Michael addition nitro enolates

Yosikoshi reported the synthesis of furan derivatives by the reaction of 1,3-diketones with nitroalkenes, in which the Michael addition of the anions of 1,3-diketones and the subsequent intramolecular displacement of the nitro group by enolate oxygen are involved as key steps (Eq. 7.40).42... 

Similar changes take place in the acidification of the enol salt of a carbonyl compound, the principal difference being the much longer life of the acf-nitro compound compared to that of an enol of a simple ketone (see Section 17-IB), Primary and secondary nitro compounds undergo aldol additions and Michael additions with suitable carbonyl compounds and basic catalysts ... 

Many carbanionic nucleophiles that would be considered too hard to react as Michael donors can be made into effective reagents for conjugate addition reactions by appending resonance or inductively stabilizing groups to soften their intrinsic Lewis basicity. Such stabilized anionic Michael donors include enolates, alkylthio-substituted carbanions, ylides and nitro-substituted carbanions. 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Highly enantioselective Michael addition of silyl nitronates (105) to cyclic o /3-unsaturated ketones (106 n = 0-2) has been accomplished by the utilization of N-spiro C2-symmetric chiral quaternary ammonium bifluoride (108) as an organocatalyst, offering a new route to the enol silyl ethers of scalemic y-nitro ketones (107 70-90% ee).156... 

The method has been used to prepare isotopically labelled amino acids. While Boc-BMI enolate adds to aldehydes with only moderate diastereoselectivity, reduction of the acylation products (5) gives allothreonine derivatives (6). Michael additions to o(,p-unsaturated esters, ketones, and nitro compounds lead to products of type (7) and (8) (for a general discussion see Suzuki and Seebach ). 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

A relatively rare example of the creation of chiral quaternary carbons has been uncovered in Michael addition-elimination reactions between lactone enolates [e.g. (444)] and a chiral nitro-alkene (445) ... 

Michael addition of the enolate of 56 to ( )-l-nitropropene gives adduct 75 with a dia-stereoselectivity of 93%. Catalytic hydrogenation of the nitro group over Raney nickel at 25 atm produces lactam 76 as a result of elimination of pivaldehyde [25]. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus, base-induced formation of enolate is followed by Michael addition to the nitroalkene and cyclization of nitronate to furnish the nitro-isocyanide after protonation. Loss of nitrous acid (HNO2) and aromatization then affords the pyrrole ester. 

Some other activated olefins have been employed as acceptors in Michael reactions with enolates under PTC conditions, using different chiral ammonium salts as catalysts. For example, a very recent and elegant report has shown that conveniently substituted heterocyclic moieties can also play the role of suitable electron releasing groups for the activation of an olefin toward conjugate addition. In particular 4-nitro-5-styrylisoxazoles were found to undergo clean... 

In contrast to the extensive use of nitroolefins in asymmetric Michael additions [10], the vinylogous analogues, nitrodienes and nitroenynes, are less frequently utilized in the conjugate addition of enolate equivalents, despite the significant synthetic utility of the resulting products which possess carbonyl, nitro, and olefin functionalities. Likewise, studies on the hetero-Michael reaction with these acceptors have been very limited, possibly because of apprehension of the site-selectivity issue [11]. 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Michael addition of 1,2-cyclohexanedione to -nitrostyrenes ArCH=C(R)N02, mediated by K2CO3 in DMF, has been reported to produce 3-aryl-5,6-dihydrobenzofuran-7(4//)-ones (357) in good yields. The reaction is believed to commence via the addition of the dione C-enolate to the j0-nitro-styrene, followed by cyclization of the resulting 0-enolate anion, elimination of nitrite ion, and air oxidation. ... 

Kitazume and coworkers used microreactors with microchaimels 100 pm wide and 40 pm deep for the synthesis of a series of organofluorine compounds [19,20]. The silylation of4,4,4-trifluorobutan-2-one and the Mukaiyama-type aldol reaction of the resulting enol silyl ether with acetals gave good yields of the desired products [20]. They also described nitro-aldol reactions of 2,2-difluoro-l-ethoxyethanol and Michael additions of nitroalkanes to ethyl 4,4,4-trifluorocrotonate and ethyl 4,4-difluorocrotonate [19,20]. Reactions were carried out at room temperature, and... 

Diones are important intermediates in a number of syntheses of cyclopent-2-enones by aldol cyclization, and several routes to them have been published (see Review section). An attractive new approach involves the Michael addition of silyl enol ethers to nitro-olefins catalysed by Lewis acids, which leads directly to the 1,4-dione without isolation of nitroketone or related intermediates (Scheme 15). A feature of the method is that it is highly regiospecific in the selective formation of 1,4-diones with no double-bond migration in the silyl enol ether. 

Conjugate addition of allylsilanes to enones results in regiospe-cific introduction of the allyl group (eq 34). The reaction can be intramolecular (eq 35). TiCU or SnCU activates nitro alkenes for Michael addition with silyl enol ethers or ketene silyl acetals. The silyl nitronate product is hydrolyzed to a 1,4-diketone or -y-keto ester (eq 36). ... 

Nitroalkenes are also reactive Michael acceptors under Lewis acid-catalyzed conditions. Titanium tetrachloride or stannic tetrachloride can induce addition of silyl enol ethers. The initial adduct is trapped in a cyclic form by trimethylsilylation.316 Hydrolysis of this intermediate regenerates the carbonyl group and also converts the ad-nitro group to a carbonyl.317... 

Since nitro groups are readily converted to carbonyls by various procedures,4142 nitroalkenes can serve as a-carbonyl cation equivalents in Michael reactions.43 For example, addition of the amide enolate (158 Scheme 22) to the nitroalkene (157) affords, in 60% yield, the Michael adduct (159), which can be con-... 

NaBHj/NiC or Raney nickel, the menthyloxy group is removed with NaBH /KOH to give 3,4-disubstituted butyrolactones with a high diastereo- and enantioselectivity (Figure 7.69). Corey and Houpis [1458] have described asymmetric Michael reactions of ketone enolates with a 2-thiophenyl crotonate of 8-phenmenthol. Chirality has also been introduced on the amino group of 2-ami-nomethyiacrylates to perform the asymmetric addition of the anion of the tert-Bu ester of cyclopentanecarboxylate [1459], More important developments have been reported with chiral a,p-unsaturated sulfoxides and nitro compounds as Michael acceptors (see below). 

An all organic catalyst system 38 has been reported by the Maruoka group for directing asymmetric additions of oxindole enolates derived from 36 to nitro-aUcenes 37 under phase-transfer conditions [26] (Scheme 10). The methodology was extended to the synthesis of a tetrahydropyrroloindole scaffold bearing two chiral centers. Asymmetric Michael and Mannich reactions of 3-aryloxindoles directed by chiral phosphonium salt phase-transfer catalysts have been described by the same group [27]. 

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