Solvent-free conditions Michael addition

Imidazole has been condensed via a 1,4 Michael addition with ethyl acrylate by use of basic clays (Li+ and Cs+ montmorillonites) under solvent-free conditions with microwave irradiation [77] (Eq. 24). 

Reactions of furan (5) under solvent-free conditions, catalyzed by Montmorillonite K10, have been described by Cintas [27]. The reaction with methyl vinyl ketone (32) produced Michael addition in positions 2 and 5, whereas reaction with symmetrically substituted cyclic dienophiles produced a mixture of the endo and exo adducts with the kinetically favored endo adduct predominating, except when maleic anhydride (39) was used as the dienophile (Scheme 9.2). 

Microwave irradiation, for 15-20 min under solvent-free conditions, promoted the regiospecific three-component one-step cyclocondensation of benzoylacetonitrile, an aromatic aldehyde, and aminopyrimidinones 460 to give 6-cyano-5,8-dihydropyrido[2,3-, pyrimidin-4(3/7)-ones 461 rather than the isomers 462. The formation of 461 proceeds via a Michael-type addition of C-5 in aminopyrimidine 460 to the activated double bond of the arylidene-benzoylacetonitrile intermediate followed by cyclization with the removal of a water molecule. Compounds 461 were also prepared conventionally by refluxing the reactants in absolute ethanol for 40 8 h <2001TL5625>. 

Kotsuki et al.909 have developed a method to effect the Michael addition of [3-ketoesters with ethyl acrylate in the presence of triflic acid under solvent-free conditions [Eq. (5.335)]. Nonactivated cyclohexanones as Michael donors and a,/3-unsaturated ketones as acceptors are also reactive. The use of menthyl acrylates did not result in any significant asymmetric induction. 

The basic ionic liquid [BmimJOH has been introduced as a catalyst for the aza-Michael addition of aromatic amines and A-heterocycles to cyclic or acyclic ketones under solvent-free conditions.138... 

A hydroxyapatite-bound La complex (LaHAP), prepared by using a cation-exchange method, has been reported to function as an efficient heterogeneous catalyst for the Michael addition of 1,3-dicarbonyls to enones under aqueous or solvent-free conditions. Further application to an asymmetric version by a fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid has also been described.171... 

Copper(II) tetrafluoroborate Cu(BF4)2xH20 has been identified as a new and highly efficient catalyst for Michael addition of thiols to o ,/5-unsaturated carbonyl compounds under solvent-free conditions and in H20 at room temperature. The reactions are very fast and are completed within 2 min to 1 h. The rate of thiol addition is dependent on the steric hindrance at the /3-carbon of the o ,/3-unsaturated carbonyl substrate. In the case of chalcones, the reactions are best carried out in MeOH as solvent.237... 

Ying A-G, Liu L, Wu G-F et al (2009) Aza-Michael addition of aliphatic or aromatic amines to [alpha], [beta]-unsaturated compounds catalyzed by a DBU-derived ionic liquid under solvent-free conditions. Tetrahedron Lett 50(14) 1653-1657... 

Modified guanidines 3 efficiently catalyzed the asymmetric Michael addition of a prochiral glycine derivatives with acrylate, acrylonitrile and methyl vinyl ketone under simple and mild conditions. Remarkably, both product formation and enantioselectivity were dramatically improved using solvent-free conditions (Scheme 12) [34]. The addition of alcohols to methyl propiolate was performed using fluorous phosphines such as P[(CH2)2 (CF2)7 CF3]3 and again better yields of 99% have been obtained under solvent-free conditions. Toluene was added to efficiently separate the product from the solid catalyst, which was then reused without loss of activity [35],... 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

An interesting thermal ring opening of a-aziridinohydrazones has been reported <07OL3461>. Aziridinecarboxylates underwent Michael type addition to l,2-diaza-l,3-butadienes under solvent-free conditions to generate a-aziridinohydrazones 66 in good to excellent yields. Subsequent 1,5-electrocyclization of these a-aziridinohydrazones in refluxing toluene afforded substituted imidazoles. 

