Chalcone Michael addition

Keywords 1,3-dicarbonyl compound, methyl vinyl ketone, chalcone, Michael addition, BiCh, CdCl2, microwave irradiation... 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of or of HC104, jS-phenylpropio-... 

Boron trifluoride etherate, is also a good catalyst for this hydride transfer to chalcone. Unlike triphenylmethyl perchlorate, however, chalcone is able to enter Michael additions with the 1,5-diketone followed by eliminations leading to unexpected products, e.g., 3-benzyl-2,4,6-triphenylpyrylium from 2-carbethoxy-l,3,5-tri-phenylpentane-l,5-dione and chalcone the benzyl group originates from chalcone, the elimination product being ethyl benzoylacetate. ... 

More serious limitations and precautions apply to compounds in which not all three R, R, and R" groups are aromatic. Autocondensation of benzylideneacetone (111) yields an unstable chloroferrate which may be 113 or 115, according to whether a Michael addition to 112 or a crotonic condensation to 114 is first involved. Since compound 113 could readily be prepared from 2,6-dimethyl-4-phenylpyrylium and benzaldehyde, the structure of the reaction product should be easily soluble. Another equivocal product is formed from two moles of benzylideneacetone, but a definite structure (116) results from chalcone and benzylideneacetone. ... 

Recently, the Texier-Boullet group [26] has prepared nitrocyclohexanols 10-77 by a twofold Michael addition/aldol reaction sequence (Scheme 10.19). Simply mixing chalcone 10-75 with nitromethane in the presence of a mixture of KF and A1203 under microwave irradiation gave 10-79 via the proposed intermediates 10-76, 10-77 and 10-78 as a single diastereomer in 65 % yield. One possible explanation for the stereoselectivity of the transformation is fixation of the reactive species onto the solid KF/A1203, as depicted in 10-79. 

Matsumoto and coworkers have introduced a new strategy for asymmetric induction under high pressure. The Michael addition of nitromethane to chalcone is performed at 10 kbar in the presence of a catalytic amount of chiral alkaloids. The extent of asymmetric induction reaches up to 50% ee with quinidine in toluene.201... 

Chiral monoaza-crown ethers containing glucose units have been applied as phase-transfer catalysts in the Michael addition of 2-nitropropane to a chalcone to give the corresponding adduct in up to 90% ee. (Eq. 4.138).202... 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

Annulation reaction of (benzotriazol-l-yl)acetone 531 with chalcones provides an efficient route to 3,5-diarylphenols 538. The reaction is catalyzed by NaOH in ethanol. In the first step, Michael addition of ketone 531 to the C=C bond of a chalcone gives diketone 532. In the second step, condensation between the carbonyl... 

The key step in Hu s synthesis of 51 was cyclization of 50 by heating with copper(I) iodide and sodium hydride in DME, followed by a 10% aqueous ammonia work-up. Intermediate 50 was prepared via Michael addition of ethyl acetamidocyano acetate to the appropriate chalcone followed by acid-catalyzed ring closure [42,43]. 

Chalcone 68a also efficiently underwent the asymmetric Michael addition with diethyl acetami-... 

The stereoselective Michael addition of the anion derived from diethyl acetyl-aminomalonate with chalcone has been found to be most effective under soliddiquid two-phase conditions in the absence of an added solvent [62]. For optimum overall conversion and enantiomeric excess (56% with 60% ee), A-benzyl-V-methyl-... 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

The strong basic sites associated with surface OH groups are responsible for the catalytic activity of the activated Ba(OH)2 in organic reactions, such as the Michael addition (285). The authors showed, for example, that the Michael addition of diethyl malonate to chalcone catalyzed by activated Ba(OH)2 yielded 95% of the Michael adduct. When Ba(OH)2 was selectively poisoned with TBMPHE, a conversion of only 5% was observed, however when Ba(OH)2 was poisoned with DNB a conversion of 58% was obtained. The small poisoning effect of DNB indicates that only a small number of reducing sites with basic character (e.g., 0 ) can act in the process as basic sites. Thus, it was concluded that the basic sites responsible for the catalytic activity must be surface OH groups on the Ba(OH)2 H2O. 

The synthesis of isoxazolines and pyrazolines via the Michael addition of hydro-xylamine and phenyl hydrazine to chalcones and related enones was also reported with activated Ba(OH)2 as a basic catalyst (293) (Scheme 45). In both cases, reactions were performed at reflux of ethanol, and excellent yields (65-80%) with 100% selectivity to the heterocyclic compounds were observed. Steric hindrance associated with the carbonyl compound as well as the electronic character of the substituents in the aromatic ring slightly affected the yields of the heterocyclic compounds. 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

Scheme 6.65 Mechanistic proposals for the biflinctional mode of action of catalyst 12 in the Michael addition of thioacetic acid to nitroalkenes (A) and to chalcones (B).

