Michael Addition Step Research Articles

Anilines as Substrates in Consecutive Four-Component Synthesis of Novel 1-Aryl-5-benzoyl-6-phenyl-3,4-dihydropyridin-2(1H)-ones

The consecutive four-component synthesis of 5-acylpyridin-2(1 H )-ones initiated by a copper-free alkynylation in a one-pot fashion has been expanded to include considerably less nucleophilic anilines as the amine component in the Michael addition step by altering the solvent system to 1,4-dioxane; 17 examples for the synthesis of 1-aryl-5-benzoyl-6-phenyl-3,4-dihydropyridin-2(1 H )-ones were obtained in moderate to good yields.

A Protocol forα-Bromination ofβ-Substituted Enones

α-Haloenone is an important building block in organic synthesis, especially in natural product synthesis. There are at least 4 different reaction modes of this class of compounds: 1, crossing coupling reactions at the α-position; 2, conjugate additions at the β-position; 3, deprotonation at the α'-position; 4, deprotonation at the γ-position. Representative examples of the utilities of α-haloenone include the syntheses of diversonol and the core structures of lomaiviticins and guanacastepenes. From a mechanistic perspective, two types of α-halogenation methods have been developed previously: one through a se- quential Baylis-Hillman-type Michael addition/α-halogenation/β-elimination process; the other one involving an electrophilic bromination followed by a β-elimination. The success of the former type of reactions highly depends on the formation of the transient enolate; the β-substituent on the enone substrates drastically slows down the rate of the first Michael addition step which is responsible for the enolate formation. The latter takes advantage of the strong electrophilicity of molecular bromine to overcome the steric effect of the substrates. However, quite a few side reactions including non-selective bromination often occur, resulting in modest to low yield and poor reproducibility of the desired product on a large scale. Here, we report a pro- tocol for α-bromination of β-substituted enones using pyridine hydrobromide perbromide as a brominating reagent. Cyclic enones prove to be suitable substrates for this reaction, and the corresponding products were obtained in >80% yield in general. Notably, β-phenyl cyclohexenone, a rather unreactive substrate due to both steric and electronic reasons, was bromi- nated smoothly. These bromination products may serve as useful synthon in organic synthesis. For acyclic enones and enoates, the reaction has to be performed at elevated temperature, which may be attributable to the rather poor acidity of the α-proton of the dibromo intermediate. The reaction is reliable on a large scale, and the reagents used are safe and low-toxic. Keywords conjugated enones; α-bromination; addition-elimination mechanism; pyridine hydrobromide perbromide; natural product synthesis

The mechanism investigation of the imidazolidinone catalyzed five‐membered ring synthesis reaction

The intramolecular asymmetric Michael addition reaction catalyzed by imidazolidinone is investigated using the density functional theory calculations. The details of the reaction mechanism, potential energy surfaces, and the influence of the acid additive are investigated. The reaction process includes two stages. The first stage is Michael addition, in which the enamine complex is created and then the Michael addition is carried out. The second stage is a product separation stage which includes an enol‐keto tautomerization and a two‐step hydrolysis. The enantioselectivity is controlled by the Michael addition step which involves a new carbon–carbon bond formation. The calculation results provide a general model which may explain the mechanism and enantioselectivity of the title reaction. Copyright © 2012 John Wiley & Sons, Ltd.

Powerful Approach to Heterocyclic Skeletal Diversity by Sequential Three-Component Reaction of Amines, Isothiocyanates, and 1,2-Diaza-1,3-dienes

By highly efficient, one-pot, three-component reactions, combining one set of 1,2-diaza-1,3-dienes (DDs), primary amines, and isothiocyanates in a different sequential order of addition, heterocyclic skeletal diversity can be achieved. The key feature discriminating the different heterocyclic core formation is the availability of the N or S heteronucleophile to give the first Michael addition step affording regioselective substituted 2-thiohydantoins or 2-iminothiazolidinones. The hydrazone or enehydrazino side chain at the 5-position of both heterocycles represents a valuable functionality to reach novel 5-hydroxyethylidene derivatives difficult to obtain by other methods.

Cooperative Catalysis in Multicomponent Reactions: Highly Enantioselective Synthesis of γ‐Hydroxyketones with a Quaternary Carbon Stereocenter

Together they make a difference: An aryl diazoacetate, H2O, and an α,β-unsaturated 2-acyl imidazole give γ-hydroxyketones with a quaternary carbon stereocenter with excellent selectivity only if all three catalyst components shown in the scheme are present. The Michael addition step did not occur when a similar reagent mixture was treated with the [Rh2(OAc)4] catalyst alone. OTf=triflate, Ts=p-tosyl.

Cocatalytic Enzyme System for the Michael Addition Reaction of in‐situ‐Generated ortho‐Quinones

AbstractA laccase‐lipase cocatalytic system was used to catalyze the domino reaction between catechols and nucleophilic reagents including 1,3‐dicarbonyl compounds and aromatic amines in aqueous medium at room temperature. Lipase acted as a catalyst for Michael addition step, and also enhanced the overall yield of the final products. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Unraveling high precision stereocontrol in a triple cascade organocatalytic reaction

