Michael additions of a, p-unsaturated ketones

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Table 2.16 Hetero Michael addition of a,P-unsaturated ketone with alcohols...

Later, Melchiorre s group employed a similar catalyst system in the P-hydroxylation of (x,P-unsaturated ketones 79 (Scheme 43.17) [28], aziridination of enones (Scheme 43.18) [29], and sulfa-Michael addition of a,p-unsaturated ketones (Scheme 43.19) [30]. High chemical yields and excellent enantioselectivities for various chiral products were obtained, which proved the use of chiral co-catalysts to be necessary for optimal enantioselection. 

Scheme 43.19 Asymmetric sulfa-Michael addition of a,p-unsaturated ketones.

Chiral guanidinium-based ligands have also been used for recognition of diastereomeric salts of saccharides [45]. Some promising ligands with guani-dinium structure have not been studied yet [46], and some of them have been used as catalysts for the nitroaldol reaction [47] and Michael addition to a,P-unsaturated ketones [48]. 

Hydrophobic interactions may also serve to purify products of combinatorial syntheses. As an example, penta-O-lauroyl-l-thio-p-galactose was subjected to a Michael addition to a,p-unsaturated ketones or to alkylation by a-chloro ketones followed by reduction of the keto groups or by reductive alkylation with amino acid esters. The reaction mixtures were passed through Cl8 silica gel, whereby the desired products were adsorbed while unwanted products were washed away. Desorption was carried out with pentane, and the hydrophobic labels were removed with methanolic sodium methoxide.The methyl laurates were finally separated from the desired products by chromatography on silica... 

The use of the carbanion derived from the chloroallylphosphonate (163) in the enantioselective synthesis of cyclopropanes (164) by Michael addition to a,P-unsaturated ketones has been the subject of a short review (Scheme 18). Denmark s group have published full details of the asymmetric Michael addition reactions of cyclic enones with carbanions derived from l,3,2-oxa2aphosphor-inane 2-oxides (165) and (167). y-Addition to give (166) predominates although the extent of this depends on the ring size of the Michael acceptor. The level of diastereoselectivity depends on the stereochemistry of the allylphosphonate used ... 

In a sulfa-Michael reaction of a,p-unsaturated ketones catalysed by the salt derived from 9-amino-9-deoxy-epz -dihydroquinine (9-e/ f-DHQA) and n-N-Boc-phenylglycine, the best results (96% ee) were obtained using fert-bulyl-thiol. ° A similar catalyst, 9-amino-9-deo y-epz-cupreidine (9-epf-CPDA) allowed a diastereodivergent reaction, where selectivity towards both product diastereomers was possible using the same catalyst by changing the acidic additive and reaction conditions (Scheme 15.31). 

Michael addition, i.e., the 1,4-addition of a,p-unsaturated ketones to a compound with a labile H atom, often leads to the formation of a single compound ... 

In a manner largely complementary to secondary amine-catalyzed asymmetric conjugate addition to enals with heteroatom nucleophiles, chiral primary amines were recently found to be the catalysts of choice for similar Michael addition to a,p-unsaturated ketones. With their previously developed cinchona-type catalyst 91, Melchiorre and coworkers achieved the asymmetric sulfa-Michael addition to a,p-unsaturated ketones with either benzyl or tert-butyl mercaptane (Scheme 5.30) [58a]. The same catalyst could be further extended to oxa-Michael addition to enones by optimizing the ratio of acidic additive and solvents (Scheme 5.30) [58b]. 

Aminopyrimidines are also known to undergo Michael additions to a,P-unsaturated carbonyl compounds. This methodology was utilized by Insuasty and co-workers using triaminopyrimidines 70 with conjugated ketones 71 to produce a variety of pyrimidine-fused diazepines 72 <00JHC193,00JHC401>. 

