Catalytic Michael Reaction Research Articles

Proline-derived carboxylic acid as a bifunctional organocatalyst for highly efficient asymmetric Michael addition of aldehydes to nitroalkenes

A novel bifunctional proline amide–carboxylic acid catalyst was used for the highly stereoselective Michael reaction of various aldehydes with different nitroalkenes. This catalyst was easily prepared using commonly available anhydrides and proline linked with a diamine spacer. The asymmetric catalytic Michael reactions afforded high yields (up to 98 %), diastereoselectivities (syn/anti ratio: up to 86:14), and enantioselectivity (up to 99 % ee) when 5 mol% of the catalyst is used with N-methylmorpholine as a base in a dichloromethane solvent at room temperature.

Organocatalytic Asymmetric Reaction between α‐Cyano Enones and Dioxindoles: Synthesis of Dihydrofuran‐Spirooxindoles

AbstractAn organocatalytic enantioselective synthesis of dihydrofuran‐spirooxindoles has been developed. Dioxindoles and trans‐α‐cyano‐α,β‐unsaturated ketones were engaged as the reaction partners in this method. The desired products were obtained via bifunctional squaramide catalyzed Michael reaction followed by Pinner reaction and isomerization.

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction.

A new synthetic strategy toward nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes with three and five contiguous stereocenters is presented. Readily available β-keto phosphonates react with conjugated nitroolefins in the presence of a chiral Ni(II) complex to give nitro keto phosphonates with two stereocenters with excellent enantioselectivity and moderate to high diastereoselectivity. These products were used for a reductive cyclization leading to pyrrolidin-3-ylphosphonic acid and for reactions with aldehydes yielding tetrahydropyranylphosphonates as individual stereoisomers. These nonracemic heterocycles containing phosphoryl moieties are useful for designing new pharmacologically active compounds.

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones.

Functionally substituted sulfones with stereogenic centers are valuable reagents in organic synthesis and key motifs in some bioactive compounds. The asymmetric Michael addition of β-ketosulfones to conjugated nitroalkenes in the presence of Ni(II) complexes with various chiral vicinal diamines was studied. This reaction provides convenient access to non-racemic 4-nitro-2-sulfonylbutan-1-ones with two stereocenters with high yield and excellent enantioselectivity (up to 99%). It has been established that the catalytic Michael reaction itself was carried out with high diastereoselectivity, but the Michael adducts may epimerize at the C-2 position at a significant rate. Conditions for the preparation of individual diastereomers were found.

Asymmetric synthesis of highly functionalized furanones via direct Michael reactions mediated by a bulky primary amine

A bulky chiral primary amine catalyzed Michael reaction of 3(2H)-furanones has been realized, leading to the construction of substituted furanone derivatives.

Organocatalytic Asymmetric Synthesis of Bridged Acetals with Spirooxindole Skeleton.

The first highly diastereo- and enantioselective synthesis of bridged O, O-acetals embedded with spirooxindoles has been developed. Dioxindoles and 2-hydroxy cinnamaldehydes were employed as the reaction partners in this method. The desired products were obtained via diaryl prolinol TBS ether catalyzed Michael reaction followed by acetal formation with TFA.

Enantioselective Total Synthesis of (+)-Plumisclerin A.

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5 ]decane and trans-fused dihyrdopyran moiety. Scalable enantioselective LaIII -catalyzed Michael reaction, palladium(0)-catalyzed carbonylation and SmI2 -mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D-ring system having six continuous stereogenic centers and two all-carbon quaternary centers. The trans-fused dihyrdopyran moiety with an exo side-chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)-plumisclerin A.

