Aza-Michael addition reaction

Xu et al reported using [bmim][OH] as a basic IL for the Aza-Michael addition reaction between various amines and a,(3-unsaturated carbonyl compounds and nitriles. The products were obtained in high yields and the IL could be recycled eight times without significant change in the product yields. 

The aza-Michael addition is an important class of carbon-nitrogen bondforming reactions, and has been demonstrated to be a powerful tool in organic synthesis. EiScient aza-Michael addition reactions of alkyl amine (Scheme 8.34)... 

Scheme 3.20 One pot synthesis of enantioenriched isoindolines based on chiral Bronsted acid catalyzed F C reaction/base catalyzed aza Michael addition reaction sequence.

Michael/Henry/dehydration/aromatisation reaction of 2-(2-oxoethyl) benzal-dehydes and nitroalkenes mediated by pyrrolidine to obtain polysubstituted naphthalene derivatives. DBU catalysed the conjugate additions of alcohols to ot,p-unsaturated nitriles, esters and ketones. Perhaps more important are the aza-Michael addition reactions of amines to a,p-unsaturated ketones, nitriles and esters. Recently, Costa, Vilarrasa and coworkers described the addition of lactams, imides, 2-pyridone, pyrimidine-2,4-diones and inosines to methyl propiolate and other similar compounds, DABCO and DMAP being the best catalysts. As mentioned before, tertiary amines give zwitterionic species with activated allynes. It was as early as 1932 when Diels and Alder used the reaction of pyridine with dimethyl acetylenedicarbojylate (DMAD) for the synthesis of heterocycles. The interception of the corresponding intermediate with Al-tosylimines and activated olefins provided access to l-azadienes ° and highly substituted butadienes (Scheme 2.6). When the quenching species of the zwitterionic intermediate is a 1,2-diketone, dibenzoyl maleates or cyclopentenedione derivatives could be obtained (Scheme 2.6). The interception of the zwitterionic species of N-methyl imidazole (NMI) and DMAD with ketenes to obtain unsaturated esters has also been shown. ... 

A novel triglyceride-based a, p-unsaturated ketone, obtained by photoperoxidation from high oleic sunflower oil, can be cross-linked with diamino diphenyl methane through the aza-Michael addition reaction. The reaction of p-toluidine with either enone-containing methyl oleate or epoxidised methyl oleate, produces an alternative to amine-cured epoxidised vegetable oil thermosets. ... 

Scheme 7.59 Domino Heck/aza-Michael addition reaction.

Recently, You and co-workers [111] reported another useful intramolecular aza-Michael addition reaction of indoles, in which the indole ring has no electron withdrawing substituents. The activation of the Michael acceptor by chiral phosphoric acid 50 and the activation of the indole moiety by insertion of electro-donating group (EDG) at the C3 position provide iV-alkylated adducts with good yields (72-98%) and enantioselectivities (69-93%) (Scheme 11.31). 

Wang, Y., Yuan, Y-Q. and Guo, S-R. 2009. Silica sulfuric acid promotes aza-Michael addition reactions under solvent-free condition as a heterogeneous and reusable catalyst. Molecules 14 4779-4789. 

Literature survey reveals that the Michael addition reaction is highly accelerated in IL. Copper(II)triflate immobilized in [bmimJBF IL is used as reaction medium for Michael addition of p-ketoesters to alkenes [10,11]. [bmim]OH has been used in Michael addition of active methylene corrtpotmds to corrugated ketones, carboxylic esters, and nitriles [12]. Michael addition of thiols and thiophosphate to conjugated alkenes in IL [pmim]Br [13] has been reported. Conjugate addition of azide ion to a,p-unsaturated carbonyl compoimds and aza-Michael addition reactions are also reported [14-17]. Recently, Zare et al. [18] reported MW-assisted aza-Michael addition of aromatic sulfonamides to various a,P-unsatirrated esters [ 19] in the presence of a catalytic amount of MgO or ZnO with [bmim]Br as the reaction solvent. Aryl nitriles can be synthesized via the Rosenmimd von Braim reaction from the corresponding hahdes in IL imder MW [20]. 

