Biginelli reaction, microwave-assiste

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],... 

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... 

Yaddav, J.S., Reddy, B.V.S., Reddy, E.J. and Ramalingam, T., Microwave-assisted efficient synthesis of dihydropyrimidines improved high yielding protocol for the Biginelli reaction,/. Chem.Res. (S), 2000,354-355. 

Building Dihydropyrimidine Libraries via Microwave-Assisted Biginelli Multicomponent Reactions... 

The DHPMs should be synthesized in solution using standard Biginelli three-component condensation reaction mixtures. Although microwave-assisted Biginelli reactions have been published under solvent-free conditions,46 50 we felt that such methods would... 

The microwave-assisted Biginelli synthesis of dihydropyrimidine was investigated in open vessels as well as sealed reaction vessels. The reaction carried out at atmospheric pressure under microwave irradiation in a solution showed no rate increase compared to... 

Since the experimental conditions for the traditional Biginelli reaction are quite straightforward, small libraries of DHPMs are readily accessible by parallel synthesis. Along these lines the generation of a 140-member single compound DHPM library by combination of 25 aldehydes, 6 ureas/thioureas, and 7 acetoacetates or acetoamides under standard reaction conditions has been reported [123, 124]. More rapid approaches make use of microwave-enhanced solution-phase protocols [88, 89, 125]. Apart from these conventional solution-phase methods, it is also possible to employ polymer-supported reagents to aid in the purification and workup protocol. Polymer-assisted solution-phase chemistry using polymer-supported... 

Scheme 17 Biginelli reaction and Dimroth rearrangement via microwave-assisted batch and CF processing...

A new microwave-assisted protocol for the generation of diversely substituted 3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes... 

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). 

SCHEME 25.5(D) Microwave-assisted Biginelli reaction (Reference 56). 

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. 

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