Ketones base-catalyzed Michael additions

The base-catalyzed Michael addition of 2-chlorocyanoacetate to a,p-unsaturated ketones or aldehydes affords 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and usefiil in the synthesis of 2,Xdisubstituted pyridines <95T(51)13177>. 

The base-catalyzed Michael addition of oxazolin-5-ones to alkynic ketones produces 4-(3-oxopropenyl) derivatives (405) (79CB3221). The latter compounds are cleaved on warming with oxalic acid dihydrate in acetic acid to y-diketones (406). The mechanism of this transformation corresponds to a vinylogous Dakin-West reaction (Scheme 90). 

Several examples have been described on Lewis acid and base catalyzed Michael additions. Cyclopentanone-2-carboxylic acid ethylester was added at room temperature to methyl vinyl ketone using 2 mol% FeCl3 -6 H20 as catalyst yielding > 90% of the addition product (Scheme 11) [31]. Cerium(III) chloride in the presence of sodium iodide [32] and trifluoro-methanesulfonic acid have been used as catalysts as well [33]. 

Fig. 13.67. Mechanism of the base-catalyzed Michael addition of active-methylene compounds (top) and of ketones (bottom), respectively. Subst refers to a substituent, and EWG stands for electron-with-drawing group.

Several transition metal-based Lewis acid catalysts such as FeCls, CrCls, SnCU, or A1(03S0Ci2H25 )s were shown to be highly effective for aza-type Michael additions of amines such as indoles and pyrroles to a,/ -unsaturated compounds in aqueous solution. Addition of thiols to a,/ -unsaturated ketones in water was also catalyzed by SDS or /3-cyclodextrin. There is also a single report on the stereoselectivity of base-catalyzed Michael additions of thiols to nitro-olefins, where moderate diastereoselectivities were obtained (Scheme 8.13). 

According to Figure 13.44, ketones often do not engage in base-catalyzed aldol additions because of a lack of driving force. Hence, ketones also are less suitable electrophiles than aldehydes in aldol condensations. However, for ketones, too, the elimination step is irreversible and they can therefore form a,/i-unsaturated carbonyl compounds. It is not always possible to isolate the a,/3-unsaturated carbonyl compounds thus formed. If the 0-/1 atom is not sterically hindered, these products can act as electrophiles and add any residual ketone enolate the f/,/1-unsaturated carbonyl compound acts as a Michael acceptor in this case (Section 13.6.1). 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

Karodia et al. reported [123] a eonvenient method for the acid-catalyzed Michael addition reactions of alcohols, thiols, and amines to methyl vinyl ketone, using the IL ethyltri- -butylphosphonium tosylate. Recently, phosphonium-based ILs have been used [124] in the degradation of phenol, esterification, Wittig reaction, Heck reactions, Suzuki cross-coupling reactions, oxidation of benzyl halides [125], etc. Phos-phonium tosylates are used as solvents in catalytic hydroformy lation reactions these catalyst systems are noncorrosive and can readily be recovered and reused [126]. 

The combination of a Diels-Alder reaction with subsequent enamine-catalyzed Michael addition has been described for the synthesis of tricyclic compounds, precursors of natural products such as penicillone A [45]. Application to ketones has been successfully achieved with the elegant synthesis of (-)-minovincine based on a Diels-Alder/Michael organocascade (Scheme 7.28) [46]. 

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

Jenner investigated the kinetic pressure effect on some specific Michael and Henry reactions and found that the observed activation volumes of the Michael reaction between nitromethane and methyl vinyl ketone are largely dependent on the magnitude of the electrostriction effect, which is highest in the lanthanide-catalyzed reaction and lowest in the base-catalyzed version. In the latter case, the reverse reaction is insensitive to pressure.52 Recently, Kobayashi and co-workers reported a highly efficient Lewis-acid-catalyzed asymmetric Michael addition in water.53 A variety of unsaturated carbonyl derivatives gave selective Michael additions with a-nitrocycloalkanones in water, at room temperature without any added catalyst or in a very dilute aqueous solution of potassium carbonate (Eq. 10.24).54... 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

In the last decade, the mesoporous molecular sieve MCM-41 has been developed (2S2) and applied as a catalyst to many acid-catalyzed reactions (2SS). However, until now, comparatively few investigations of mesoporous molecular sieves as base catalysts have been reported (169,211-214,234,235). For example, sodium- and cesium-exchanged mesoporous MCM-41 were shown to be mildly selective, water-stable, recyclable catalysts for the base-catalyzed Knoevenagel condensation, and mesoporous MCM-41 containing intraporous cesium oxide particles prepared by impregnation with aqueous cesium acetate and subsequent calcination was found to have strong-base activity for the Michael addition (211,213) and rearrangement of co-phenylalkanals to phenyl alkyl ketones (212). 

In an important new application of crown ethers Cram and Sogah have recently reported that potassium bases complexed to chiral crown ethers catalyze the stereoselective Michael addition of a /3- ketoester to methyl vinyl ketone in high optical yields (81CC625). With chiral crown (46), carbanion (47) gave alkylated products with an optical yield of about 99% enantiomeric excess. These impressive results were rationalized by complex structure (48) in which the crown-complexed K+ and the carbanion form an ion pair. One face of the associated carbanion is shielded from electrophilic attack by the flanking binaphthyl groups and the approach of methyl vinyl ketone occurs in a stereoselective manner. 

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... 

Chiral crown ethers. Cram and Sogah4 have observed that potassium bases [KOC(CH3)3 or KNHj] complexed by the chiral crown ethers 1 or 2 catalyze asymmetric Michael additions to methyl vinyl ketone and to methyl acrylate to give adducts in 60 99% optical purity. 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

In recent years, many chiral catalysts for the enantioselective synthesis of optical active 1,5-dicarbonyl compounds have been developed, such as chiral crown ethers with potassium salt bases and chiral palladium complexes, including bimetallic systems. Nakajima and coworkers reported on enantioselective Michael reactions of S-keto esters to a,/3-unsaturated carbonyl compounds in the presence of a chiral biquinoline N,N dioxide-scandium complex, which catalyzed the additions in high yields and with enan-tioselectivities up to 84% ee . Kobayashi and coworkers found that the combination of Sc(OTf)3 with the chiral bipyridine ligand 149 (equation 41) was also effective as a chiral catalyst for asymmetric Michael additions of 1,3-dicarbonyl compounds 147 to a,/3-unsaturated ketones 148. The corresponding Michael adducts 150 were obtained in good to high yields with excellent enantiomeric excesses in most cases (Table 10). 

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