Qu and co-workers have developed organocatalytic asymmetric aza-Michael addition reaction of achiral purine bases (486) to a,p-unsaturated aldehydes (487) followed by reduction of aldehyde group to give optically active products (488) in 82 89% yield and up to 99% ee (Scheme 121). They were readily converted to phosphonic acids (489) in high yields and high enantioselectivities. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Scheme 1.1.6 Tandem aza-Michael addition/a-ester enolate alkylation or aldol reaction.

In 2008 Yang and coworkers have reported an efficient synthesis of substituted a-alkilidene-fi-lactams via aNaOH- promoted intramolecular aza-Michael addition of a-carbamoyl, a-(l-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution reaction in alcoholic media (Scheme 90), [198]. 

A double aza-Michael addition was enforced by high pressure in the reaction of primary amines with the ,/l-unsaluraled bis ester (92) to afford the azanorbomyl derivatives (93).141... 

In the catalytic presence of tetrabutylammonium fluoride, a trimethylsilyl group is cleaved from AKtrimethylsilyl)rnethylbenzylimine to form the resonance-stabilized 2-aza-allyl anion which undergoes a Michael addition reaction with, for example, methyl acrylate, giving y-aminoesters.333 These types of aminoesters serve as a starting material for the elaboration of diversely substituted pyrrolidones.334... 

Polshettiwar V, Varma RS (2010) Nano-organocatalyst magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Tetrahedron 66 1091-1097... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

The heterobimetallic catalyst prepared from (R,R)-3-aza-benzyl-l,5-dihydroxy-l,5-diphenylpentane was used for the asymmetric Michael addition reaction of malo-nates and thiophenols to enones [49]. The polymer-supported version of the chiral... 

Development in the area of asymmetric aza-annulation reactions paralleled achievements in the analogous area of asymmetric Michael addition reactions with chiral imines.111 Induction of asymmetry has been primarily controlled through substitution at the nitrogen of the imine or enamine that becomes incorporated into the heterocycle. Restricted rotation of this asymmetric substituent led to preferred conformational isomers, which provided stereofacial bias for carbon-carbon bond formation. 

Scheme 6.10 Aza- or thia-Michael addition reactions of amines or thiols...

The use of silicon carbide inserts has proved valuable in the uncatalyzed aza-Michael addition between piperazine and methyl acrylate. The reaction was low yielding using pure toluene as the solvent since the maximum temperature that could be attained was 170 °C. Adding the passive heating elements to the reaction mixture allowed for temperatures of 200 °C to be reached and, with this, a dramatic increase in the yield for the reaction was observed (Scheme 2.10). The product isolation procedure was trivial and consisted of physical removal of the heating element using a pair of tweezers followed by removal of the solvent. 

Conjugate Addition Reactions. Besides copper salts, a number of other catalyst systems, such as Ni(acac)2/DIBAL, ZnEt2, InCls, and Pd(PPh3)4/LiCl, catalyze Michael addition of various enones at the 8-carbon to form new C-C bonds. In addition to the formation of C-C bonds, FeCls 6H2O, when combined with a stoichiometric amount of TMSCl, can also catalyze the aza-Michael addition to form new C-N bonds. For example, in the presence of 5% of FeCl3 6H2O and 1.1 equiv of TMSCl, stirring a mixture of 2-cyclohexenone and ethyl carbamate in dichloromethane provides an 89% yield of the protected /3-aminocyclohexanone (eq 41). 

Oxa- and aza-Michael additions followed by intramolecular cyclizations occur when propargyl alcohols are treated with a, -unsaturated nitroalkenes in the presence of t-BuOK in THF. Although exo-3-methylene tetrahydrofurans are usually the major products of these reactions, 3,4-dihydropyrans are also obtained in some cases, depending upon the substituents present within the donor and acceptor. Equation 59 shows the results of the reactions of propargyl alcohol with four nitroalkenes. Similar reactions of methyl propargylamine with these same acceptors give exclusively 3-methylenepyrrolidines."... 

The investigation of catalyst-free mechanochemical aza-Michael addition of amines with chalcones by Li et al. led to the formulation of an efficient synthetic protocol (Scheme 3.74) [49]. By applying optimal reaction conditions, a number of aliphatic and aromatic amines 278 in equimolar ratio were reacted with chalcones 277 to obtain azo-Michael products 279 in 44-99% yields (Table 3.37). Compared with conventional methods, the main advantages of the mechanochemical procedure are milder conditions, higher yield, shorter reaction time, and occurrence of no side reactions. 

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