Aminodecalone Scaffolds – Enantioselective Synthesis, Indole and Quinoline Annulation

Optically active benzo[b]carbazole and benzo[b]acridine derivatives were prepared by Fischer indole or Friedländer quinoline annulation from 2‐oxodecalone‐4a‐carboxylates with a quaternary stereocenter. As an additional point for diversification, the target compounds carry a nitro function, which was transformed to an amide or lactam after reduction. The scaffold itself was accessed by asymmetric, copper catalyzed Michael reaction of a β‐oxoester with methyl vinyl ketone utilizing l‐valine diethyl amide as chiral auxiliary. Two enantiopure, epimeric compounds were obtained with 99 % ee and 92 % ee, which were separated and in parallel sequences submitted to intramolecular aldol reaction and catalytic hydrogenation furnishing the 2‐oxodecalone scaffolds. As a precursor for the primary amino group, the scaffolds contained a nitro function at their 6‐positions, which was reduced at the end of the synthetic sequence. The relative and absolute configurations of all three stereocenters were established by X‐ray crystallography.

Two chiral catalysts in action: insights into cooperativity and stereoselectivity in proline and cinchona-thiourea dual organocatalysis.

Increasing use of two chiral catalysts in cooperative asymmetric catalysis in recent years raises some fundamental questions on chiral compatibility between the catalysts, modes of activation, and relative disposition of substrates within the chiral environment of the catalysts for effective asymmetric induction. We present molecular insights into a one-pot catalytic Michael reaction cascade between a dicarbonyl compound (7-oxo-7-phenylhept-5-enal) and nitrostyrene, catalyzed by two chiral organocatalysts (proline and cinchona-thiourea), leading to a densely functionalized tetra-substituted cyclohexane product. The density functional theory (SMD(toluene)/M06-2X/6-31G**) computations helped us identify the role of the organocatalytic catalytic dyad in providing a lower energy pathway. The covalent activation of the aldehydic end by (S)-proline results in an enamine, which then adds to the noncovalently activated nitrostyrene in the first Michael addition to give a nitronate anion. The configuration at two of the four chiral centers of the product gets fixed in this step whereas that of the remaining two is determined by intramolecular cyclization between the nitronate and the enone. Important mechanistic features such as (a) a lower energy pathway as compared to a proline-only route for the formation of the syn-enamine and its participation in the first Michael addition and (b) the origin of the preferred prochiral faces in the C-C bond formation are traced to the active involvement of the cinchona-thiourea catalyst in conjunction with proline in each step of the reaction. The true cooperative action by both the catalysts is identified as enabled by a network of hydrogen bonding, and π···π stacking between the aryl ring of the cinchona-thiourea catalyst as well as other noncovalent interactions between the catalysts themselves, and that between the catalysts and substrate.

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin-Hammett Scenario?

The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and β-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.

B(C6F5)3-Catalyzed Michael Reactions: Aromatic C-H as Nucleophiles.

The Michael reaction is a widely used reaction for the C-C coupling of electron-poor olefins and C(sp3)-H pronucleophiles. Herein we report the Michael reaction between alkenes and aromatic as well as heteroaromatic compounds as aromatic C(sp2)-H nucleophiles under mild conditions. The reaction is catalyzed by readily available Lewis acidic B(C6F5)3 and proceeds with high regioselectivity for a wide substrate scope.

A Metal‐Free Based New Approach to 2,4‐Disubstituted Pyridines via One‐Pot Sequential Reaction of Cyclic Sulfamidate Imines with β‐Substituted Acroleins

AbstractA novel and efficient L‐proline catalyzed Michael reaction of several 4‐aryl/heteroaryl‐substituted cyclic sulfamidate imines with a variety of β‐styryl/aryl/alkyl‐substituted acroleins, followed by in situ elimination‐iminocyclization‐dehydration sequence process in the presence of DABCO as a base is reported for the first time. By this unconventional one‐pot sequential protocol, a number of 2‐aryl/heteroaryl‐4‐styrylpyridines and 2,4‐diarylpyridines have been prepared in good to high yields under metal‐free conditions. Besides, the synthesized 4‐styrylpyridine derivatives were also further utilized for the synthesis of commercially as well as pharmaceutically important 2‐arylisonicotinic acids.