Figure 6.39 Cinchona alkaloid-thioureas prepared from quinine (121), dihydroquinine (122), C9-epi-quinine (123), and quinidine (124) catalytic efficiency evaluated in the Michael addition of nitromethane to tram-chalcone 1,3-diphenyl-propenone at 10mol% loading and rt.

Scheme 6.124 Product range of the asymmetric Michael addition of diethyl malonate to various trcms-chalcones promoted by 122.

In 2007, Chen and co-workers reported the 122-catalyzed (10mol% loading) enantioselective Michael addition [149-152] of ethyl a-cyanoacetate to various electron-rich and electron-deficient trans-chalcones [283]. The reaction was performed for a broad spectrum of chalcones and gave the corresponding adducts in yields of 80-95% and in ee values of 83-95%, but at low sy /a ti-diastereoselectiv-ities as shown for representative products 1-8 in Scheme 6.125. 

In the presence of thiourea 121 (20mol% in toluene at 4°C/20°C), the aza-Michael addition [149-152] of 0-benzylhyroxylamine to numerous frans-chalcones bearing electron-rich and electron-deficient (hetero)aromahc subshtuents as well as aliphatic side chains provided the respective P-keto hydroxylamines 1-8 in moderate to very good yields (35-94%) and low to moderate (30-60%) ee values... 

Scheme 6.139 Typical products of the aza-Michael addition of O-benzylhydroxylamine to frans-chalcones under bifunctional 121 -catalysis.

Highly substituted [l,6]naphthyridines have been prepared by the Michael addition and subsequent Thorpe-Ziegler cyclization of a series of chalcones with malononitrile in the presence of pyrrolidine, over extended periods of heating <1999SC3881>. Attempts to reduce the reaction times using microwave irradiation gave mixtures of products... 

Michael addition of the carbanion flanked on one side by a 3-thienyl group, and on the other by a sulfoxide or a sulfone, to chalcone has been reported (81TL5097). Cyclization of the resultant anion with a suitable ortho-substituent is followed by elimination to give a benzo[6]thiophene derivative (Scheme 105). 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Several other high inductions have been reported by using crown ethers as catalysts (Scheme 10.8). The Toke group has used a chiral crown 11 (Chart 10.2), which incorporates a glucose unit, for the addition of 2-nitropropane to a chalcone (Scheme 10.8) [38], Several other effective chiral crowns (12-17, Chart 10.2 and Scheme 10.8) are noted [24e,39-42,48b]. An interesting study of the Michael addition under both solvent-free (0% ee) and liquid-liquid conditions (up to 70% ee) was reported by Diez-Barra and co-workers, who also addressed the question of free -OH quats (28, 58% ee) verses O-benzyl quats (30, 46% ee) [43]. 

Three equivalents of FeCl3 are required for the reaction of chalcone 41 j with ethyl cyanoacetate to give a-pyridone derivative 72 (Scheme 8.32) [100]. The reaction is carried out at 140 °C under strongly acidic conditions (FeCl3 dissolved in propionic acid). It proceeds presumably by an initial Michael addition yielding intermediate 73. Excess of iron(III) is required, because this is the oxidizing reagent for the introduction of the second C—C double bond in intermediate 74. 

Recently, Maruoka and coworkers addressed the importance of dual-functioning chiral phase-transfer catalysts such as 70a for obtaining a high level of enantio-selectivity in the Michael addition of malonates to chalcone derivatives (Scheme 5.35) [37]. For instance, the reaction of diethyl malonate with chalcone in... 

Scheme 8.3 Crown ether-induced asymmetric Michael addition of 2-nitropropane to chalcones.

In 1978, Wynberg and coworkers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone (Scheme 9.1) [3]. The reaction was performed in toluene at 20 °C with 10mol% of chiral ammonium salt 1 or 3a and excess potassium fluoride (KF, 15 equiv.), yielding the y-nitro ketone with 10-23% enantiomeric excess (ee). The requisite chiral... 

Cobalt(II) complexes prepared in situ from (AcO Co and two novel chiral spiro nitrogen-containing ligands, 7,7/-bis(2-pyridinecarboxamido)-l,l/-spirobiindane (SIPAD) and 7,7/-bis(2-quinolinecarboxamido)-l,l/-spirobiindane (SIQAD), are efficient cata- lysts for the asymmetric Michael addition of malonates to chalcone derivatives. The alkylation products were obtained in high yields with moderate enantioselectives.169... 

According to Yerma et al. [35] the mechanism of the reaction may be rationalized as involving (3-oxygenation of the bismuth(III) nitrate activated chalcone enolate, which may then undergo a Michael addition to a second a, 3-unsaturated ketone (Scheme 4.52) to form a 1,5-diketone enolate adduct 180. Subsequent heteroannulation with o-PDA via condensation and retro-aldol disproportionation may form 2-hydroxy-1,2,4,6-tetraaryl-1,2,3,4-tetrahydro-pyridine derivatives 181, which may undergo dehydration to yield 1,2,4,6-tetraaryl-1,4-dihydropyridines 177. 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

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