Michael addition to unsaturated acceptors

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Some Michael additions of unsaturated reagents to imidazoles involve the neutral species of the heterocycles, but others may be reactions of the anion. Fluoride ion catalyzed addition of 2-methyl-4-nitroimidazole (113) to a suitable Michael acceptor gives almost quantitative yields of the 1-substituted 4-nitroisomers (114) (90JOC3702,91JCR(S)35o). 

The chiral, nonracemic oxazepine derivative (46 Scheme 18) was studied as donor in the Michael addition to prochiral a,p-unsaturated carbonyl compounds.134-133 The products were obtained with 44-55% ee after removal of the chiral auxiliary group. With 1-nitrocyclohexene as acceptor, somewhat better se-lectivities (62% ee) were observed.136... 

The strategy of the sequence is a Michael addition to an a,/3-unsaturated ketone followed by an intramolecular aldol reaction. Treatment of a ketone enolate with a Michael acceptor gives a diketone intermediate which is poised to produce a six-membered ring if an enolate is produced and it intramolecularly adds to the carbonyl group. 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

In addition to enoiate ions, other kinds of carbon nucleophiles add to ,/ -unsaturated acceptors in the Michael reaction, greatly extending the usefulness and versatility of the process. Among the most important such nucleophiles are enamines. Recall from Section 19.9 that enamines are readily prepared by reaction between a ketone and a secondary amine ... 

Conjugate addition of a nucleophile to an activated olefin is generally referred to as a Michael addition reaction (1). Of particular interest is the addition of delocalized carbanions to unsaturated acceptors, a process resulting in the construction of a carbon-carbon bond, often stereoselectively (2). However, the addition of metal enolates to unsaturated acceptors is not completely general and two major modifications have been developed wherein covalently bound enolate equivalents are added to unsaturated acceptors. 

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 steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

In the eyes of a synthetic chemist this might be called a nitrogen-Michael-ad-dition to the a,P-unsaturated acid moiety as the 1,4-acceptor. Thus, it occurred to us that our favourite auxiliary, the hydrazine SAMP, might be used as a chiral ammonia equivalent in asymmetric hetero Michael additions to enoates. 

A general model for understanding the stereochemistry of intramolecular Michael reactions has been proposed, based on the addition of -ketoester enolates to a,[l-unsaturated esters and imide moieties bearing adjacent stereocentres in the chain connecting the Michael donor to an acceptor (225) (226) (X, Y = H, Me, OR in the syn- or unti-configuration). A dipole-minimized chair-like transition state appears to offer the best rationalization. ... 

As we saw in Chapter 1, Michael additions to a,jS-unsaturated ketones occur best when the nucleophile is only weakly basic. In entries 1 and 2 of Scheme 2.2, we note examples of Robinson annulation reactions in which the nucleophiles are derived by deprotonation of a /3-diketone and a /3-keto ester, respectively. The Michael acceptor is methyl vinyl ketone in entry 1 and is ethyl vinyl ketone in... 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

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. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

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