Ketones as Michael Donors

As has already been mentioned, the low reactivity of enamine nucleophiles needs a highly electrophilic Michael acceptor for the reaction to proceed with good conversions in an acceptable time. In this context, the Michael reaction of aldehydes and ketones with nitroalkenes can be regarded as one of the most studied transformations in which the enamine activation concept has been applied. This reaction furnishes highly functionalized adducts with remarkable potential in organic synthesis, due to the synthetic versatility of the nitro group and the presence of the carbonyl moiety from the donor reagent. 

The first attempts in the field were carried out in the context of the proline-catalyzed Michael reaction of ketones with nitrostyrene, which was initially 

This catalyst design in which the stereochemical outcome of the reaction is controlled by hydrogen bonding interactions with an acidic site at the catalyst has been applied to other differently modified chiral secondary amines, generally consisting of a 2-substituted pyrrohdine motif. Some representatives are 

An alternative catalyst design consists of the introduction of bulky groups at the pyrrolidine ring, which would exert their stereochemical influence via steric shielding of one of the diastereotopic faces of the enamine intermediate. In this context, a wide variety of different proline derivatives have been employed in this transformation, including prolinol silyl ether homoprolinol silyl 

Nevertheless, as was pointed out before, a straightforward solution to the rather limited substrate scope of the reaction with regard to the ketone reagent and also a good way to overcome the lack of reactivity of ketones toward enamine activation has been the use of primary amines as organocatalysts. In fact, literature examples indicate that primary amines are much more active catalysts for the Michael addition of both cyclic and acyclic ketones to nitroalkenes compared to the same reaction using a secondary amine catalyst like most of the proline-based derivatives already presented before. 

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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. 

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. 

Using methyl vinyl ketone as Michael acceptor, it was found (42) that a variety of donors gave optically active products when quinine was used as the chiral catalyst. Figure 7 lists the donors. Unfortunately in none of these cases... 

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. 

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. 

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. 

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). 

A direct approach to trifluoromethyl ketones is by reaction of esters (also oxazolidin-5-ones ) with MejSiCF, activated by TBAF (7 examples, 68-95%). A similar reaction of acylsilanes leads to l,l-difluoro-2-siloxyalkenes which may be used as Michael donors for the synthesis of 2,2-difIuoro-1,4-diketones. ... 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

Alkenyl ketones. 1-Silyl-l-alken-2-yltitanium reagents generated from 1-silyl-alkynes with (-PrMgCl/(i-PrO)4Ti are used as Michael donors in the presence of Li2Cu(CN)Cl2. 

Michael additions. 1,5-Ketoaldehydes are formed on the admixture of vinyl ketones, aldehydes, and MCjSiNEt at room temperature and without solvent. It is unusual that the aldehydes behave as Michael donors. 

On the other hand, several primary amines have also been successfully employed as catalysts in the reaction using aldehydes as Michael donors. Important representative examples are shown in Figure 2.7, like bifunctional sulfamide 36 and primary amine-thioureas 37a and 23b,the latter being developed by Jacobsen and very similar to that used by the same group in the reaction with ketones as donors (see Scheme 2.7) and which performs exceptionally well in the Michael reaction of a,a-disubstituted aldehydes to both aromatic and aliphatic nitroolefins. 

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

It has to be pointed out that simple enolizable aldehydes and ketones, which are not acidic enough compounds to be directly used as pro-nucleophiles in this context, can nevertheless be employed as Michael donors in the reaction with enals or enones, which have been previously activated as the corresponding iminium ion, but their use requires prior activation via enamine activation. In these cases, it is usually proposed that the amine catalyst is involved in a dual activation profile interacting with both the Michael donor and the acceptor, although the enamine activation of the pro-nucleophile is mandatory for the reaction to occur, the activation of the acceptor being of less relevance in most cases. For these reasons, this chemistry has been covered in Chapter 2. 

It also has to be remembered that enolizable aldehydes or ketones can also be used as Michael donors in this reaction using thiourea-containing catalysts for... 

In a much more recent report, conveniently O-protected a-hydroxymethyl aryl ketones were also successfully employed as Michael donors in the conjugate addition to methyl acrylate and acrylonitrile using a cinchonine-based ammonium salt as catalyst. Bis-quinidine-based ammonium salt 105 has also shown to be useful in the reaction of cyclic p-ketoesters to methyl and ethyl acrylate. ... 

The synthetic route shown relies on an enolate serving as a Michael donor and attacking the 3 position of an a,[3-unsaturated ketone. The process will not work because enolates are not stable enough to function as Michael donors. This transformation requires a stabiHzed enolate, or some species that will behave like a stabilized enolate. Gilbert Stork (Columbia University) developed a method for such a transformation in which the ketone is converted into an enamine by treatment with a secondary amine. 

Enamines act as Michael donors in conjugate addition reactions (Section 21.12). Draw the structure of the product formed by reaction of the enamine of cyclohexanone and pyrrolidine with methyl vinyl ketone. 

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). 

Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an cr,/3-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C—C bond made in the Michael addition step is the one between the a- carbon of the ketone donor and the /3 carbon of the unsaturated acceptor. 

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