Knoevenagel/Michael reaction sequence

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

Figure 6.91 Use of alkyl C C]acetoacetates in a tandem Knoevenagel-Michael reaction sequence...

Yuan and coworkers have reported an enantioselective three-component domino Knoevenagel/Michael/cyclization sequence using 226, a 1,3-dicarbonyl compound 228, and malononitrile 227 catalyzed by cinchona alkaloid cupreine 229 (Scheme 6.32). The spirocychc oxindole pyrans 231 were obtained in high yields (85-99%) and enantioselectivi-ties (up to 96% ee) [63]. Inconveniently, the reaction requires high dilutions (0.1-0.005 M) resulting in a large amount of used solvents. Macaev and coworkers have used chiral catalyst (-)-(S)-brevicolline 230 for the obtainment of the same... 

In 2012, Rueping et al. reported the proline-mediated reaction of 1,3-diketones with aldehydes to provide 2-hydroxy-3,4-dihydro-2//-pyran derivatives in good to excellent yields [46]. The reaction mechanism involves a Knoevenagel-Michael addition sequence with subsequent hemiacetalization. The haniacetal was oxidized with TPAP/ NMO or PCC to give the corresponding lactones 96. An enantioselective variant utilizing stoichiometric amounts of an... 

A similar reaction was published by Song et al. in 2013 (Scheme 13.29) [47]. 2-Hydroxynaphthoquinone 75 was reacted with aromatic aldehydes 97 and ethyl 4,4,4-lrifluoro-3-oxobutanoate 98 catalyzed by a mixture of ammonium acetate and acetic acid (25mol% each). A Knoevenagel-Michael addition sequence was followed by hemiketal formation to give the desired product 99 in moderate to good yields. Dehydration of the product yielded the 4 f-pyran derivatives. 

A three-component reaction related to the Hantzsch-synthesis of dihydropyrid-ines was recently reported by Yuan and colleagues who developed a domino cascade Knoevenagel/Michael/cyclization sequence converting isatin derivatives 182, malonitrile (183), and symmetrical acyclic 1,3-diketones or (3-ketoesters 184... 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

Scheme 8.22 Domino reaction involving Michael/Knoevenagel reaction sequence.

The use of special enamines in the three-component Knoevenagel-Michael addition/cyclization sequence directly led to Af-alkyl- or Af-aryl-substituted 2-amino-4//-pyrans. Perumal et al. therefore applied catalytic amounts of piperidine in ethanol at ambient temperature to add ( )-Al-methyl-l-(methylthio)-2-nitroethenamine 49 to the previously formed Michael acceptor in a one-pot fashion (Scheme 13.16) [7]. This protocol provides the desired lV-methyl-2-amino-4//-pyrans 50/51 in good yields. The methylthio substituent serves as a good leaving group facilitating the cyclization subsequent to the Michael addition reaction by nucleophilic substitution. 

In the amine-catalyzed reactions, a Knoevenagel addition/ketalization/ intramolecular retro-Claisen cascade is detected (Scheme 2.32). The retro-Claisen step is enabled by the ketalization of the Knoevenagel addition product Q. The ketalization of the Knoevenagel product (Q S) is initiated by the hydroxyl groups of the carbohydrate moiety, as in-house NMR-experiments suggest (formation of intermediate ketal structure K in Knoevenagel condensation/ketalization/oxa-Michael cascade reaction Scheme 2.16). Products derived from this reaction sequence (Scheme 2.16)... 

An acid-catalyzed version of this reaction was published by Wang et al. in 2013 [50]. A substoichiometric amount of acetic acid in refluxing ethanol mediates the Knoevenagel/ enamine-Michael addition/cyclization sequence to provide the spirodihydropyridines in high yields. 

Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

The morpholine-promoted reaction of Af-alkyl piperi-dine-4-one with malonodinitrile and p-nitrostyrene derivatives in refluxing EtOH directly led to substituted tetrahydroisoquinoline derivatives in moderate to good yields [121], The reaction is initiated by a Knoevenagel condensation, in which a Michael addition/Thorpe-Ziegler sequence follows. Oxidation by air is the last step to occur providing the desired products. 

Within a sequence of Knoevenagel condensation, Michael addition and condensation, Meldrum s acid can be used as a CHj-C(O) equivalent, through the elimination of acetone and subsequent decarboxylation (Scheme 13.86). In this sequence, other 1,3-dicarbonyl compounds within the reaction mixture serve as nucleophile in the Michael addition. By addition of a nitrogen source to this reaction... 

Similar to the mechanism described in Scheme 2.16, a Knoevenagel reac-tion/ketalization cascade of hydroxyacetone with 1,3-dicarbonyl compounds is assumed. In Scheme 2.16, a Knoevenagel condensation/ketalization reaction is depicted. This sequence allows a subsequent oxa-Michael addition, which yields the corresponding C-glycosides. In contrast, a Knoevenagel addition/ketalization occurs under the reaction condition described in Scheme 2.28, which is followed by an intramolecular retro-Claisen step. As a result of that, the corresponding esters were obtained (Scheme 2.29). 

These results differ considerably from those obtained by Lubineau reactions. In the Lubineau series, a Knoevenagel condensation followed by an oxa-Michael/intermolecular retro-Claisen process is proposed. As a result of the Lubineau sequence, the loss of an acetate-fragment occurs in reactions with acetylacetone. 

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