Reactions Michael-aldol-dehydration

Scheme 7.20 Cascade Michael/aldol/dehydration reaction for the formation of cyclopentenes.

Scheme 10.23 Three-component domino Michael/Michael/aldol/dehydration reaction.

Wang et al. [49] obtained enantioenriched thiochromenes through a cascade sulfa-Michael-aldol-dehydration reaction between 2-mercaptobenzaldehydes and a,p-unsaturated aldehydes, catalyzed by 17a (Scheme 14.17a). Cordova and coworkers [50] obtained comparable results despite some minor changes of the reaction conditions. An analogous process with cyclic enones afforded tetrahydrothioxanthe-nones in only moderate enantioselectivities (Scheme 14.17b). In this case, chiral pyrrolidines 18 and 19 gave the best results in terms of enantioselectivities [51]. 

Scheme 2.5 Domino Michael-aldol-dehydration reaction catalysed by a combination of a chiral diamine and a chiral dicarboxylic acid.

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

In addition to conventional Diels-Alder reactions, consecutive [4-1-2] reactions have been subjected to extensive investigation through the iminium-enamine catalytic sequence. Wang, Rios, and others simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines. An initial strategy for a one-pot synthesis of chiral thiochromenes with good to high enantioselectivities was reported (Schemes 1.46 and 1.47) [71]. 

One of the most important reactions for the construction of six-member rings (the Diels-Alder reaction is another) is based on a tandem reaction sequence a Michael addition reaction followed by an intramolecular aldol-dehydration reaction. This sequence is called the Robinson annulation (Sir Robert Robinson, Nobel Prize, 1947). " ... 

Scheme 7.3 Enantioselective Michael/aldol/dehydration cascade reaction for the synthesis of functionalized cyclohexenes.

Using this approach, benzothiopyrans have been prepared by means of a sulfa-Michael/aldol/dehydration cascade and access to dihydroquinolines has been achieved by using an aza-Michael/aldol/dehydration approach (Scheme 7.52). In general, all these reactions proceeded with excellent yields and... 

Most recently, a new bifunctional phosphine catalyst, (2 -hydroxybiphenyl-2-yl)-diphenylphosphane 225, has been developed for the selective aza-MBH reaction and aza-MBH domino reaction of iV-sulfonated imines with acrolein under mild conditions in moderate to excellent yields (Scheme 2.111). The possible catalytic cycle of the domino reaction and aza-MBH reaction has been proposed. The aza-MBH/Michael/aldol/dehydrate domino reaction also provides an efficient method to synthesize tetrahydropyridine... 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

Scheme 7.54 Domino Michael-lactone-opening-aldol-dehydration reaction catalysed by chiral amine catalysis and platinum catalysis followed by esterification.

In a continuation of enantioseleclive cascade sulfa-, oxa-, and aza-Michael/aldol/ dehydration cascade reactions, Wang et al. envisioned that the employment of a nucleophilic carbon atom for the initial Michael addition could enable the generation of two new C—C bonds in sequential [3+2] reactions. 

Simple addition to carbonyl compounds occnrs nnder mild acidic conditions. Examples given illns-trate reaction with acetone, an aldol-like reaction, and conjngate addition to methyl vinyl ketone, a Michael-like reaction. The first-formed alcohol products in aldol-like reactions usually dehydrate to give a 3-alkylidene-3//-indolium cation. 

The most impressive result of the catalytic Michael-aldol cascade is the kinetic resolution of the racemic cyclopentenone 458 shown in Sch. 64. The reaction is performed with 10 mol % (S)-ALB to give the tandem Michael-aldol adduct 459 in 97 % ee and 75 % yield based on malonate 390f. Asymmetric induction in 459 was measured after dehydration of the hydroxyl group, as was done for 451. Clearly, this demonstrates the viability of this new asymmetric strategy for the synthesis of a variety of fully functionalized prostaglandins. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Michael/aldol reaction. The key step in a synthesis of the alkaloid huperzinc A (3) involves a Michael/aldol reaction of the /3-kcto ester 1 with methacrolcin to provide the bridged ketol 2. The usual Michael reaction catalysts (NaOCHy, Bu4NF, ZnCl2) are ineffective, but the desired reaction can be effected in 93% yield with tetramethylguanidine as catalyst. DBU can also catalyze this reaction. Conversion of 2 to 3 is effected by dehydration of the ketol (45% yield), Wittig reaction of the ketone... 

On the other hand, Wang and co-workers [28, 29] made two important contributions to the synthesis of cyclopentene derivatives. Both reactions were initiated with a carbo-conjugated addition of malonates derivatives. The first one was a double Michael addition between enals and 7-malonate-a,(3-imsaturated esters catalyzed by XII rendering the final cyclopentanes with three stereogenic centers in good yields (87-92%) and excellent stereoselectivities (84—99% ee) [28]. As for the second one, Wang and co-workers focus on the synthesis of cyclopentenes. This reaction was based on a Michael-aldol sequence followed by dehydration, between aromatic enals and dimethyl 2-oxoethylmalonate [29]. A set of densely functionahzed chiral cyclopentenes were synthesized in high yields (63-89%) and excellent enantiose-lectivities (91-97% ee) (Scheme 10.13). 

The Michael condensations can take place between molecules or intramolec-ularly to yield a cyclic product. As an example of the former, the reaction between mesityl oxide and acetone yields three products, two of which arise from the aldol-dehydration sequence and the third one is the result of a Michael addition of... 

Michael reaction with an o , S-unsaturated ketone followed by an intramolecular aldol reaction has proven to be a valuable method for the synthesis of 2-cyclohexenones. An especially important example of a Michael-aldol sequence is the Robinson annulation, in which treatment of a cyclic ketone, 8-ketoester, or S-diketone with an a,)8-unsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring. When the following racemic 8-ketoester, for example, is treated with methyl vinyl ketone in the presence of sodium ethoxide in ethanol, the Michael adduct forms and then, in the presence of sodium ethoxide, undergoes a base-catalyzed intramolecular aldol reaction followed by dehydration to give a racemic substituted cyclohexenone. 

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