (AIA) has been developed by using a chiral secondary amine organocatalyst and salicylic acid as a co‐catalyst. The corresponding 3‐nitro‐2H‐chromenes were obtained in moderate‐to‐good yields with up to 91% ee under mild conditions. Based on the experimental results and ESI‐mass spectrometric detection of the intermediates, a plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.     

Synthesis of 2,3,4‐Trisubstituted Thiochromanes using an Organocatalytic Enantioselective Tandem Michael–Henry Reaction

Enantioenriched 2,3,4‐trisubstituted thiochromanes have been synthesized by using a cupreine‐catalyzed tandem Michael addition–Henry reaction between 2‐mercaptobenzaldehydes and β‐nitrostyrenes. Good diastereoselectivities and enantioselectivities were obtained for the title compounds, which may be further improved through a single recrystallization (up to 98% de and>99% ee).     

Synthesis of Optically Active 2H‐Thiopyrano[2,3‐b]quinolines with Three Contiguous Stereocenters via an Organocatalytic Asymmetric Tandem Michael–Henry Reaction

Optically active 2H‐thiopyrano[2,3‐b]quinolines with three contiguous stereocenters have been synthesized via a chiral bifunctional squaramide‐catalyzed tandem Michael–Henry reaction between 2‐mercaptoquinoline‐3‐carbaldehydes and nitroolefins. The reactions proceed with excellent diastereo‐ and enantioselectivity to give the title compounds in high yields with high levels of diastereo‐ and enantioselectivity (up to >99/1 dr and >99% ee, respectively).     

A New Henry/Michael/Retro‐Henry/Henry Domino Sequence Promoted by Bifunctional Organocatalysts

A highly stereoselective route to densely functionalized cyclohexanes is described, via a Cinchona‐based bifunctional organocatalyzed Henry/Michael/retro‐Henry/Henry domino reaction. The peculiar stereoconvergent mechanism allows the creation of up to four contiguous stereocenters in a highly stereodefined manner starting from both achiral aldehydes and racemic nitro alcohols. The simple and efficient protocol can be exploited to synthesize a wide range of substrates and also useful bioactive molecules.     

The Application of a Recyclable Organocatalytic System to the Asymmetric Domino Michael/Henry Reaction in Aqueous Media

A new type of pyrrolidine‐based organocatalyst has been developed and found to be very effective for the domino Michael/Henry reaction in aqueous solvents. For the reaction involving pentane‐1,5‐dial and various nitroolefins, good yields (65–85%) and excellent enantioselectivities (99%) were obtained using this catalyst. In addition, the catalyst could be recycled up to four times resulting in good yields and up to seven times with good enantioselectivity.     

Asymmetric Synthesis of Polyfunctionalized Pyrrolidines via a Thiourea Catalyzed Domino Mannich/Aza‐Michael Reaction

The domino Mannich/aza‐Michael reaction of γ‐malonate‐substituted α,β‐unsaturated esters with N‐protected arylaldimines has been achieved. Catalyzed by bifunctional thioureas, 2,5‐cis‐configured polysubstituted pyrrolidines are obtained in good to excellent yields (76–99%), enantioselectivities (75–94%) and excellent diastereoselectivities (de >95%). The pure stereoisomers are available by crystallization and removal of the racemates.     

Enantioselective Aza‐Henry Reaction of Imines Bearing a Benzothiazole Moiety Catalyzed by a Cinchona‐Based Squaramide

An efficient enantioselective aza‐Henry reaction of nitroalkanes to imines bearing a benzothiazole moiety catalyzed by a Cinchona‐based squaramide has been developed. In the reaction of imines, the corresponding products were obtained in good to excellent yields (up to 99%) with excellent enantioselectivities (up to >99% ee) for most of the aromatic substituted imines. The imines with electron‐withdrawing groups gave better yields than those bearing electron‐donating groups in the aza‐Henry reaction. Moreover, a one‐pot three‐component enantioselective aza‐Henry reaction using 2‐aminobenzothiazoles, aldehydes, and nitromethane was also developed. Moderate to good yields and high enantioselectivities were obtained in the one‐pot cases (up to 98% ee).     