Microwave irradiation of a mixture of cyclohexenones and ethyl acetoacetate adsorbed on the surface of solid lithium 5-(2)-prolinate leads to the stereoselective construction of bicyclo[2.2.2]octanone (69) systems through Michael addition and subsequent intramolecular aldolization (Ranu et al., 2000). Electron-rich aromatic compounds react with formaldehyde and a secondary amine under solvent-free condition and microwave irradiation in a microwave oven to produce amino ethylated products (70) in good to excellent yields (Mojtahedi et al., 2000). 

Recent examples, for instance, of the catalytic application of the commercially available macroporous Amberlyst-15 include the Michael addition of pyrroles to a,P-unsaturated ketones (Scheme 10.4) [48]. In this process, the acid ion exchange resin (dry, 10% w/w) allows on to obtain mono and dialkylated pyrroles 5 and 6 in reasonable yields. Similarly, this catalyst (dry, 30% w/w) can catalyze the aza-Michael reaction of amines with a,P-unsaturated ketones, esters and nitriles to afford 7 in 75-95% yields under solvent-free conditions. Interestingly, yields were significantly lower using typical solvents such as DCM (dichloromethane), CH3CN, THF, DMF or EtOH [49], Recycling the catalyst is possible in both cases, but a smooth decrease in the yield is observed for each new run. 

A second example is the competition between Diels-Alder cycloaddition and Michael addition during the reaction of 2-methoxythiophene III with DMAD under solvent-free conditions [73] (Fig. 4.12). 

Nitrocyclohexanols were synthesized by a double and diastereoselective Michael addition followed by ring closure (Eq. 45). When performed in the presence of KF-alumina under solvent-free conditions, an important microwave effect was observed ... 

Reproduced from Hestericova M, Sebesta R. Higher enantloselectivltles In thiourea-catalyzed Michael additions under solvent-free conditions. Tetrahedron 2014 70 901-5. Copyright (2014), with permission from Elsevier. 

Michael additions of aldehydes to nitroalkene with catalyst Cl can also be performed under solvent-free conditions in a ball-mill. The reaction was considerably more efficient under ball-milling conditions than with conventional stirring. Ball-milling reactions proceeded faster and afforded the... 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

Scettri et al. reported the aza-Michael addition of aniline to chalcones under solvent-free conditions, promoted by cinchonine. The corresponding products were obtained in good yield but with poor ee (11-58%). The enantioselectivity was improved up to 99% by the addition of an achiral silicon-based Lewis acid catalyst such as trimethylsilyl iodide (TMSI). ... 

A chemoenzymatic approach has been employed to synthesize enantioneriched P-amino acid esters. The aza-Michael addition of benzyl amine to P-alkyl substituted enoates, under solvent-free conditions, and subsequent hpase-catalyzed resolution via enantioselective aminolysis afforded the corresponding p-amino esters in moderate yields (19-36% yield) and with high enantioselectivities (93-99% ee) [96]. 

An efficient protocol for the aza-Michael addition of aliphatic and aromatic amines to electron-deficient alkenes using 1,1,3,3-tetramethylguanidinium lactate as catalyst under solvent-free conditions has been established. ... 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

Firouzabadi, H., Iranpoor, N., Jafarpour, M. and Ghaderi, A. 2006a. Zr0Cl2-8H20 as a highly efficient and the moisture tolerant Lewis acid catalyst for Michael addition of amines and indoles to a, 3-unsaturated ketones under solvent-free conditions. J. Mol. Catal. A Chem. 252 150-155. 

Pore et al. (2006) documented the thia-Michael addition involving the conjugate addition of thiols to a,p-unsaturated ketones in the presence of SSA as a heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 5.53). The catalytic activity was comparatively studied with potassium phosphate. Studies revealed that SSA is suitable for electron-deficient a,P-unsaturated compounds, whereas K3PO4 catalyzed the reactions of both electron-deficient as well as electron-rich enones. SSA catalyzes a rapid, green, and chemoselective aza-Michael addition of amines and thiols... 

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. 

A green synthetic protocol under solvent-free conditions for the synthesis of phos-phono malonates (162) from alkenes (160) and phosphorous nucleophiles (161) using nanoflake ZnO at 50°C has been documented (Scheme 9.52) (Hosseini-Sarvari and Etmad 2008). The reaction is an example of one of the most powerful and important C-P bond-forming reactions, which is the phospha-Michael addition. The advantages of this method include mild reaction conditions, a simple set up, high yields, and so on. The formylation of amines (163) with formic add (70) under solvent-free... 

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