Biginelli optimization

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

Fig. 5.5 Optimization of reaction temperature and time forthe Biginelli cyclocondensation in AcOH/EtOH (3 1) with 10 mol% ofYb(OTf)3.

The yields for the optimized microwave-assisted Biginelli condensations are in general comparable to or higher than those obtained using the standard reflux conditions. More importantly, however, reaction times have been brought down from several hours (4—12 h) under reflux conditions to 10-20 min employing microwave... 

The manufacturer of the commercially available Syrris Africa system [14] reports on the optimization of several multicomponent reactions Passerini, Biginelli and Ugi reaction. However, only the details of the three-component Passerini reaction were available [15]. 

Fig. 6. Optimization of reaction time and temperature for the Biginelli condensation involving ethyl acetoacetate, benzaldehyde, and urea [see Eq. (1)] in a 3 1 AcOH/EtOH solvent mixture with 10 mol% Yb(OTf)3 as a catalyst.

A comprehensive study on the scalability of optimized small-scale microwave protocols in single-mode reactors to large-scale experiments in a multimode instrument has been presented by Kappe and coworkers [26]. As a model reaction, the classical Biginelli reaction in acetic acid/ethanol (3 1) as solvent was rim in parallel in an eight-vessel rotor system of the Anton Paar Synthos 3000 synthesis platform (Fig. 8) on a 8 x 80 mmol scale [26]. Here, the temperature in one reference vessel was monitored with the aid of a suitable probe, while the surface temperature of all eight quartz reaction vessels was also monitored (deviation less than 10 °C, see Fig. 16). The yield in all eight vessels after 20 min hold-time at 120 °C was nearly identical, resulting in an overall amount of approximately 130 g of the desired dihydropyrimidine. 

The microwave-assisted Biginelli reaction was also optimized by the same authors under continuous flow conditions [90]. An equimolar reaction mixture of benzaldehyde, ethyl acetoacetate and urea was injected at a flow rate of 2 mL/min at a ceiling temperature of 120°C providing 52% of the desired DHPM 41 in 13 min of total processing time (5 min residence time in the cell). This flow rate allows the preparation of compound 41 on a 25 g/h scale (Scheme 30). 

Dihydropyrimidinones (DHPMs) are well-known calcium antagonistic agents and are most commonly prepared by acid-catalyzed cydocondensation of urea, p-ketoesters, and aromatic aldehydes. Ever since its discovery in 1893, this so-called Biginelli reaction (Scheme 17.19) has been subject of numerous optimization studies and many modified procedures have resulted [vide infra). The Biginelli reaction and its modifications are still popular tools for the preparation of DHPMs 26 and have been extensively reviewed by Kappe et al. [56],... 

Sotelo and coworkers explored the activity of an extensive collection of optimized 3,4-dihydropyrimi-din-2(17f)-one structures as a novel family of (nonxanthine) receptor antagonists with an unusually high selectivity profile (Scheme 9.24) [73]. The library was synthesized following a typical Biginelli MCR using ZnCl catalyst, affording a great variety of compounds... 

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