Wang and co-workers developed a 121-catalyzed enantioselective Michael addition [149-152] of IH-benzotriazole to a variety of a,P-unsaturated ketones such as the model substrate 3-(4-chloro-phenyl)-l-phenyl-propenone affording the N-1 product 1 (Scheme 6.136) [291]. The evaluation of the reaction medium revealed... 

Oxidation of a,P-unsaturated ketones with alkaline hydrogen peroxide produces the corresponding keto epoxides in good yields. This nucleophilic epoxidation proceeds via an initial Michael-type addition of the hydroperoxide anion to the enone system, which is then followed by elimination of HO. It should be noted that the inductive electron-withdrawing effect of the neighboring oxygen in HOO makes it a weaker base than HO" but a better nucleophile than hydroxide. 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

A popular and useful application of the conjugate addition reaction is the combined conjugate addition-intramolecular aldol strategy, commonly known as the Robinson annulation. When the Michael donor is a ketone and the Michael acceptor an a,p-unsaturated ketone, the product is a 1,5-diketone which can readily undergo cyclization to a six-membered ring. Typical Michael donor substrates are 2-substituted cyclohexanones, which condense with alkyl vinyl ketones to give the intermediate conjugate addition products 42 (1.52). The subsequent intramolecular... 

Chiral secondary and primary amines are able to promote Michael addition on a,p-unsaturated aldehydes and ketones. The mechanism involves the formation of a... 

It was also possible to perform the pyrrole 5 Michael addition with a variety of a,p-unsaturated ketones 2 catalyzed by MSSA in the same fashion, affording 2-substituted pyrroles 6 in good yields (Scheme 1.3b). Furthermore, MSSA was used as a solid acid heterogeneous catalyst to synthesize 1,1,3-triindolyl compounds through the tandem Michael addition and Friedel-Craft reaction of a, P-unsaturated aldehydes or ketones and indole (3) (Scheme 1.4). The authors found two protocols of general applicability employing 1 mmol of a,P-unsaturated compound and 4 mmol... 

Using a chiral primary amine salt derived from 9-amino-(9-deoxy)-e/>i-hydroquinine, Melchiorre et al. achieved an organocatalytic asymmetric protocol for the highly enantioselective sulfa-Michael addition, which was applicable to a large variety of a,p-unsaturated ketones. The highest enantioselectivities of up to 96% ee combined with high yields were obtained with benzyl mercaptan as a nucleophile, as shown in Scheme 1.69. 

The Michael reaction is an alkylation in which carbanions, such as the enolates derived from (3-diketones, p-keto esters, and diethyl malonate, react with a,p-unsaturated ketones by conjugate addition. The a,p-unsaturated ketone serves the same kind of electrophilic role that alkyl halides do toward the enolate. 

What combination of a,P-unsaturated ketone and a ketone is required to synthesize each of the following compounds by a Michael addition followed by Robinson annulation ... 

Probably the most important organocatalytic addition to a,P-unsaturated ketones is the synthesis of the Wieland-Miescher ketone. This bicyclic diketone is obtained by a Robinson aimulation consisting of a first Michael addition to vinyl methyl ketone followed by an intramolecular aldol reaction. 

To obtain a formal P-fluoromethylation of ketones, Shibata, Tom, and coworkers employed FBSM (62) as Michael donor in the enantioselective conjugated addition to a,P-unsaturated ketones [87]. The reaction was catalyzed by a quaternary salt derived from cinchona alkaloid (103), affording the frnal products 104 in high yields (up to 91%) and excellent enantioselectivities (Scheme 33.29). 

In addition to the consecutive aldol reactions of aldehydes, Barbas s group also reported enamine-activated Diels-Alder reactions (or double Michael reactions) between a,P-unsaturated ketones and nitroolefm (Scheme 1.15) for the first time in 2002 [17], hi contrast to MacMillan s iminium catalysis for Diels-Alder reactions, wherein a,P-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3], an alternative strategy involving the in situ generation of 2-amino-1,3-dienes from a,P-unsaturated ketones... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Addition of Carbanions to a,p-Unsaturated Ketones The Michael Reaction... 

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