Ammonium Michael reactions

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

Tetrahydropyrrolo[4,3-. ]pyridines can be synthesized from 5,5-dimethyltetramic acid, 84, in a sequence of steps that begins with aryl aldehydes to generate arylmethylene-substituted tetramic acids. A Michael reaction with methyl acetoacetate followed by treatment with ammonium acetate yields the tetrahydropyrrolopyridine derivatives (Scheme 20) <2005H(65)377>. A similar reaction can be carried out with aroyl-substituted butenolides to give substituted furopyridine derivatives. 

A chiral quartemary ammonium salt works as a chiral-phase transfer catalyst, and this chemistry has been applied to asymmetric Michael reaction by Corey et al. (Scheme 8D.16) [33]. It has been shown that the cinchonidine salt 28, which has been designed by rigidifying... 

Arai et al. also reported another BINOL-derived two-center phase-transfer catalyst 31 for an asymmetric Michael reaction (Scheme 6.11) [8b]. Based on the fact that BINOL and its derivatives are versatile chiral catalysts, and that bis-ammonium salts are expected to accelerate the reaction due to the two reaction sites - thus preventing an undesired reaction pathway - catalyst 31 was designed and synthesized from the di-MOM ether of (S)-BINOL in six steps. After optimization of the reaction conditions, the use of 1 mol% of catalyst 31a promoted the asymmetric Michael reaction of glycine Schiff base 8 to various Michael acceptors, with up to 75% ee. When catalyst 31b or 31c was used as a catalyst, a lower chemical yield and selectivity were obtained, indicating the importance of the interaction between tt-electrons of the aromatic rings in the catalyst and substrate. In addition, the amine moiety in catalyst 31 had an important role in enantioselectivity (34d and 34e lower yield and selectivity), while catalyst 31a gave the best results. 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Polymer-supported quaternary ammonium hydroxides have been used to catalyse Michael reactions between various alkyl methacrylates, acrylonitrile, and methyl vinyl ketone as acceptors and nitro or keto derivatives as donors.[116,117]... 

Another interesting feature of polymer-supported catalysts containing quaternary ammonium salts involves the development of enantioselective catalysis using salts derived from cinchonia or ephedra alkaloids.11341 The first application of such chiral supported catalysts in the Michael reaction between methyl 1-oxoindan-2-carboxylate and methyl vinyl ketone revealed a high chemical yield in condensation product (60-100 %) although the enantioselectivities were only moderate (ee <27 %). 

Quaternary ammonium hydroxides anchored on MCM-41 provide stronger base catalysts than amine analogues11731 and were able to catalyse the same reaction as previously reported namely for the intermolecular Michael reaction leading to flavanone.[181] Moreover, this catalyst induced the successive intramolecular olefinic attack of the phenolic group from the Knoevenagel condensation product of salicylaldehyde and diethyl glutaconate (Scheme 9.6). This fast cyclization leads to chromene derivatives (1) from which subsequent conversions induced by proton abstraction from the alpha position of the ester function gives coumarin... 

Hodge, P., Khoshdel, E. and Waterhouse, J. Michael reactions catalyzed by polymer-supported quaternary ammonium-salts derived from cinchona and ephedra alkaloids, J. Chem. Soc., Perkin Trans. 1, 1983, 2205-2209. 

Benzylquininium chloride has been studied as a catalyst for the asymmetric Michael reaction. Reaction of amidoma-lonate (5) and chalcone (4) with catalytic base and a variety of chiral, nonracemic ammonium salts in the absence of solvent produced (6) in yields of 41-68% and 20-68% ee (eq 2). The quinine-derived salt (1) was of intermediate effectiveness (38% ee, 47% yield) when compared to ephedrine-based catalysts. Although (1) was not specifically tested with regard to solvation effects, it is suggested that increased aggregation of reactive species under solid-liquid PTC conditions leads to enhanced organization and selec-... 

One synthesis approach towards y-hydroxylated ionic liquids is a Michael-type addition of a protonated ammonium salt to a a, /l-an sal uni led carbonyl compound such as methylvinyl ketone yielding an oxobutyl functionalized cation. Intrinsically unstable due to retro-Michael reaction, this OS could however be transformed by a heterogeneous catalyzed hydrogenation reaction yielding a hydroxyl functionalized TSIL [24] (Fig. 7). 

Michael reaction of a-substituted t-butyl cyanoacetates to t-butyl prop3moate establishes a quaternary carbon center in the adducts. Excellent asymmetric induction is achieved by much more bulky ammonium salt. ... 

