Michael donors ketones

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

A variety of Michael donors such as ketones, esters, thioesters, amides, lactones and lactams may be used and in all of these cases the problems of stereoselectivity apply. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

The wide range of Michael donors and acceptors in 1,4-additions are of great utility. Consequently, fnrther exploration on the addition of a-snbstituted P-ketoester addition to a,p-nnsatnrated ketones have captured the attention of many chemists. The transformation is a versatile methodology to access all-carbon qnatemary stereocenters. 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Magnesium enolates derived from hindered ketones are also possible Michael donors. For example, enolization of f-butyl alkylketones with (i-Pr)2Mg allows the 1,4-addition on the chalcone. A long reaction time (>3 h) limits the competing 1,2-addition and increases the proportion of the threo isomer (equation 77). 

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 first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

In the same way as in Type I reactions, a simple aromatic ketone, for example acetophenone, can also be used as a Michael donor in a Type II reaction (Scheme 21). Using 50% KOH as a base, the reaction proceeded smoothly in the... 

Scheme 21. Use of a simple aromatic ketone as a Michael donor in a Type II reaction.

The following example shows lithium divinylcuprate serving as a Michael donor, adding to the double bond of an a,/3-unsaturatcd ketone. In this conjugate addition, the vinyl group adds to the (3 carbon atom to give an enolate ion. Protonation at the a carbon gives the product. 

Michael additions are useful in acetoacetic ester syntheses and malonic ester syntheses because the enolate ions of both of these esters are good Michael donors. As an example, let s consider the addition of the malonic ester enolate to methyl vinyl ketone (MVK). The crucial step is the nucleophilic attack by the enolate at the carbon. The resulting enolate is strongly basic, and it is quickly protonated. 

A 1,4-addition (conjugate addition) of a resonance-stabilized carbanion (the Michael donor) to a conjugated double bond such as an a,/3-unsaturated ketone or ester (the Michael acceptor), (p. 1086)... 

A ketone that has been converted to an enamine can act as a Michael donor in a reaction known as the Stork reaction. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Tn and coworkers reported on both kinetically and thermodynamically controlled Michael addition of the lithinm enolates of ketone 135 to nitroethylene 136 as the key step in the total syntheses of the alkaloids ( )-y-lycorane (139) and ( )-crinane (142) (equation 39) °. Both reactions started from the same Michael donor (135) with nitroethylene (136) as a C-C-NH2 synthon for the construction of aryl-substituted... 

The substrate 292 was specifically designed to prepare five-membered systems via a sequence of inter- and intramolecular Michael additions. This option is viable when active Michael acceptors such as methyl vinyl ketone are used, otherwise competing Michael reactions between two molecules of 292 are difficult to avoid. The reaction proceeds through intermediate 293, which contains both a Michael donor and acceptor site and undergoes spontaneous conversion into the cyclic product 294. 

By applying this system to a,yS-unsaturated ketones, even more general and pronounced 1,4-selectivity (> 99 1) can be achieved, and a variety of alkyllithiums can be used as Michael donors [137]. In addition, this ATPH-alkyllithium system enables the introduction of perfluoroalkyl or perfluoroaryl substituents at the fi position of carbonyl functions [138], An example of cyclohexenone (133) as a Michael acceptor is shown in Sch. 101. 

Tandem inter- and intramolecular Michael addition using the enolates of aj3-unsa-turated ketones as Michael donors has also been successfully achieved [139]. For instance, treatment of cyclohexenone (133)-ATPH complex in toluene with a THF solution of the benzalacetone lithium enolate at -78 °C, then reflux for 13 h gave the stereochemically homogeneous annulation product 134 in 50 % yield (> 84 % de) as indicated in Sch. 102. 

Feringa et al. developed aqueous Michael reactions catalyzed by Yb(OTf)3 (Eq. 1) [4]. fi-keto esters and a-nitro esters could be used as Michael donors for the reaction. a,y3-Unsaturated ketones and a,/5-unsaturated aldehydes without /S-substituents were good Michael acceptors for the reaction but the reaction did not proceed with ethyl acrylate or acrylonitrile. The reported yields were excellent, though the reaction required prolonged reaction time (3-5 days). 

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