Synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones via Biginelli reaction promoted by bismuth(III)nitrate or PPh₃ without solvent

2.1 Procedure (M₁)

Ethanol (20 mL) and concentrated HCl are introduced into a round-bottomed flask equipped with a cooling device. The aldehyde (4 mmol), urea or thiourea (5 mmol), the 1,3-dicarbonyl compound (5 mmol) are added and the solution is permitted to react for 18 h under reflux with magnetic stirring. The mixture is then washed with water and filtrated. The resulting product is recrystallized in ethanol.

2.2 Procedure (M₂)

Acetonitrile (20 mL) and Bi(NO₃)₃ (0.2 mmol) are introduced into a round-bottomed flask equipped with a cooling device. The aldehyde (4 mmol), urea or thiourea (5 mmol), the 1,3-dicarbonyl compounds (5 mmol) are added and the solution is permitted to react for 2.5 h with magnetic stirring at room temperature. The mixture is then washed with water and filtrated. The resulting product is recrystallized in ethanol.

2.3 Procedure (M₃)

A mixture of aldehyde (4 mmol), 1,3-dicarbonyl compound (4 mmol), urea or thiourea (6 mmol) and catalytic amount of PPh₃ (0.4 mmol) are introduced into a round-bottomed flask equipped with a cooling device. The reaction mixture was heated with stirring at 100 °C for 3 h. The product was filtrated, washed with water. The solid crude products were recrystallized in ethanol.

2.4 Recording of spectra

¹H (300 MHz) and ¹³C (75 MHz) NMR spectra are recorded on a Bruker spectrometer in DMSO-d₆, with tetramethysilane as internal reference.

All the products were confirmed by comparing their melting points, ¹H NMR and ¹³C NMR data with the literature data (Joseph et al., 2006; Kumar and Parmar, 2008; Shaabani et al., 2003; Chitra and Pandiarajen, 2009; Chari et al., 2005; Gholap et al., 2008; Kapadia et al., 2009; Falsone and Kappe, 2001).

3.1 Solvent effect

The results of Table 1 reveal that bismuth nitrate is a suitable catalyst for Biginelli reactions. The nature of the solvent is not innocent as higher values of the dielectric constant induce higher yields. Water is a noticeable exception. This proves the ionic character of the reaction. Thus, the Biginelli reaction catalyzed by bismuth nitrate in acetonitrile at room temperature is an efficient synthetic procedure for the preparation of dihydropyrimidinones from benzaldehyde or butanal as aldehydes, ethyl acetoacetate and urea (see Fig. 1).

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Figure 1

Bismuth(III)nitrate catalyzed Biginelli reaction.

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3.2 Biginelli reaction catalyzed by Bi(NO₃)₃ in acetonitrile

Generalization of the method leads to the results exposed in Table 2 (see Fig. 2).

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Figure 2

Synthesis of dihydropyrimidinones/thiones catalyzed by bismuth(III) nitrate in acetonitrile.

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Table 2 shows that yields range from 42% to 95% under similar conditions as in Table 1. The results, at first sight, are surprising since an increase of the chain length of aliphatic aldehydes implies higher yields. Further analysis of the results reveals that aldehydes bearing donor or electron withdrawing groups react without exception to afford dihydropyrimidinones in excellent yields. Again, bismuth nitrate is revealed as an appropriate catalyst making the method attractive compared to Atwal’s multistep procedure (O’Reilly and Atwal, 1987). Aldehydes substituted by various functional groups conferring interesting pharmacological properties can be used without altering the excellent yields. In this context, Banik et al. reported that Biginelli reaction occurs rapidly and gives quantitative yields in presence of Bi(NO₃)₃ under the influence of microwave irradiation in the absence of solvent (Banik et al., 2007).

The reaction begins with the condensation of the aldehyde and urea yielding an intermediate of acylimine type. A further step follows by cyclization and dehydration to liberate the Biginelli product. However, it seems that Bismuth salt may stabilize the acylimine intermediate due to the presence of vacant d-orbital. As an example, the mechanism of the reaction involving benzaldehyde, urea and ethylacetoacetate can be schematised as follows:

• –

  formation of the acylimine (see Fig. 3),

• –

  enolization of ethylacetoacetate (see Fig. 4),

• –

  condensation of this enol with the acylimine to give an intermediate which undergoes cyclization followed by dehydration to eventually afford the corresponding dihydropyrimidinone (see Fig. 5).

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Figure 3

Formation of acylimine intermediate.

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Figure 4

Enolization of dicarbonyl compound.

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Figure 5

Formation of the dihydropyrimidinone.

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3.3 Synthesis of dihydropyrimidinones without solvent

As we have been involved in reactions under solventless conditions, we have been prompted to examine the Biginelli reaction in the presence of triphenylphosphine. The reactions involve aromatic aldehydes, 1,3-dicarbonylated compounds and urea (Table 3) (see Fig. 6).

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Figure 6

PPh₃ catalyzed Biginelli reaction under solvent free conditions.

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Table 3 shows that triphenylphosphine is an efficient catalyst for the synthesis of a variety of 3,4-dihydropyrimidinones by means of a three-component condensation of an aldehyde, β-ketoester and urea in one pot under solvent-free conditions. These results are in agreement with those reported by Debache et al. (2008).

The proposed mechanism includes formation of an acylimine as a first step. The second key intermediate is the 1,3-dicarbonylated compound in enolate form. Indeed, the triphenylphosphine plays the role of a Lewis base by interaction with electrophilic carbon of aldehyde, than a deprotonation of the 1,3-dicarbonylated compound which offers an enolate. A condensation between the enolate and the acylimine follow-up of a cyclization and dehydration to form the corresponding dihydropyrimidinone (Fig. 7).

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Figure 7

Suggested mechanism for the Biginelli reaction catalyzed by triphenylphosphine under solvent-free conditions.

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