Versatile Michael Reactions

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

The developmenf of self-curing resins, i.e., systems curing without photoinitiators or, in some cases, with just small amounts of photoinitiators, has been reported recently. Such resins are synthesized by Michael reaction of acrylic functional materials with Michael donor compounds such as acetoacetates. The resulting product has an increased molecular weight compared to the parent acrylate(s). This provides resins with reduced volatility and propensity for skin absorpfion. This new technology is versatile and flexible and opens a possibility of synfhesis of a large number of different acrylate resins. The novel resins reportedly exhibit unique depth of cure capability. In the absence of a photoinitiator (PI), film of approximately 10 mils (0.25 mm) thick can be cured at a line speed of 100 fpm (30.5 m/min). When only 1% of PI is added, the thickness of film that can be cured increases to over 100 mils (2.5 mm). 

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. 

In addition ta molate iona. other kinds of carbon nucleophiles add unaatarated acceptors in th Michael reaction greatly extending the usefulness ami versatility of the procew. Among (he most important such nucleophiles are eruimines- Recall from Section 19 9 that enamines are reedily prepared by reaction between a ketone and a socondary amine ... 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

La-linked-BINOL complex 23 was introduced as a stable, storable, and reuse-able asymmetric catalyst for the Michael reaction [120]. Optimization of the reaction between dibenzyl malonate and 2-cyclohexene-1-one in DME afforded the Michael adduct in 94% yield and >99% ee. The extraordinary versatility of LnLB catalyts is also documented in the highly efficient Michael addition of thiols to a,y9-unsaturated carbonyl compounds [121] and tandem Michael-aldol reactions [122]. 

It is difficult to overemphasize the importance of the Michael reaction in synthesis. It is one of the mildest, most versatile, and most efficient methods for forming C-C bonds. 

Ye, W., Jiang, Z., Zhao, Y. et a/. (2007) Chiral bicyclic guanidine as a versatile Brdnsted base catalyst for the enantioselective Michael reactions of dithiomalonates and P-keto thioesters. Advanced Synthesis and Catalysis, 349, 2454-2458. 

As has already been mentioned, the low reactivity of enamine nucleophiles needs a highly electrophilic Michael acceptor for the reaction to proceed with good conversions in an acceptable time. In this context, the Michael reaction of aldehydes and ketones with nitroalkenes can be regarded as one of the most studied transformations in which the enamine activation concept has been applied. This reaction furnishes highly functionalized adducts with remarkable potential in organic synthesis, due to the synthetic versatility of the nitro group and the presence of the carbonyl moiety from the donor reagent. 

Finally, the high versatility of this Michael strategy was also shown in the total synthesis of the antimalarial agent (+)-polyanthellin A (170), which was described recently by Johnson et al. 160). The first step was similar to that depicted in Scheme 38, only using (/ )-159 as a catalyst for the Michael reaction between... 

In the same area, an asymmetric domino double Michael reaction was initiated by this catalyst, providing an expedited access to chiral multi-functionalised live-membered rings. This time, the reaction occurred between a nitroalkene and ethyl 2-acetyl-5-oxohexanoate, yielding the desired double Michael adducts in high yields and excellent diastereo- and enantio-selectivities (Scheme 1.66). An immense potential of synthetic versatility of the... 

For the same purpose, various chiral pyrroUdine catalysts such as 50-54 have also been introduced [242-250]. The versatile nature of pyrrolidine catalysts has been recognized by other transformations aldol reaction [251], Mannich-type reaction [252, 253], and oxa-Michael reaction [254]. Among these, Maruoka s work on anti-selective Mannich reactions is noteworthy (Scheme 1.19, compare with Scheme 1.8) [253]. In this case, the remote hydrogen-bonding form 57 derived from catalyst 56 can overcome the steric preference so that the opposite sense of stereochemistry should be observed. 

The O-TMS-diphenylprolinol 103/BzOH catalytic system is also applicable as an organocatalyst of Michael reactions of nitroalkanes with a, i-enals in aqueous medium [117]. However, functionalized task-specific ionic liquids incorporated in the chiral-pyrrolidine unit, apart from being very efficient and versatile organo-catalysts of Michael and some other asymmetric reactions, show much worse behavior in asymmetric aldol reactions, where their performance is inferior to IL-supported catalysts bearing the a-amino acid fragment [118]. 

The versatility of this reaction is extended to a variety of aldehydes. The bisphenol derived from 2,6-di-/ f2 -butylphenol and furfural, (25) where R = furfuryl (13), is also used as an antioxidant. The utility of the 3,5-di-/ f2 -butyl-4-hydroxyben2yl moiety is evident in stabili2ets of all types (14), and its effectiveness has spurred investigations of derivatives of hindered alkylphenols to achieve better stahi1i2ing quaUties. Another example is the Michael addition of 2,6-di-/ f2 -butyl phenol to methyl acrylate. This reaction is carried out under basic conditions and yields methyl... 

The Michael addition reaction of amines and thiols with bismaleimides or functionalized monomaleimides is a versatile tool ia the synthesis of chain-extended maleimide-terroinated prepolymers. These prepolymers generally are soluble ia organic solvents from which they can be processed to prepreg and molded to high quaUty, void-free laminates. 

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