Using Michael acceptors as electrophiles

A reminder from Chapter 22 a Michael acceptor is a compound capable of undergoing conjugate addition—an a,[5 unsaturated carbonyl compound or nitrile for example. Many Michael acceptors are toxic and carcinogenic compounds, and must be handled with care. 

One of the most important ways of making the direct addition reversible is to use a more stabilized enolate, since expulsion of the stable anion from the direct addition product is more favourable. An additional consequence of adding a second electron-withdrawing group such as C02Et is that the direct addition product is more hindered (and therefore less stable) than the conjugate addition product. 

The nature of the carbonyl group in the a,P-unsatuiated electrophile is also important as the more electrophilic carbonyl groups give more direct addition and the less electrophilic 

Less reactive Michael acceptors promote conjugate addition by  

P-Diesters (malonates and substituted derivatives, see p. 595) combine three useful features in conjugate addition reactions  

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In a similar manner, alkynes can undergo sequential carbometallation reactions, previously illustrated in equation (32).136 It is possible to combine carbocupration of alkynes with the use of a Michael acceptor as electrophile when that electrophile is a vinylphosphonium salt, carbocupration can be coupled to Wittig alkenation to result in a stereospecific synthesis of dienes via a one-pot, four-component, four carbon-carbon bond-forming reaction sequence.302... 

Summary This is an example of alkylations of enolates using a Michael acceptor as electrophile O (i) base P P... 

Addition of a 1,3-diene to a solution of the acyltetracarbonylcobalt complex 4.213 results in insertion, with formation of an ti -allyl complex 4.214 (Scheme 4.77) acylation occurring at the less-hindered terminus of the diene. ° In the presence of a base, the allyl complex undergoes elimination to give an acyl diene 4.215. As the allyl complex is electrophilic, it can also be attacked by some nucleophiles, such as malonate anions and nitronates (see Chapter 9, Section 9.1). Allenes can be used in place of the 1,3-diene (Scheme 4.78). The reaction is especially useful in an intramolecular sense. The products are useful Michael acceptors. ... 

As depicted in Scheme 11, ylides 39 derived from 4-methyl-[l,2,3]triazolo[l,5- ]pyridine react with Michael acceptors, which, upon nucleophilic attack at C3 and ring opening, lead to nucleophilic displacement of nitrogen. The intermediate diradical led to a mixture of compounds, including alkenes and a cyclobutane derivative when methyl acrylate was used, and the indolizine 40 with methyl propiolate as the electrophile <1998T9785>. Heating 4-methyl triazolopyridine with benzenesulfonyl chloride in acetone also confirmed decomposition via a radical pathway. 

Similar schemes can be developed easily for analogous reactions of acceptor-substituted polyenes. For example, a triene with an acceptor group in 1-position can form six regioi-someric products of Michael addition and electrophilic capture, and each of these exists as E/Z stereoisomers, diastereomers and/or enantiomers. Thus, reactions of this type are only useful if both the regio- and stereoselectivity can be controlled fortunately, only one isomeric Michael adduct is formed in many cases. This is true in particular for polyunsaturated Michael acceptors which bear at least one triple bond besides one or more double bonds. An additional feature of the latter substrate type is that nucleophilic additions can... 

Regiospeciflc, uncatalysed hydrophosphination of typical Michael acceptors, such as methyl acrylate, has been reported to proceed readily with alkenyl- an alkynyl-phosphine oxides, e.g. R(l )P(H)0. Good stereoselectivity was observed when a chiral electrophile was used. The reaction is believed to proceed owing to the strong... 

Aliphatic substrates also perform well, forming five membered rings in good yield and high enantioselectivity Eq. 6a. Typical Michael acceptors, however, are not sufficiently electrophilic to induce cyclization to form six-membered aliphatic rings. In order to effect this cyclization, use of a more electrophilic Michael acceptor, such as alkylidene malonate 83, was required Eq. 6b [70]. The difference in reactivity is presumably due to the extra conformational freedom of the aliphatic linker compared to the fused aromatic linker of substrate 79 coupled with potential competing non-productive pathways. 

Phenol complexes of [Os] display pronounced reactivity toward Michael acceptors under very mild conditions. The reactivity is due, in part, to the acidity of the hydroxyl proton, which can be easily removed to generate an extended enolate. Reactions of [Os]-phenol complexes are therefore typically catalyzed using amine bases rather than Lewis acids. The regio-chemistry of addition to C4-substituted phenol complexes is dependent upon the reaction conditions. Reactions that proceed under kinetic control typically lead to addition of the electrophile at C4. In reactions that are under thermodynamic control, the electrophile is added at C2. These C2-selective reactions have, in some cases, allowed the isolation of o-quinone methide complexes. As with other [Os] systems, electrophilic additions to phenol complexes occur anti to the face involved in metal coordination. 

Another less common class of nucleophile that does conjugate addition is nitriles. We used unsaturated nitriles a moment ago as Michael acceptors, and nitriles are usually electrophiles rather than nucleophiles. We did see in Chapter 17 that nitriles will act as nucleophiles in the S>jl reaction (the Ritter reaction). The next reaction is related to the Ritter reaction. 

FriedelCrafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation at the pyrimidine 5-position can be carried out on pyrimidines which have at least two strongly donating groups, and more readily with three such groups. Thus, -haloketones and -bromocarboxylic esters can be used for direct alkylation of 6-aminouracils 131, for example, in the formation of 132. The 5-position can also act as the nucleophile for Michael additions (e.g., 131 133) <1992AHC(55)129>. A microwave-assisted procedure allows formation of 5-hydroxymethy-luracil 135 from 134 in 98% yield, in just 3 min <2002SL2043>. Barbituric acids also add to Michael acceptors < 1985AHC(38)229>. 

Nitroalkenes, vinyl sulfones and vinylphosphonium salts have been shown as good Michael acceptors for 2-lithio-l,3-dithiane derivatives. Nitroalkene sugar derivative 246 has been used as electrophile for the synthesis of branched-chain cyclitols397 - 399. Seebach and Langer studied the addition to simple nitroalkenes using the chiral solvent (,S ,.S )-DDB (247) with some degree of diastereoselectivity400,401. 

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

The A -diphenylmethylene protection has also been used in the solid-phase mode for the synthesis of either unnatural amino acidst 1 or peptides (Scheme 67)J 1 Thereby, both Merrifield or Wang resins were used and the best base proved to be the organic soluble, nonionic phosphazene bases of Schwesinger, e.g. 2-tert-(butylimino)-2-(ethylamino)-l,3-di-methyl-l,3,2-diazaphosphinane (BEMP). As electrophiles alkyl halides,aldehydes, and Michael acceptors have been used. 

A variety of secondary amines have been used for enamine alkylation. Nonetheless, the three most commonly used, pyrrolidine, piperidine and morpholine, appear to still represent the best compromise between ease of access to the amine and formation of the enamine and the degree of conversion to mono-alkylated product. Pyrrolidine appears to be the best amine for the specific case where the electrophilic paitner for the enamine is a Michael acceptor, such as an a, 3-unsaturated ester, - and enamines derived from this base are generally more reactive than the piperidine and morpholine analogs. The use of optically active amines for asymmetric induction will be covered in Section 4.1.2.3. 

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