Asymmetric Synthesis of cis‐3,4‐Disubstituted Chromans and Dihydrocoumarins via an Organocatalytic Michael Addition/ Hemiacetalization Reaction

The organocatalytic domino Michael/hemiacetalization reaction between various aldehydes and ortho‐nitrovinylphenols has been developed. Under the catalysis of diphenyl prolinol trimethylsilyl ether, cis‐3,4‐disubstituted chromanols are obtained in high to excellent yields (81–98%) and stereoselectivities (dr: 86:14 to >99:1, ee 96 to >99%). The corresponding disubstituted chromans are available by dehydroxylation of the domino products in good to excellent yields (58–95%). Furthermore, oxidation of the domino products with pyridinium chlorochromate provided 3,4‐dihydrocoumarins in good yields (65–83%) without any epimerization.     

Asymmetric Domino Nitro‐Michael/Horner–Wadsworth–Emmons Reaction for Disubstituted Cyclohexenecarboxylate Annulation: Efficient Synthesis of Dipeptidyl Peptidase IV Inhibitor ABT‐341 and Influenza Neuraminidase Inhibitor

An asymmetric domino nitro‐Michael/Horner–Wadsworth–Emmons (HWE) reaction involving α,β‐unsaturated aldehydes and nitro phosphonates has been developed, which gave 4,5‐disubstituted cyclohexenecarboxylates with high stereoselectivities (dr up to >20:1, ee 83–92%) in good yields (44–76%). Furthermore, using this methodology as a key step, a short and practical synthesis of pharmaceutically useful compounds (such as the dipeptidyl peptidase IV inhibitor ABT‐341 and an influenza neuraminidase inhibitor) has also been accomplished.     

Bifunctional Squaramide Catalysts with the Same Absolute Chirality for the Diastereodivergent Access to Densely Functionalised Cyclohexanes through Enantioselective Domino Reactions. Synthesis and Mechanistic Studies

We have developed a procedure for the stereoselective and diastereodivergent synthesis of densely functionalised cyclohexanes containing four stereocentres through an asymmetric Michael‐initiated ring closure (MIRC) cascade reaction employing hydrogen‐bond catalysis, which is able to prepare adducts with different absolute configurations starting from the same starting materials. The overall process involves a highly diastereo‐ and enantioselective Michael/Henry cascade reaction between a wide range of nitroalkenes and α‐nitro‐δ‐oxo esters, allowing access to different diastereoisomers of the final adduct by introducing subtle changes in the general (R,R)‐configured bifunctional tertiary amine/squaramide catalyst structure. Moreover, this methodology is also amenable to a three‐component one‐pot procedure, leading to the formation of the same adducts with very good results directly from commercially available reagents, on a multigram scale, and employing a very low catalyst loading. Furthermore, a detailed experimental and computational study is described which shows the origin of the diastereodivergent behaviour of these structurally similar catalysts and the nature of the substrate–catalyst interaction.

     

Superparamagnetic Nanoparticle‐Supported (S)‐Diphenyl‐ prolinol Trimethylsilyl Ether as a Recyclable Catalyst for Asymmetric Michael Addition in Water

A new superparamagnetic nanoparticle‐supported (S)‐diphenylprolinol trimethylsilyl ether (Jørgensen–Hayashi catalyst) was synthesized and applied for the asymmetric Michael addition of aldehydes to nitroalkenes in water, which gives products in moderate to good yields (up to 96%), good enantioselectivity (up to 90% ee) and diastereoselectivities (up to 99:1). The immobilized catalyst could be easily separated from the reaction by an external magnet and recycled for four times without significant loss of catalytic efficiency.     

Organocatalytic Enantioselective Synthesis of Polysubstituted Spirooxindoles using a Tandem Michael–Michael Reaction

A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with four contiguous stereogenic centers, including two adjacent quaternary stereogenic centers, was realized through an organocatalytic tandem Michael–Michael reaction. By employing a quinidine‐derived thiourea organocatalyst, the reaction between (E)‐2‐cyano‐2‐(2‐oxo‐1‐tritylindolin‐3‐ylidene)acetates and (E)‐1‐alkyl‐6‐nitro‐hex‐2‐en‐1‐ones yields the desired spirooxindole products in good yields (up to 90%) and with excellent stereoselectivities (up to 95:5 dr and 98% ee).

