Issue in Honor of Prof. Fritz Sauter ARKIVOC 2001 (ii) 122-134
leads to the final DHPM product 4. The reaction mechansim can therefore be classified as an aamidoalkylation, or more specifically as an a-ureidoalkylation. 17
Scheme 3
In order to promote conditions that would favor the formation and interception of such an iminium ion intermediate (i.e. 11) in the Biginelli reaction – thereby minimizing side reactions – we have now investigated a variety of reaction conditions more specifically employed in Nacyliminium ion based amidoalkylations. 18 One of the most efficient reagents tested proved to be polyphosphate ester (PPE), which has been demonstrated to mediate acyliminium ion-based condensations in the past such as the somewhat related dihydropyridone formations shown in Scheme 3.19,20 Here we report in full detail the development of improved conditions for performing Biginelli condensations, using PPE as mild cyclization reagent. 21
Results and Discussion
Polyphosphate ester (PPE) is one of the phosphate-based reagents that are related to polyphosphoric acid (PPA). It differs from PPA in that it is aprotic and soluble in organic media. It is often compared to the related polyphosphoric acid trimethylsilyl ester (PPSE). In general, the advantages of PPE include its solubility in organic solvents, the mild conditions under which it is used, and its relatively nonhazardous, nonnoxious nature. 19 Although the reagent is not commercially available it is readiliy prepared by treatment of phosphorous oxide with anhydrous ether (see Experimental). As reagent, PPE has been used successfully in Bischler-Napieralski reactions, Friedel-Crafts acylations, Beckmann rearrangements, and in the conversion of carboxylic acids to esters, thiol esters, amides, and nitriles. 19
Our initial attempts focused on the use of neat PPE as reaction mediator (i.e. solvent) as described by Marson for similar cyclizations. 20 Although the yields of crude dihydro-pyrimidone 4a were respectable (ca. 80%), the solubility of urea in cold PPE and side-reactions leading to unwanted by-products (see below) initially created a problem. In addition, for complete conversion reaction times of 24 h at 40 °C were necessary. This method was further complicated by the work-up procedure: adding a large amount of water or ice to the reaction mixture resulted not only in the precipitation of the desired product, but also precipitated by-products such as the Knoevenagel product 15 (see Scheme 2) 16 and the 6-styryl-derivative 18 (see below). Although we have recently shown that by using a microwave-assisted protocol these problems can be overcome and neat PPE can still be used effectively (in particular for the parallel and small-scale synthesis of DHPM libraries); 22 we felt that using a co-solvent could also eliminate some of the
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