Michael-allylic substitution

Scheme 3.9 Tandem Michael-allylic substitution reaction catalysed by a combination of chiral copper catalysis and palladium catalysis.

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

Furthermore, following an analogous methodology, combining the Morita-Baylis-Hillman reaction and the Trost-Tsuji reaction, Krische and co-workers have obtained allyl-substituted cyclopentenones 94 [84], Reaction was initiated by Michael addition of tributyl phosphine to an enone moiety 92, generating a latent enolate 93 which reacts intramolecularly with a jr-allylPd complex as the electrophile partner. A final -elimination step of trib-utylphosphine, favored by the presence of the methoxide ion, delivered the substituted cyclopentenones 94 (Scheme 36). 

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 lithium cuprates 39, prepared from a- and P-2-deoxy-D-glucopyranosyl-stannanes a- and P-38 are configurationally stable and provide the corresponding Michael addition products 40 on reaction with methyl vinyl ketone [Eq. (14)] [27]. The cuprates a-39 [28] and 41 [29] have been used by Kocienski et al. for allylic substitution at q -molybdenum complexes. 

Baylis-Hillman carbonate is a good substrate for asymmetric allylic substitution reaction, and various nucleophiles have been involved in this transformation. As shown in Scheme 9.36, the intermediate 72 (mechanistically formed by Michael... 

Based on the enantioselective Michael addition/ISOC (intramolecular silyl nitronate olefin cycloaddition)/lragmentation sequence previously developed by the group of Rodriguez [33a], Shao and coworkers proposed an extrapolation for the construction of spirooxindoles catalyzed by a bifunctional tertiary amine-thiourea catalyst XV between 4-allyl-substituted oxindoles 63 and nitrostyrenes 64 (Scheme 10.21) [33b]. After the addition of TMSCl and EtgN at -30 C, the Michael adduct underwent an ISCX3 to afford the spiro oxime derivatives 65 in very good yields (85-85%), and excellent diastereo (up to >30 1) and enantioselectivities (94-99% ee) after the treatment with TBAF. 

Evans DA, Campos KR, Tedrow JS, Michael FE, Gagne MR. Application of chiral mixed phosphonis/sulfur ligands to palladium-catalyzed allylic substitutions. J. Am. Chem. Soc. 2000 122 7905-7920. 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Some particular features should be mentioned. Instead of Michael additions, a-nitroolefins are reported to yield allyl sulfones under Pd catalysis (equation 21). Halogenated acceptor-olefins can substitute halogen P to the acceptor by ipso-substitution with sulfinate (equation 22 , equation 23 ) or can lose halogen a to the acceptor in the course of a secondary elimination occurring P to the introduced sulfonyl groups (equation 24). On the other hand, the use of hydrated sodium sulfinates can lead to cleavage at the C=C double bond (equation 25). 

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