Michael reaction cyclic enone acceptor

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

The use of a-thiophenyl enones (106 Scheme 12) allows the preparation of phenols such as (107) from cyclic ketones (18).30 The same product can also be obtained by normal Robinson annulation of methyl vinyl ketone (30) and the p-keto sulfoxide (lOS).30 Acceptors other than a, 3-unsaturated carbonyls have been used in both the Michael reaction and the Robinson annulation process. For example, nu-... 

For Type II reactions also a variety of useful compounds can be synthesized by changing the combination of the starting materials. In the Michael reaction with cyclic enones, availability of the La-linked-BINOL complex broadened the scope of the Michael acceptor (Scheme 14). It should be noted that less reactive medium-ring-size cyclic enones (7-9membered ring size) underwent conjugate addition highly enantioselectively (up to > 99 % ee) [17]. 

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 ... 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

In the presence of TMSOTf, BFs.OEtz and dimethyl sulfide, the iminium ions 204 (masked as N,0-acetals) have been employed to couple with a very board range of readily available Michael acceptors, including acrolein and acrylates, in both an inter- and intramolecular MBH-type reaction to give densely functionalized heterocycles 207 (Scheme 1.78). The process has been rendered asymmetric and high enantioselectivity is obtained in reactions of iminium ions 210 (masked as N,0-acetals) and cyclic enones (Scheme 1.79). Finally, the usefulness of the methodology has been exemplified in a short synthesis of ( + )-heliotridine 208 and (-)-retronecine 209 (Scheme 1.78). ... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

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