     

Kinetics of Michael addition polymerizations of n,n′‐bismaleimide‐4,4′‐diphenylmethane with barbituric acid

With the addition of sufficient hydroquinone to completely suppress the free radical polymerization, the kinetics of Michael addition polymerizations of N,N′‐bismaleimide‐4,4′‐diphenylmethane (BMI) and barbituric acid (BTA) with BMI/BTA = 2/1 (mol/mol) in 1‐methyl‐2‐pyrrolidone was investigated independently. A mechanistic model was developed to adequately predict the polymerization kinetics before a critical conversion (ca. 60%), at which point the diffusion‐controlled polymer reactions started to predominate in the latter stage of polymerization. The Michael addition polymerization rate constants and activation energy in the temperature range 383–423 K were determined accordingly. Beyond the critical conversion, a relatively stationary limiting conversion (ca. 69%) independent of the reaction temperature was achieved. A diffusion‐controlled polymerization model taken from the literature satisfactorily predicted the limiting conversion data. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers     

Facile Construction of Vicinal Quaternary and Tertiary Stereocenters via Regio‐ and Stereoselective Organocatalytic Michael Addition to Nitrodienes

A highly regio‐ and stereoselective protocol for the synthesis of vicinal quaternary and tertiary stereocenters has been developed. The 6′‐OH Cinchona alkaloids ( BnCPN or BnCPD ) at low catalyst loading (0.5–5 mol%) catalyze the Michael addition of trisubstituted carbon nucleophiles to nitrodienes in good to excellent yield (up to >99), high enantioselectivity (up to 99% ee) and high diastereoselectivity (up to >99:1 dr) under mild reaction conditions.     

Asymmetric Organocatalytic Cascade Michael/Michael/Henry Reaction Sequence: Control of All Stereocenters in One Cyclohexane Skeleton

The highly diastereo‐ and enantioselective relay cascade Michael/Michael/Henry reaction catalyzed by combination of readily available diphenylprolinol silyl ether and the quinine thiourea in a one‐pot fashion has been developed. Up to 70% yield and up to >99% enantioselectivity of the single major isomer were obtained from the cascade reactions.     

Aza‐Henry Reaction of Isatin Ketimines with Methyl 4‐Nitrobutyrate en Route to Spiro[piperidine‐3,3′‐oxindoles]

A new enantioselective route to spiro[piperidine‐3,3′‐oxindoles] from isatin ketimines is described. The aza‐Henry reaction of N‐Boc‐isatin ketimines with methyl 4‐nitrobutyrate in the presence of a Ph₂BOX‐CuBr₂ complex provided the corresponding nitro amino esters with good diastereoselectivity and excellent enantioselectivity (up to >99% ee). The aza‐Henry adducts were transformed into spiro[piperidine‐3,3′‐oxindoles] after reduction of the nitro group to oxime, and cleavage of the N‐Boc group and lactamisation.

     

Organocatalytic Multiple Cascade Reactions: A New Strategy for the Construction of Enantioenriched Tetrahydrocarbazoles

A novel cascade Friedel–Crafts alkylation/Michael addition/aromatization reaction of 2‐vinylindoles with α,β‐unsaturated aldehydes has been developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in up to 97% yield and with excellent stereoselectivities (ee up to>99%, dr up to>99:1).     

Recyclable Enantioselective Catalysts Based on Copper(II) Complexes of 2‐(Pyridine‐2‐yl)imidazolidine‐4‐thione: Their Application in Asymmetric Henry Reactions

This paper describes the preparation of enantioselective catalysts based on derivatives of imidazolidine‐4‐thione and their subsequent anchoring by means of a sulfur atom on a polymeric carrier. First, we verified the catalytic activity and enantioselectivity in the Henry reaction of the homogeneous variants of the catalysts, i.e., the copper(II) complexes of 2‐(pyridine‐2‐yl)imidazolidine‐4‐thiones and 4‐benzylsufanyl‐2‐(pyridine‐2‐yl)imidazolines themselves. It was found that these catalysts exhibit high enantioselectivity (up to 98% ee). Subsequently, the imidazolidine‐4‐thione catalysts were immobilized by anchoring to polymeric carriers based on a copolymer of styrene and 4‐vinylbenzyl chloride. These heterogeneous catalysts were analogously tested with regard to their catalytic activity and enantioselectivity in the Henry reaction, and moreover, the possibility of their separation and reuse was studied. It was found that all the prepared immobilized catalysts are highly enantioselective (up to 97% ee). Their recycling ability was tested in Henry reaction of 2‐methoxybenzaldehyde with nitromethane. It was found that they can be recycled more than ten times without any decrease of their enantioselectivity. Therefore, they present a better means of catalysis than the original copper(II) complexes of imidazolidine‐4‐ones from both economic as well as ecological points of view. Thus, such immobilized catalysts exhibit high application potential for the asymmetric Henry reaction.