Biginelli adducts

The method was extended to other classes of fluorinated p-dicarbonyl compounds, including p-ketoesters (Table 42, Entry 1), p-diketones (Entry 2), P-ketosulphones (Entry 3), p-ketosulphamides (Entry 4), and p-ketophosphonates (Entries 5 and 6). It should be noted that in case of some p-diketones (i.e. 1,1,1,5,5,5-hexafluoroacetylacetone), the products of principal pyrimidine synthesis were formed instead of Biginelli adducts under reaction conditions [568]. Apart from urea and thiourea, other classes of NCN binucleophiles were also introduced, including A-alkylureas (Entries 7 and 8, note different stereochemistry of the products), aminotriazoles (Entries 9 and 10), aminotetrazole (Entry 11), and 2-aminobenzimidazole (Entry 12). 

Karimi-Jaberi and co-workers [16] reported the use of trifluoroacetic acid (TFA CAT-6) as an organic catalyst to synthesize Biginelli adducts (Table 2). The use of CAT-6 afforded a series of Biginelli adducts with short reaction times and excellent yields (Table 2). CAT-6 catalyzed the Biginelli reaction efficiently with a wide variety of aldehydes, 1/5-dicarbonyl compoxmds, and urea or thiourea. The reaction in the absence of CAT-6 produced lower yields (20%), as starting materials were primarily recovered from the reaction medium [16]. 

Sagar and collaborators [18] described phenyl phosphonic acid (CAT-8) as a useful catalyst in Biginelli reactions (Table 2). CAT-8-catalyzed reactions were explored it was found that aromatic aldehydes with electron-donating or electron-withdrawing substituents, aliphatic aldehydes, and heteroaromatic aldehydes were good substrates in such reactions. The Biginelli adducts were obtained in excellent yields (86-97%) when urea was employed, and moderate-to-good yields (65-72%) were observed with thiourea (Table 2) [18]. 

Tajbakhsh and co-workers [21] showed that silica-bonded S-sulfonic acid (CAT-11) afforded the Biginelli adducts in good yields (Table 3). Aromatic aldehydes with both electron-donating and electron-withdrawing subshtuents gave the corresponding products in good yields, whereas low yields were observed with nonaromahc aldehydes. 

Cellulose sulfuric acid (CAT-15) was also shown to be an effective catalyst in the Biginelli reaction and afforded good yields (Table 3). In fact, CAT-15 catalyzed these reactions with 65-95% and 70-90% yields for the Biginelli adducts derived from thiourea and urea, respectively. This catalyst was reused up to 4 times with no loss in catalytic activity [25]. 

Hankari and collaborators studied the catalytic efficiency of hybrid zwitterionic acids (CAT-17) in the Biginelli reaction (Table 3) [27]. In this work, the authors showed that reusing catalyst CAT-17 is possible without losing its catalytic ability for at least for five cycles. The non-catalyzed reaction produced Biginelli adducts in less than 10% yield [2. ... 

L-Proline and its derivatives are often used as stereoselective catalysts in the Biginelli reactions [29-31]. This amino acid leads to the formation of enamines, key intermediates involved in the formation of Biginelli adducts (Table 4) [29]. 

Pandey and collaborators reported the use of L-proline (CAT-19) in combination with TEA in Biginelli reactions (Table 4). The Biginelli adducts were obtained in good yields (>79%) and with a cis relative configuration, as determined by NOESY experiments (Figure 6). In these experiments it was shown that H-4 is cis to H-5 and trans to H-10 (Figure 6) [29]. 

Chohamarani and Zamani reported the use of L-proline supported on silica (CAT-20). This methodology provided the Biginelli adducts in good yields (>80%) from aromatic aldehydes. However, the adducts prepared from benzal-dehyde and thiomea gave poor yields (50%, Table 4) [30]. 

Silva and collaborators described calixarenes (CAT-30) as efficient catalysts in the Biginelli reaction [41]. They found that the presence of a sulfonyl group on these calixarenes improved their catalytic properties, and the calix-arene CAT-30 showed better results for the preparation of Biginelli adducts than other catalysts (Table 6). They also showed that macrocyclic monomers, in amounts equivalent to CAT-30, resulted in lower efficiency, justifying the use of calixarenes as supramolecular catalysts in these reactions. Aromatic aldehydes were good substrates (yields >52%), while nonaromatic aldehydes were poor substrates (yields >34%). CAT-30 was reused in up to five cycles without any loss of efficiency. 

In 2011, Li used a chiral calixarene (CAT-31) to perform an asymmetric version of the Biginelli reaction (Table 6). CAT-31 produced the Biginelli adducts in moderate yields and enantioselectivities (54% 44% ee). As possible additives, a piperidine-TFA salt and p-toluic acid were used to provide the Biginelli adducts in 42% yield and 68% ee. The monomer did not efficiently promote enantioselectivity in these reactions. From all tested aldehydes, those with substituents in the metfl-position had a better ee (80-98%), while those with substituents in the para-position had a lower ee (20-69%). The proposed mechanism by the authors involved the enamine intermediate, which interacts with the calixarene cavity in some manner, as confirmed by NMR experiments [42]. 

Asghari and collaborators demonstrated the catalytic properties of sulfonated /J-cyclodextrin (CAT-34, Table 6). The catalyst works better under solvent-free conditions, and the Biginelli adducts were obtained in good yields (>71%) under these conditions [45]. Zhou and collaborators showed that /3-cyclodextrin, in combination with FlCl (CAT-35), provided the Biginelli adduct in 48% yield after 12 h (Table 6) [46]. Aliphatic aldehydes were good substrates, and excellent yields (>84%) were observed when aromatic aldehydes were employed [46]. 

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

Biginelli compounds can also modulate the protein Hsp 70 [65]. DHPM-peptoid (Figure 10) is one of the most active Biginelli adducts on Hsp 70 [66]. This protein, known to be overexpressed in some cancer cell lines, is responsible for many cellular processes, such as rearrangement and transport of protein complex [66]. 

N.A. Liberto, S.P Silva, A. de Fatima, S.A. Fernandes, /3-Cyclodextrrn-assisted synthesis of Biginelli adducts under solvent-free conditiot . Tetrahedron 69 (2013) 8245-8249. 

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