Domino Knoevenagel—hetero-Diels—Alder reaction

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

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]. 

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... 

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-... 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

As the first multi-component domino reaction on solid phase the above mentioned domino-Knoevenagel-hetero-Diels-Alder reaction was performed using a 1,3-dicarbonyl compound bound to a modified Merrifield resin.171... 

In this process the primary step is the formation of an anion, which is a synonym for a nucleophile, mostly by deprotonation using a base. It follows a reaction with an electrophile to give a new anion which in the anionic-anionic process again reacts with an electrophile The reaction is then completed either by addition of another electrophile as a proton or by elimination of an X group. Besides the anionic-anionic process there are several examples of anionic-pericydic domino reactions as the domino-Knoevenagel-hetero-Diels-Alder reaction in which after the first step an 1-oxa-l,3-butadiene is formed. 

Jimenez-Alonso S, Chavez H, Estevez-Braun A, Ravelo AG, Feresin G, Tapia A (2008) An efficient synthesis of embelin derivatives through domino Knoevenagel hetero Diels-Alder reactions under microwave irradiation. Tetrahedron 64 8938-8942... 

Tietze LF, Bohnke N, Dietz S (2009) Synthesis of the deoxyaminosugar (-l-)-D-forosamine via a novel domino-Knoevenagel-hetero-Diels-Alder reaction. Org Lett 11 2948-2950... 

The Domino-Knoevenagel-hetero-Diels-Alder Reaction and Related Transformations... 

Scheme 5.6. Diastereoselective domino-Knoevenagel-hetero-Diels—Alder reaction with chiral aliphatic aldehydes.

One of the most reactive 1,3-dicarbonyl compounds used in the domino-Knoevenagel-hetero-Diels-Alder reaction is N,N-dimethyl barbituric acid 2. It has been shown that the fairly stable products can easily been transformed into other compounds via a reduction of the urea moiety with DIBAL-H [20]. Thus, reaction of 30 with DIBAL-H at 78 °C led to 46, which can be hydrolyzed to give 47 (Scheme 5.9). In a similar way, 48 was transformed into 50 via 49 and 12 to 52 via 51. The obtained compounds containing a lactone and an amide moiety can again be further transformed using DIBAL-H followed by an elimination. In this way, dihydropyran 54 is obtained from 50 via 53 as one example. 

Scheme 5.14. Domino-Knoevenagel-hetero-Diels—Alder reaction of oxathiolanes.

---