Michael reactions with enamines

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

An efficient preparation of 1,5-diketones as precursors to D-ring annulated heterosteroids was elaborated by R.C. Boruah et al. [96] (Scheme 24). Readily available 16-dehydropregnenolone acetate (16-DPA) was used in a Michael reaction with enamines. 

Fluorme-containing Michael addition acceptors have been used as synthons, a portion of a molecule recognizably related to a simpler molecule, for the introduction of fluorine into the organic molecules Their reactions with enamines and ketones lead to a condensarion-cyclization process... 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

Perhaps the major disadvantage of the copper-catalysed Michael reaction is the need to protect functional groups. Michael reactions with heteroatom nucleophiles or functionalised carbon nucleophiles are usually carried out without copper. Many such nucleophiles, particularly enol equivalents, are excellent at Michael reactions, and are often to be preferred for ease of working. Silyl enol ethers, enamines, and stabilised enolates all carry out Michael reactions. In the next chapter we shall look at specific enol equivalents in more detail and note which ones are good at Michael additions. 

As in the uncatalyzed reactions with enamines (vide supra), there is potentially more than one point where stereochemical differentiation can occur (Scheme 59). Selectivity can occur if the initial addition of the enol ether to the Lewis acid complex of the a,/J-unsaturated acceptor (step A) is the product-determining step. Reversion of the initial adduct 59.1 to the neutral starting acceptor and the silyl enol ether is possible, at least in some cases. If the Michael-retro-Michael manifold is rapid, then selectivity in the product generation would be determined by the relative rates of the decomposition of the diastereomers of the dipolar intermediate (59.1). For example, preferential loss of the silyl cation (or rm-butyl cation for tert-butyl esters step B) from one of the isomers could lead to selectivity in product construction. Alternatively, intramolecular transfer of the silyl cation from the donor to the acceptor (step D) could be preferred for one of the diastereomeric intermediates. If the Michael-retro-Michael addition pathway is rapid and an alternative mechanism (silyl transfer) is product-determining, then the stereochemistry of the adducts formed should show little dependence on the configuration of the starting materials employed, as is observed. 

The second chapter, by David A. Oare and Clayton H. Heathcock, deals with the stereochemistry of uncatalyzed Michael reactions of enamines and of Lewis acid catalyzed reactions of enol ethers with a,/ -unsaturated carbonyl compounds. It is effectively a continuation of their definitive review of base-promoted Michael addition reaction stereochemistry that appeared in the preceding volume of the series. 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

Despite the fact that extensive studies have been conducted on secondary-amine-catalyzed Michael addition of unmodified a-monosubstituted aldehydes, there are few reports on the use of a,a-disubstimted aldehydes as nucleophiles, probably due to the high hinderance during the formation of enamine intermediates. By using (5)-l-(2-pyrrolidinylmethyl)pyrrolidme/TFA salt 19 as catalyst, Barbas and co-workers [13] reported the first application of a,a-disubstituted aldehydes in the enantiose-lective Michael reactions with nitroalkenes (Scheme 5.6). The corresponding Michael adducts bearing an all-carbon quaternary stereocenter were obtained in moderate diastereoselectivities and with moderate to good enantioselectivities (up to 91%). 

Much like enolates, enamines are also nucleophiUc at the Ct position. However, enamines do not possess a net negative charge, as enolates do, and therefore, enamines are less reactive than enolates. As such, enamines are effective Michael donors and will participate in a Michael reaction with a suitable Michael acceptor. 

Examples of [4+2] Reactions with Enamine-Activated Dienes It is well known that Diels-Alder reactions can usually be regarded as double Michael... 

Development of such a catalytic cascade process requires a stable and electron-rich carbon species as a nucleophile, which should be compatible with electrophihc aldehyde functionality in one of the chemical entities 144 (Schane 1.53) [90]. Undesired reaction of 144 with the catalyst to produce an iminium or aiamine could significantly complicate the cascade process. Potentially, the iminium 144a could undergo reversible intramolecular cyclopropanation and thus slow down the desired cascade process. Moreover, the enamine 144b could participate in the Michael reaction with iminium 144c. 

Nitroalkene acceptors in reactions with enamines Dihydrooxazine oxides (406) have now been identified as stable, key intermediates in the Michael addition of aldehydes to nitroalkenes, catalysed by pyrrolidines (405) (Scheme 15). Theoretical calculations suggest that these intermediates are protonated directly (e.g. by p-nitrophenol), without the formation of the zwitterion species. The latter protonation accounts for both the role of the acid cocatalyst and the stereochemistry.257 Theoretical studies of the proline-catalysed Michael addition of aldehydes and ketones to 0-nitrostyrene (MP2/6-311-l-G //M06-2X/6-31G ) suggest that, contrary to the... 

The forward scheme is shown here. The starting ketone is first treated with a secondary amine in acidic conditions (with removal of water) to give an enamine. This enamine is then used as a Michael donor in a Michael reaction with an a,P-unsaturated ketone. Aqueous acidic work-up gives the desired product. 

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