The mechanism and stereoselectivity in an organocatalyzed triple cascade reaction between an aldehyde, electron deficient olefin and an alpha,beta-unsaturated aldehyde are investigated for the first time using density functional theory. The factors responsible for high levels of observed stereoselectivity (Enders et al., Nature, 2006, 441, 861) towards the generation of cyclohexene carbaldehyde with four contiguous stereocentres are unravelled. The triple cascade reaction, comprising a Michael, Michael and aldol sequence as the key elementary reactions, is studied by identifying the corresponding transition states for the stereoselective C-C bond-formation. In the first Michael addition step between the enamine (derived from the chiral catalyst and propanal) and nitrostyrene, energetically the most preferred mode of addition is found to be between the si-face of (E)-anti-enamine on the si-face of nitrostyrene. The addition of the si-face of the nitroalkane anion on the re-face of the iminium ion (formed between the enal and the catalyst) is the lowest energy pathway for the second Michael addition step. The high level of asymmetric induction is rationalized with the help of relative activation barriers associated with the competitive diastereomeric pathways. Interesting weak interactions, along with the steric effects offered by the bulky alpha-substituent on the pyrrolidine ring, are identified as critical to the stereoselectivity in this triple cascade reaction. The predicted stereoselectivities using computed energetics are found to be in perfect harmony with the experimental stereoselectivities.

Stereoselective and enantioselective synthesis of five-membered rings via conjugate additions of allylsulfone carbanions

Abstract This lecture describes some of our studies of lithio derivatives of allyl sulfone carbanions which add α-regioselectively as well as anti diastereoselectively to Michael acceptor olefins. This can be ascribed to chelation in the Michael addition step. When the reaction leads to subsequent ring closure by using a bromoallyl sulfone, the latter acts as a methylenemethane synthon in a (3+2) Michael-initiated ring closure, affording highly functionalized cyclopentane derivatives. Such additions proceed with high stereoselectivity and with asymmetric induction leading to nonracemic substituted cyclopentanones. Additions of allyl sulfone carbanions also proceed stereoselectively to C=N systems containing a chiral auxiliary on N. These can be used in the synthesis of optically active five- and six-membered ring N-heterocycles. Furthermore, chiral groups on the allyl sulfone moiety can induce significant remote asymmetric induction, made possible by the presence of an aromatic π-system which promotes intramolecular chelation to the Li cation.

Sequential 1,3-dipolar cycloadditions in the synthesis of bis-isoxazolo substituted piperidinones

A strategy for the efficient synthesis of novel bis-isoxazolo substituted piperidinones has been developed. The protocol consists of the Michael addition of an unsaturated alkoxide to beta-nitrostyrene followed by an intramolecular nitrile oxide cycloaddition (INOC) or an intramolecular silyl nitronate olefin cycloaddition (ISOC) to give III. Grignard addition to this isoxazoline intermediate followed by DCC coupling of the resulting isoxazolidine with nitroacetic acid gave II, and a second intramolecular cycloaddition via 1,3-dipoles result in the formation of the targeted novel tetracycles (I). A solid-supported scavenger was employed to increase the efficiency and yield of the Michael addition step.

Diastereoselective Conjugate Addition to (+)-Camphorsulfonic Acid Derived Nitroalkenes: Synthesis of alpha-Hydroxy and alpha-Amino Acids.

Diastereoselective tandem conjugate addition of both oxygen- and nitrogen-centered nucleophiles to the novel (1S)-10-camphorsulfonic acid derived nitroalkenes 9, 10, and 11 and ozonolysis gave the alpha-hydroxy and alpha-amino thiol acid derivatives 12, 13, and 14. In all cases, the (R)-diastereomer was formed as the major component albeit with only modest levels of selectivity (33-71% de). The structures of the products and the stereochemistry of the Michael addition step were unequivocally established by X-ray crystallographic studies of nitroalkenes 9 and 10 and (2S)-12c and (2R)-13a and by alternative syntheses from (S)-alanine, (S)-valine, and ethyl (S)-lactate.

A General Synthesis of Methylenecyclopentanes by a Stereoselective [3 + 2] Approach

The [3 + 2] cyclopentanation involving 3-(phenylsulfonyl)-2-(bromomethyl)-1-propene (1) and representative (E) α,β-unsaturated acyclic esters and ketones has been studied. High yields and complete stereoselectivity were observed in all reactions leading to tri- or tetrasubstituted methylenecyclopentanes. The anti-diastereoselectivity in the first, Michael addition step is rationalized by a chelation-controlled transition state in which MO interactions of the two π systems are involved. The Michael reactions of methallyl sulfone 8 with (E) enoates in the absence and presence of HMPA confirms the influence of chelation on the diastereomeric ratio of adducts. Cyclopentanations involving 1 with cyclohexenone, 2(5H)-furanone, and 5,6-dihydro-2-pyranone, respectively, were also studied with emphasis on the factors influencing the stereochemical outcome of the annulation process.

Semiempirical molecular orbital study on the transition states for the anti-selective Michael addition reactions of the lithium Z-enolates of N-alkylideneglycinates to α,β-unsaturated esters

Semiempirical molecular orbital calculations (MNDO and PM3) show that the lithium Z-enolates derived from N-alkylideneglycinates react with α,β-unsaturated esters through a stepwise mechanism via the intermediate formation of Michael adducts. The initial step involves an anti-selective carbon–carbon bond formation through a Michael addition process and the second step consists of stereoselective ring formation or a 1,3-dipolar cycloaddition. The energy difference between the transition states for each step depends upon the steric hindrance caused by the alkylidene moiety: bulky alkylidene substituents prefer the formation of Michael adducts and small ones prefer 1,3-dipolar cycloadducts. The exclusively high anti-selectivity observed in the Michael addition step is due to the attractive molecular orbital interaction working between the imine moiety of donor molecules and the α-carbon of the acceptors.