Michael-acceptor

Synthesis You will see that there are problems in both the routes found by the analysis. For route a it is known that malonate attacks exclusively the less hindered side of some Michael acceptors ... 

Both are possible but we are more used to (1) since we can use a Michael acceptor and cyanide ion for the two synthons. How would you actually do a s mthesis this way ... 

Route (ii) could use a Michael acceptor together with a suitable one carbon nucleopliile... 

Each of these approaches may be the best for any given lactone the one in the last frame for example would allow you to use any Michael acceptor and any aldehyde. 

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

Benzothiazole, 2-(thiocyanomethylthio)-food preserative, 1, 411 Benzothiazole, 2-trimethylsilyl-reactions, 6, 292 Benzothiazole, 2-vinyl-in organic synthesis, 6, 329 Michael acceptor, 1, 467 2-Benzothiazole, 4-morpholinyl-disulfide... 

Regiooomreiied synthesis of live membered mgs from silylallenes and Michael acceptors in the presence of TICI4... 

The Bsmoc derivative is formed from the chloroformate or the A -hydroxy-succinimide ester. It is cleaved rapidly by a Michael addition with tris(2-aminoethyl)amine at a rate that leaves Fmoc derivatives intact. More hindered bases, such as A -methylcyclohexylamine or diisopropylamine, do not react with the Bsmoc group, but do cleave the Fmoc group, illustrating the importance of steric effects in additions to Michael acceptors. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

The anion of A-nitromethyIphthalimide 17 also acts as a formyl anion equivalent with Michael acceptors to afford 1,4-dicarbonyl compounds 18 in good to excellent yields, although difficulty was experienced in isolating the products under the conditions required for removal of the phthalimide group (77CJC2919). 

Copper-mediated Addition Reactions to Extended Michael Acceptors... 

Auxiliary-bourtd Chiral Michael Acceptors and Auxiliary Chiral Metal Complexes... 

Diastereoselective conjugate additions to chital Michael acceptors in which the part initially heating the chital information is removable ii.e., a chital auxiliary) provides a means to synthesize enantiomerlcally pure conjugate adducts. Chital auxiliaries iduould ideally he readily available in both enantiomeric fornts. Tliey should... 

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

When 3-butyne-2-one 7 is used as a Michael acceptor component, a 2,5-cyclohexadienone, e.g. 8, is obtained as the annulation product ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Exceptions to this rule may be a result of steric hindrance. However when the Stork enamine method is applied, for example with enamine 10, the less substituted a-carbon becomes connected to the Michael acceptor ... 

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 ... 

VinyIpyridine (26) exhibits many of the properties of a Michael acceptor. Thus, this molecule will undergo conjugate addition of methoxide ion. There is thus obtained methyridine (27), an antinematodal agent used in veterinary practice. 

The reaction of relatively simple starting materials, coumarin 40, piperidone 37 and ammonium acetate, leads in a single step to the complex bridged tetracyclic compound 44. The reaction can be rationalized by assuming formation of the iminc 38 from reaction of 37, with ammonia. Conjugate addition of the eneamine-like tautomer 39 to the excellent Michael acceptor 40 will... 

Dehydration of fi-nitro iilcohols provides an important method for the preparation of nitroalkenes. Because lower nitroalkenes such as nitroethylene, Tnitro-Tpropene, and 3-nitro- Tpropene tend to polymerize, they must be prepared careftdly and used immediately after preparation. Dehydration v/ith phthalic anhydride is the most reliable method for such lower nitroiilkenes. Such lower nitroalkenes have been used as important reagents for Michael acceptors or dienophiles in the Diels-Alder reacdon, which v/ill be... 

Michael acceptors and 1,4-addiiion of alkyl group is a normal process. The reaction mechanism is not clear, but the process via addition of alkyl radicals and subsequent elimination of NO radical is one of the possible routes. Recently, several related reactions have been reported, as shown in Eq. 4.76, Eq. 4.77, and Eq. 4.78, in which alkyl radicals are involved. The reaction of trialky Igalliiim compounds with nitrostyrene gives also a similar snbsdtiidon product fEq. 4.791. ° ... 

Polyfiincdonalizeduitro compounds are prepared by the Michael addidon using 2-alkenyl-snbsdtiited 2-siloxycyclopropiinecarboxylates as Michael acceptors fEq. 4.120. ... 

Nitroalkenes are shown to be effective Michael acceptor B units In three sequential re fA + B + C couplingi in one reaction vessel. The sequence is initialed by enolate nucleophiles fA and is terminated by aldehydes or acrylate electrophiles fC. The utility of this protocol is for rapid assembly of complex stnictures from simple and readily available components. A short total synthesis of a pyrroLmdine alkaloid is presented in Scheme 10.16. ... 

Table 23.1 Some Michael Acceptors and Michael Donors Michael acceptors Michael donors...

The formed vinyl sulfones are powerful Michael acceptors, which by treatment of the y-emti-product with base, undergo ring closure to diastereomerically pure 4-sulfonyltetrahydrofurans39. 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

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