In this context, there is a relevant example of a newly designed cinchona-alkaloid derived bis-ammonium salt 105 employed as catalyst in the Michael reaction of cyclic p-ketoesters with methyl vinyl ketone (Scheme 5.12). Excellent yields and moderate enantioselectivities of the corresponding Michael adducts were obtained under the best reaction conditions, which also allowed the use of an organic base (Hiinig base) for the deprotonation of the p-ketoester. However, perhaps the most relevant feature associated to the use of this catalyst is the fact that it can be easily separated from the reaction medium by precipitation in ether, which allowed its recycling for further uses without loss of activity. 

Scheme 5.16 Enantioselective Michael reactions catalyzed by A -spiro ammonium salts 106a and 106b.

Finally, it should also be pointed out that enantioselective Michael reactions to enones under PTC conditions do not exclusively rely on the use of chiral ammonium salts as catalysts and, for example, chiral phosphonium salts can also be successfully employed in this context. This is the case of binaphthyl-containing phosphonium salt 110, which was demonstrated to be an outstanding catalyst in the conjugate addition of oxindoles to enones under PTC conditions (Scheme 5.20). The Michael adducts were obtained in excellent yields and enantioselectivities for a wide variety of differently substituted 3-aryl oxindoles tested as Michael donors. Remarkably, the high acidity of the 3-aryloxindoles employed as Michael donors allowed the use of a very mild base such as potassium benzoate for the activation of the nucleophile. 

On the other hand, axially chiral A-spiro ammonium salt 106d has been found to catalyze the Michael reaction of a serine nucleophile equivalent with ethyl... 

Scheme 5.27 Enantioselective Michael reaction of tert-butyl glydnate benzophenone imine with methyl acrylate catalyzed by TADDOL-based ammonium salts.

The use of ot,p-unsaturated aldehydes as Michael acceptors always represents a challenging situation because of the tendency of enals to undergo 1,2- rather than the desired 1,4- addition reaction. Moreover, working under phase-transfer catalysis conditions incorporates an additional element of difficulty, because of the propensity of enolizable enals to undergo self-condensation side reactions. For this reason, there are only a few examples reporting enantioselective Michael reactions with ot,p-unsaturated aldehydes as Michael acceptors under PTC conditions, both coming from the Maruoka research team and also both making use of chiral tV-spiro quaternary ammonium salts as catalysts. 

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... 

The first step in the Katritzky pyridine synthesis is believed to be the Michael addition of a a-benzotriazolyl ketone 2 to the a,p-unsaturated carbonyl compound 1 to generate a 1,5-diketone derivative 4. The 1,5-diketone is not typically isolated although its formation has been confirmed via preparation under typical Michael reaction conditions in the absence of ammonium acetate. 1,5-Diketone derivatives are known intermediates in the synthesis of pyridines and undergo condensation with ammonia or its equivalent followed by cyclization to form dihydropyridine 5. Elimination of benzotriazole completes the aromatization process and generates the pyridine ring. 

An alternative method for the synthesis of tran -alkenyl /f-phosphinates involved AIBN initiated radical addition of ethyl phosphinate to alkenes and alkynes. The method was applied to the preparation of GABA analogues. A new route to chiral phospholanes has been presented. Enantiomerically pure P-chiral dicyclohexyl-ammonium 2-(phosphinyl)acrylates (236) have been obtained by an asymmetric Michael reaction with imine, which opens a new general route to the enantioselective synthesis of a-methylene-6-valerolactones (237) (Scheme 97). ... 

Xu LW, Li JW, Zhou SL, Xia CG (2004) A green, ionic liquid and quaternary ammonium salt-catalyzed aza-Michael reaction of a,p-ethylenic compounds with amines in water. New J Chem 28 183-184... 

Scheme 1.69 Sulfa-Michael reactions catalysed by cinchona alkaloid ammonium salt.

Mukaiyama-Michael Reactions. 1,4-Addition of ketene alkyl silyl acetals to a./S-unsaturated carbonyl compounds (eq 10) is promoted by a variety of Lewis acids (for example, TiCU, Ti(OR)4, SnCU, trityl perchlorate, lanthanide salts, Al-montmo-rillonite clay), or Lewis bases such as fluoride ion (eq 11), or quaternary ammonium carboxylates. Lanthanide salts are particularly effective catalysts, and in the case of ytterbium(III) tri-fluoromethanesulfonate, the catalyst can be recovered (eq 10). ... 

Recently, Hodge et prepared polymer-bound chiral quaternary ammonium chlorides by the reaction of chlomethylated crosslinked polystyrene with cinchonidine, cinchonine or (— )-A -methylepledrine and carried out several Michael reactions. Catalysts prepared from cinchonidine(I) achieved optical yields of < 27% of the S-adduct in the addition of methyl-l-oxoindan-2-carboxylate(II) to methyl vinyl ketone. 

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