Michael addition ionic liquids

Thiolates, generated in situ by the action of ammonium tetra-thiomolybdate on alkyl halides, thiocyanates, and disulfides, undergo conjugate addition to a, (1-unsaturatcd esters, nitriles, and ketones in water under neutral conditions (Eq. 10. II).29 Conjugate addition of thiols was also carried out in a hydrophobic ionic liquid [bmim]PF6/water-solvent system (2 1) in the absence of any acid catalyst to afford the corresponding Michael adducts in high to quantitative yields with excellent 1,4-selectivity under mild and neutral conditions (Eq. 10.12). The use of ionic liquids helps to avoid the use of either acid or base catalysts... 

A basic ionic liquid, l-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and l-butyl-3-methyl-methylimidazolium tetrafluoroborate ([bmim]BF4), has been introduced as a catalyst and reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC3991 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the a,P-unsaturated ester <06S3859>. 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

A systematic investigation of the effect of Cl impurity was reported for a metal-catalyzed Michael addition of acetylacetone to methyl vinyl ketone in [BMIM]BF4 (77(5). The time required for the completion of the reaction was used as a measure of the effect of Cl . With a Ni(acac)2.2H20 catalyst, the Michael addition was completed in 2, 5, and 9h when the ionic liquid contained 0, 0.62, and 1.62% CP, respectively. 

A chiral phase transfer catalyst was dissolved in ionic liquid media for the enantioselective Michael reaction of dimethyl malonate with l,3-diphenylprop-2-en-l-one with K2CO3 203). The phase-transfer catalyst was a chiral quininium bromide (Scheme 20). The reaction proceeded rapidly with good yield and good enantioselectivity at room temperature in all three ionic liquids investigated, [BMIM]PF6, [BMIM]BF4 and [BPy]BF4. In the asymmetric Michael addition, the enantioselectivity or the reaction in [BPy]Bp4 was the same as in conventional organic solvents. 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

The Michael reaction is the nucleophilic addition of a carbanion to ot,p-unsaturated carbonyl compounds. It is a useful way to make C-C and C-hetero atom bonds. Karodia s group studied the use of the ionic liquid ethyltri- -butylphosphonium tosylate ( -Bu3PEtOTs) as a solvent for... 

Ni, B., Zhang, Q. and Headley, A.D. (2007) Functionalized chiral ionic liquid as recyclable organocatalyst for asymmetric Michael addition to nitrostyrenes. Green Chem., 9 (7), 737-739. 

The basic ionic liquid [BmimJOH has been introduced as a catalyst for the aza-Michael addition of aromatic amines and A-heterocycles to cyclic or acyclic ketones under solvent-free conditions.138... 

The catalytic application of L-proline in the asymmetric Michael addition of unmodified aldehydes or ketones with nitroalkenes in ionic liquids has been studied. The ... 

A task-specific ionic liquid, [bmIm]OH, has been introduced as a catalyst and as a reaction medium for Michael addition. The addition of open-chain 1,3-dicarbonyls to ,/Tunsaturatcd ketones gave the mono-addition products, whereas a,fi-unsaturated esters and nitriles afforded mainly bis-addition products.162... 

Ying A-G, Liu L, Wu G-F et al (2009) Aza-Michael addition of aliphatic or aromatic amines to [alpha], [beta]-unsaturated compounds catalyzed by a DBU-derived ionic liquid under solvent-free conditions. Tetrahedron Lett 50(14) 1653-1657... 

Finally, it should be noted that Lewis acids and bases can also be used in other non-conventional media, as described in Chapter 7, e.g. fluorous solvents, supercritical carbon dioxide and ionic liquids by designing the catalyst, e.g. for solubility in a fluorous solvent or an ionic liquid, to facilitate its recovery and reuse. For example, the use of the ionic liquid butylmethylimidazolium hydroxide, [bmim][OH], as both a catalyst and reaction medium for Michael additions (Fig. 2.45) has been recently reported [151]. 

Sulfonic acid functionalised ionic liquids may also be prepared via a zwitterionic intermediate from a Michael-type addition, as shown in Scheme 2.5.[84 85] In the first step 1-methylimidazole reacts with the sulfonic acid precusor 1,3-propane sultone to form a zwitterionic intermediate. Protonation with Bronsted acids affords ionic liquids with high purity that have proven to be highly efficient reaction media in, for example, esterification reactions.[86] Task-specific ionic liquids may also be prepared using semi-combinatorial methods.1871... 

Michael additions of various aldehydes and ketones to 2-(/3-nittovinyl)thiophene have been carried out in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate. Yields were in general better with aldehydes than with ketones. The best catalyst was L-proline <2004EJ01577>. 

In terms of chiral ionic liquids, the discussion will focus on Michael addition reactions (Figure 6.8). This reaction has been performed using lactate as... 

Figure 6.8 Asymmetric Michael addition reactions using chiral ionic liquids (a) derived from lactate, (b) derived from proline.

A mixture of l-methyl-3-ethylimidazolium chloride with aluminum chloride also gives an ionic liquid that may be used as electrolytic medium [437]. The medium is not quite inert for example, quinone reacts with an excess of chloride to 2-chlorohydroqui-none in an acid-catalyzed Michael addition [438]. As reference electrode an aluminum wire was used. l-Methyl-3-ethylimidazolium chloride is in MeCN reduced at —2.35 versus Ag in 0.1 M TBAP [439]. 

Wang Z M, Wang Q, Zhang Y, et al. Synthesis of new chiral ionic liquids from natural acids and their applications in enantioselective michael addition. Tetrahedron Lett. 2005. 46, 4657-4660. 

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). 

Recently, Wasserscheid and co-workers [103] introduced a complementary method for functionalized ionic liquid synthesis (11). In a one-pot, two step synthesis, the protonation of an imidazolium or pyridinium cation followed by a Michael-type addition to methyl vinyl ketone was reported. The only drawback is the limited thermal stability of the cations, which at moderately elevated temperatures undergo a retro-Michael reaction ... 

The Pd-catalyzed Michael addition of indoles to enones occurs readily in ionic liquids,... 

Scheme 19. Synthesis of camphor based ionic liquids by Michael addition and asymmetric hydrogenation. An example of transfer of the chiral infor-mation through ion-pairing effects.

Table 7.14 Asymmetric Michael addition of cyclohexanone to P-nitrostyrene using ionic liquid-supported chiral pyrrolidines as a catalyst.

However, despite the rapid design of news CILs, successful applications in synthesis remained elusive for some time. Only in the last 2-3 years have some significant results been obtained. Leitner and co-workers in 2006 reported a high enantiomeric excess (84% ee) by using a chiral anion containing ionic liquid for an aza-Baylis-Hillman reaction (Scheme 4.11), whereas CILs with an imidazolium or a benzimidazolium unit attached to (5)-pyrrolidine have been used with success as solvents or catalysts for asymmetric aldol reactions and Michael additions to nitroolefins (ee up to 99%). ... 

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