ChemInform Abstract: Synthesis of Novel 5‐Monoalkylbarbiturate Derivatives: New Access to 1,2‐Oxazepines.

Abstract A simple and straightforward route to 5-monoalkylbarbiturates by the NHEt2 catalyzed Michael reaction of 1,3-dimethylbarbituric acid and α,β-unsaturated ketones is described. Significantly, the reaction exclusively furnished 5-monoalkylbarbiturates. Under neat conditions, the mixing and grinding of a representative 1,5-diketone and hydroxylamine hydrochloride gave the corresponding 1,2-oxazepine in very good yield.

ChemInform Abstract: Organocatalytic and Enantioselective Michael Reaction Between α‐Nitroesters and Nitroalkenes. Syn/anti‐Selectivity Control Using Catalysts with the Same Absolute Backbone Chirality.

The asymmetric and catalytic Michael reaction between α-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases.

ChemInform Abstract: Higher‐Order Cyclopropenimine Superbases: Direct Neutral Broensted Base Catalyzed Michael Reactions with α‐Aryl Esters.

AbstractA higher‐order superbase incorporating a cyclopropenimine functionality catalyzes conjugate addition reactions of α‐aryl ester pro‐nucleophiles.

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality.

The asymmetric and catalytic Michael reaction between α-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases.

Synthesis of novel 5-monoalkylbarbiturate derivatives: new access to 1,2-oxazepines

A simple and straightforward route to 5-monoalkylbarbiturates by the NHEt2 catalyzed Michael reaction of 1,3-dimethylbarbituric acid and α,β-unsaturated ketones is described. Significantly, the reaction exclusively furnished 5-monoalkylbarbiturates. Under neat conditions, the mixing and grinding of a representative 1,5-diketone and hydroxylamine hydrochloride gave the corresponding 1,2-oxazepine in very good yield.

Higher-Order Cyclopropenimine Superbases: Direct Neutral Brønsted Base Catalyzed Michael Reactions with α-Aryl Esters.

The synthesis and characterization of six new classes of higher-order superbases, including five that incorporate cyclopropenimine functionality, has been achieved. We propose a nomenclature that designates these as the CG2, GC2, PC3, PC1, C3, and GP2 classes of superbases. The pK(BH+) values were measured to be between 29.0 and 35.6 in acetonitrile. Linear correlations of ten superbase basicities vs that of their substituents demonstrated the insulating effect of the cyclopropenimine core. The molecular structures of several of these materials were obtained by single-crystal X-ray analysis, revealing interesting aspects of conformational bias and noncovalent organization. The types of superbasic cores and substituents were each reliably shown to affect selectivity for deprotonation over alkylation. Higher-order cyclopropenimine and guanidine superbase stability to hydrolysis was found to correlate to basicity. Finally, a GC2 base was found to catalyze conjugate additions of α-aryl ester pronucleophiles, representing the first report of a neutral Brønsted base to catalyze such reactions.

ChemInform Abstract: Enantioselective Construction of Tetrasubstituted Stereogenic Carbons Through Broensted Base Catalyzed Michael Reactions: α′‐Hydroxy Enones as Key Enoate Equivalent.

Abstractα‐Hydroxy enones undergo asymmetric Michael reactions with a broad variety of Michael donors catalyzed by varying chiral catalysts.

Primary-secondary diamines catalyzed Michael reaction to generate chiral fluorinated quaternary carbon centers

Asymmetric Michael reactions of α-fluoro-β-ketoesters to nitroolefins have been achieved by using readily accessible primary-secondary diamines as the organocatalysts through enamine activation mode, affording the useful Michael adducts bearing chiral fluorinated quaternary carbon in good yields, with high diastereoselectivities and enantioselectivities (up to 87% yield, >20:1 d.r. and 99% ee).