Biginelli scaffold

As summarized recently [61], a large scope of Brpnsted and Lewis acids catalyze this multicomponent reaction to promote the DHPM formation. The heterocyclic Biginelli scaffold has also been obtained under eco-Mendly conditions, as illustrated... 

Pd/C-catalyzed transfer hydrogenation conditions have also been appUed in the microwave-assisted (120 °C for 2 min) reduction of a nitro substituent on a Biginelli scaffold 36 (see Scheme 21) [42]. 

In recent decades, the Biginelli-type dihydropyrimidinones (DHPM) have received considerable attention, because of the interesting pharmacological properties of this heterocydic scaffold [30]. It was soon established that DHPM has a similar pharmacological profile to the well-known dihydropyridine (DHP) caldum-channel modulations of the Hantzsch type [31]. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

Fig. 4.8. Uncommon pyrimidine scaffolds derived from Biginelli-type condensations.

Dondoni, A., Mass , A. Decoration of dihydropyrimidine and dihydropyridine scaffolds with sugars via Biginelli and Hantzsch multicomponent reactions An efficient entry to a collection of artificial nucleosides. Mol. Divers. 2003, 6, 261 -270. 

In searching for further expansions of dihydropyrimidine scaffold, Kappe and co-workers [359] immobilized 4-chloroacetoacetate on hydroxymethylpolystyrene resin by a microwave-assisted transesterification in 1,2-dichlorobenzene. The subsequent Biginelli condensation with the aldehyde and the urea components was performed in dioxane at 70 °C in the presence of catalytic amounts of HCl. Low yields, observed in the case of two out of twelve aldehyde building blocks employed, were attributed to the low solubility and reactivity of the bisureide side products. Further manipulations of the BigineUi products, involving thermal, amine-, or hydrazine-mediated cyclizations, gave access to various dihydropyrimidine-condensed heterocycles (461), (462), and (464) respectively (Scheme 95). 

Shaabani A, Sarvary A, Rethmad A, Rezayan H (2007) Ionic Uquid/silica sulfuric acid promoted fast synthesis of a Biginelli-like scaffold reaction. Lett Oig Chem 4 68-71... 

A comprehensive study has investigated multidirectional cyclative cleavage transformations leading to bicyclic dihydropyrimidinones [61]. This approach required synthesis of 4-chloroacetoacetate resin as the key starting material this was prepared by microwave-assisted acetoacetylation of commercial available hydroxymethyl polystyrene resin under open-vessel conditions. This resin precursor was subsequently treated with urea and a variety of aldehydes in a Biginelli-type multi-component reaction, leading to the corresponding resin-bound dihydropyrimidinones (Scheme 16.40). The desired furo[3,4-d]pyrimidine-2,5-dione scaffold was obtained by a novel procedure for cyclative release under the action of micro-wave irradiation in sealed vials at 150 °C for 10 min. 

Another procedure for preparation of valuable heterocyclic scaffolds involves the Biginelli condensation on a PEG Support [75, 76]. Polymer-bound acetoacetate was prepared by reacting commercially available PEG 4000 with 2,2,6-trimethyl-4H-l,3-dioxin-4-one in toluene under reflux (Scheme 16.52). The microwave-assisted cyclocondensation was performed with nonvolatile polyphosphoric acid (PPA) as a catalyst in a domestic microwave oven [76]. During microwave heating the PEG-bound substrate melted, ensuring a homogeneous reaction mixture. After the reaction diethyl ether was added to precipitate the polymer bound products. The desired compounds were released by treatment with sodium methoxide in methanol at room temperature. All dihydropyrimidines were obtained in high yield purification was achieved by recrystallization from ethanol. 

A number of high-yielding variants of the traditional three-component Biginelli condensation employing a variety of catalysts, reagents, and reaction conditions/techniques have been developed (09M115) these are beyond the scope of this review. Reference is made to some excellent reviews (Tables 1-4). However, scaffold decoration of Biginelli DHPMs is presented by us. 

More recently, Moorthy and Saha have reported a highly enantioselective Biginelli reaction catalyzed with organo-catalyst 47 containing a chiral secondary amine scaffold and a strong hydrogen-bonding moiety (Scheme 9.17) [56]. 

B. Piqani, W. Zhang, Beilstein J. Org. Ghem. 2011, 7, 1294— 1298. Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications. 

However, many MCRs result in a single type of scaffold structure, for example, the Biginelli reaction or the Hantzsch dihydropyridine synthesis, which clearly... 

Dissection of the reaction sequence results in a tandem Knoevenagel condensation/A-carbamoyl-Mannich/condensation reaction sequence, which was first exploited by Biginelli in 1891. The resulting dihydropyrimidone scaffold is represented in many medicinal products, which are now produced by this efficient. 

---