Knoevenagel/Diels-Alder reaction

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

Scheme 2.182. Amino acid-catalyzed asymmetric three-component Knoevenagel/Diels-Alder reactions.

Scheme 9.21. DMTC-catalyzed asymmetric three-component domino-Knoevenagel-Diels—Alder reaction.

Scheme 10.31 Three-component domino Knoevenagel/Diels-Alder reaction.

D. B. Ramachary, N. S. Chowdari, C. F. Barhas IB, Angew. Chem. Int. Ed. Engl. 2003, 42, 4233 237. Organocatalytic asymmetric domino Knoevenagel/Diels-Alder reactions a hioorganic approach to the diastereospecific and enanti-oselective construction of highly suhstituted spiro[5,5] undecane-1,5,9-triones. 

A. Palasz, Synthesis 2010, 4021—4032. A green approach to the synthesis of fused uracils pyrano[2,3-Knoevenagel/Diels-Alder reactions. 

Tandem sequences involving Knoevenagel condensation followed by electrocyclization have not been employed as extensively as other tandem reactions (such as the tandem Knoevenagel-Diels-Alder reaction), but have been used in a few cases with great success, rapidly constructing complex polycyclic cores. 

On another occasion, Barbas s group developed the first organocatalytic diastereospecific and enantioselective direct asymmettic domino Knoevenagel/ Diels-Alder reactions that produce highly substituted spiro[5,5]undecane-l,5,9-triones 57 from commercially available 54, aldehydes 55, and 2,2-dimethyl-l,3-dioxane-4,6-dione 56 (Scheme 1.16) [18]. Among the catalysts screened, 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield, and provided 57 in 88% yield and 86% ee. Up to 93% yield and 99% ee were observed when the reaction was extended to other substrates. It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58. 

Inspired by the unexpected formation of symmetric 58, Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldol/Knoevenagel/Diels-Alder reaction sequence in one pot (Scheme 1.18) [22]. The Diels-Alder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products. 

SCHEME 1.18 Pyrrolidine-catalyzed stereospecific multicomponent aldol/Knoevenagel/ Diels-Alder reaction. 

Literature articles, which report the formation and evaluation of difunctional cyanoacrylate monomers, have been published. The preparation of the difunctional monomers required an alternative synthetic method than the standard Knoevenagel reaction for the monofunctional monomers, because the crosslinked polymer thermally decomposes before it can revert back to the free monomer. The earliest report for the preparation of a difunctional cyanoacrylate monomer involved a reverse Diels-Alder reaction of a dicyanoacrylate precursor [16,17]. Later reports described a transesterification with a dicyanoacrylic acid [18] or their formation from the oxidation of a diphenylselenide precursor, seen in Eq. 3 for the dicyanoacrylate ester of butanediol, 7 [6]. 

The following example is a sequence consisting of a Knoevenagel condensation and a subsequent hetero-Diels-Alder reaction. An aromatic... 

A large number of aldehydes and structurally different CH-acidic methylene compounds can be employed in such a domino-Knoevenagel + hetero-Diels-Alder reaction. 

Domino Knoevenagel hefero-Diels-Alder reactions [7]... 

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

Peer-reviewed journals [18] sections in review [89]. A Knoevenagel condensation is described imder 4.8.2 Cycloadditions - The Diels-Alder Reaction, since both reactions were performed combined in a domino-type process. 

Scheme 2.163. The domino Knoevenagel/hetero-Diels-Alder reaction.

The domino Knoevenagel/hetero-Diels-Alder reaction is a prominent example of the great advantage of domino processes as it not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates, but also permits the preparation of highly diversified molecules. Due to the vast number of reports that have been made, only a few recent publications can be discussed here, although several excellent reviews on this topic have been produced that provide a more detailed insight into this useful method [372]. 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

Other valuable substrates for the domino Knoevenagel/hetero-Diels-Alder reaction are chiral oxathiolanes such as 2-778, which are easily accessible by condensation of 2-thioacetic acid and a ketone in the presence ofpTsOH, followed by oxidation with hydrogen peroxide [390]. As described by Tietze and coworkers, the Knoevenagel condensation of 2-778 with aldehydes as 2-777 can be performed in... 

Scheme 2.169. Chiral 1,3-dicarbonyl compounds and chiral Lewis acids for the dominr Knoevenagel/hetero-Diels-Alder reaction.

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The three-component domino Knoevenagel/hetero-Diels-Alder-reaction is especially fruitful if one uses aldehydes containing a protected amino function. In such... 

Another class of alkaloids recently synthesized by Tietze and coworkers using a three-component domino Knoevenagel/hetero-Diels-Alder reaction included the Ipecacuanha alkaloids such as emetine (2-798) [402], and the Alangium alkaloids such as tubulosine (2-799) [403]. Both types belong to the group of tetrahydroi-soquinoline alkaloids, and are formed in Nature from dopamine and the monoter-... 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

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