Microwave-assisted Biginelli synthesis

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... 

Scheme 12.24 Microwave-assisted Biginelli dihydropyrimidine synthesis.

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. 

This was followed by the attachment of a suitable urea-bearing carboxylic acid to generate the handle for the synthesis of the heterocyclic moiety (Scheme 8.5). The dihydropyrimidine core was then assembled using a standard microwave-assisted Biginelli reaction at 140°C for 40 min using DMF/HCl (4 1), followed by a TFA-mediated cleavage of the target molecule from the resin. 

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],... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

The Biginelli procedure is amenable to microwave technology, and several microwave-assisted procedures have now been published <2002SC147, 2004SL235>. An example is the microwave-assisted solution-phase synthesis of dihydropyrimidine C-5 amides and esters 723 using ytterbium triflate as the Lewis acid catalyst <2006T4651>. 

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. 

Liu Q, Pan N, Xu J, Zhang W, Kong F (2013) Microwave-assisted and iodine-catalyzed synthesis of dihydropyrimidin-2-thiones via biginelli reaction under solvent-fiee conditions. Synth Commun 43 139-146... 

Kappe CO, Kumar D, Varma RS (1999) Microwave-assisted high-speed parallel synthesis of 4-Aryl-3,4-dihydropyrimidin-2(lH)-ones using a solventless biginelli condensation protocol. Synthesis 10 1799-1803... 

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... 

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