Addition, conjugate chalcones

Since Corey s group first reported 0(9)-allyl-N-(9-anthracenylmethyl) cinchonidi-nium bromide as a new phase-transfer catalyst [13], its application to various asymmetric reactions has been investigated. In particular, this catalyst represents a powerful tool in various conjugated additions using chalcone derivatives (Scheme 3.2). For example, nitromethane [14], acetophenone [15], and silyl eno-lates [16] produce the corresponding adducts in high enantioselectivity. When p-alkyl substrates are used under PTC conditions, asymmetric dimerization triggered by the abstraction of a y-proton proceeds smoothly, with up to 98% ee [17]. 

A binaphthol-based chirally modified acetylide 116 was shown to undergo conjugate addition to chalcone 40 to give adduct 117 in 90% ee (Scheme 14) [63], Enones capable of achieving an s-cis conformation are claimed to be suitable substrates for this addition reaction. 

Asymmetric -methylation of a, -enones. Chiral bidendate ligands derived from L-prolinol can be used for asymmetric Michael additions to a, 3-enones with cuprates of the type CH,L CuMgBr (10, 266). The highest optical yield in conjugate addition to chalcone is observed when L is (S)-N-methylprolinol (88% ee). The tridentate chiral ligand 1 is equally effective for asymmetric 3-methylation of chalcone with CH,L CuLi and CuBr the chemical yield is 95%. Reduction of the amide carbonyl group of 1 results in practically total loss of chiral induction. 

Asymmetric nitro-Michael reactions of methyl vinyl ketone (MVK) in the presence of bicyclic guanidine with a benzhydryl group led, disappointedly, to low asymmetric induction (9-12%) [21a] Trials for the reaction of 0 ,p-unsaturated y- or 8-lactones with pyrrolidine in the presence of the conjugate acids of a bicyclic guanidine [50] or the Murphy s guanidine [24a] (R = Me in Scheme 4.7) resulted in the production of racemic compounds. The latter phase transfer catalyst (PTC) catalyses the nitro-Michael addition of chalcone but with limited range (70% yield, 23% ee) [24c]. 

Similar to oxindole derivatives, benzofuranones are also suitable donors in Michael reactions. Recently, Luo and Cheng fulfilled the successful application of benzofuranones in the conjugated addition to chalcones [95] and malemides [96] utilizing bifunctional amine thiourea 75 and 90, respectively (Scheme 5.46). These reactions provide powerful methods for the synthesis of chiral benzofuranone derivatives with different functional groups. 

Brunner and Hammer in 1984, who employed Co(acac)2 combined with a chiral C2-symmetric diamine ligand which provided enantioselectivities of up to 66% ee. Later in 1988, Soai et al developed the first asymmetric conjugate additions performed under chiral nickel(ii) catalysis/ The process, which involved dieth-ylzinc addition to chalcones, provided the corresponding 1,4-products in low to moderate enantioselectivities (<55% ee) by using an ephedrine derivative as the chiral ligand, as shown in Scheme 2.1 (first equation). Soon after, better enantioselectivities of up to 90% ee were achieved by the same authors using Ni(acac)2 as the nickel source instead of NiBr2, bipyridine as additive, and acetonitrile as solvent (Scheme 2.1, second equation). ... 

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

The conjugate addition of lithium dimethylcuprate to chalcone in the presence of (2S)-1-(2,2-dimethyl-l-oxopropyl)-2-diphenylphosphinomethylpyrrolidine gave the corresponding S-adduct with 84% ec in 79% yield79. 

In 2000, Gennaii et al. discovered a new family of chiral Schiff-base ligands, with the general structure, Af-alkyl-p-(A -salicylideneamino)alkanesulfonamide, depicted in Scheme 2.28. These ligands were successfully implicated in the copper-catalysed conjugate addition of ZnEt2 to cyclic enones (Scheme 2.28) and, less efficiently, to acyclic enones such as benzalacetone (50% ee) or chalcone... 

Nickel catalysts can be used instead of copper catalysts to promote the conjugate addition reaction, providing, in some cases, better results than the corresponding copper catalysts. In 2000, Yang et al. discovered a series of (li ,25, 3i )-3-mercaptocamphan-2-ol derivatives, which proved to be efficient ligands in the conjugate addition of ZnEt2 to chalcone upon catalysis with Ni(acac)2 (Scheme 2.29). 

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

Upon fonnation of intermediate LI, conjugate addition to a chalcone and subsequent proton transfer is proposed to lead to enolate LIII (Scheme 37). An intramolecular aldol addition provides activated carboxylate LIV in which alkoxide acylation regenerates the catalyst and delivers p-lactone LVI which, upon decarboxylation, gives rise to a trisubstituted cyclopentene. 

A combined system consisting of a Ni(ll) complex and (2S)-DAIB effects the conjugate addition of diethylzinc to chalcone, resulting in the formation of (R)-1,3-diphenylpenta-1-one in 85% ee.°... 

The copper-catalysed enantioselective 1,4-conjugate addition of Et2Zn to chalcones was investigated in the presence of a catalytic amount of Af,P-ferrocenyl ligand (179) with central and planar chirality under mild conditions (0 °C to room temper- ature). Chalcones with ortho-substituents (from ortho-substituted benzaldehydes and acetophenones) exhibited a dramatic improvement in the enantioselectivities (<92% ee).229... 

Molecular orbital theory also predicts that a nucleophile of the sulfide type will bond at the carbon terminus of a conjugated ene carbonyl system that is, the nucleophile will bond with the electrophile in the Michael addition mode of reaction (20). Thus, the reaction of polysulfide dianion with an enone represented by a chalcone may proceed initially in such a manner as shown in Scheme 2, which reproduces one of the several pathways... 

Chalcones such as 80 are very easily made by an aldol reaction between acetophenone and benzaldehyde conjugate addition of the enolate of 81 and cyclisation occur all in the same reaction.15 The ester 82 is formed as a mixture of diastereomers in high yield hydrolysis and decarboxylation give 78. 

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