Green High-Yielding One-Pot Approach to Biginelli Reaction under Catalyst-Free and Solvent-Free Ball Milling Conditions

A simple, green, and efficient approach was used to synthesize 3,4-dihydropyrimidines derivatives. We showed that the application of the planetary ball milling method with a ball-to-reagent weight ratio of 8 for the Biginelli reaction provides 3,4-dihydropyrimidines derivatives with excellent yields (>98%) in a short reaction time from the one-pot, three-component condensation of aldehydes, ethyl acetoacetate, and urea (or thiourea).


Introduction
The development of new efficient methods to synthesize organic heterocycles that are both economical and eco-friendly presents a great challenge for the scientific community.
Solvent-free reactions are highly significant from both economical and synthetic points of view. These kinds of reactions ensure an essential facet of green chemistry to reduce the risks to humans and the environment.
Multicomponent reactions (MCRs) have gained importance because of their efficiency and effectiveness as a method for one-pot synthesis of a wide range of heterocycles [1][2][3][4][5][6]. The optimal MCR is sufficiently flexible. Thus, it can be conducted to generate adducts with a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products.
In this study, we propose a new and highly efficient approach to the one-pot synthesis of Biginelli 3,

Materials and Techniques
The ball mill used in this study was a Planetary Micro Mill PULVERISETTE 7 (Fritsch, Idar-Oberstein, Germany) classic line with 45 mL tempered steel vials and 10 mm tempered steel grinding balls. The melting points were determined with a Stuart SMP10 melting point apparatus (Bibby Scientific, Staffordshire, UK). All of the compounds used in this study were purchased from Aldrich (St. Louis, MO, USA). IR spectra were obtained with an FT-IR-Tensor 27 spectrometer in KBr pellets (Bruker, Ettlingen, Germany). 1 H and 13 C-NMR spectra were determined with a Bruker 400 NMR spectrometer (Bruker Biospin, Rheinstetten, Germany) in DMSO-d6 with TMS as the internal standard. Chemical shifts were expressed as δ ppm units. The elemental analysis was performed on a PerkinElmer 2400 CHN Elemental Analyzer (Wellesley, MA, USA). The progress of all reactions was monitored through TLC on silica gel 60 with 1:1 hexane/ethyl acetate.

General Procedure for Synthesis of 3,4-Dihydropyrimidine Compound 4a
An equimolar amount (0.02 mol) of benzaldehyde (1a), ethyl acetoacetate (2), and urea (3a) (total mass 5.92 g) was placed into tempered steel vials with 47.36 g of tempered steel balls (22 balls of 10 mm in diameter). The vials were closed and then placed in a Planetary Micro Mill Pulverisette 7, which is set to 750 rpm. The 3,4-dihydropyrimidine compound 4a was obtained in pure form after 30 min of milling without further purification.

Materials and Techniques
The ball mill used in this study was a Planetary Micro Mill PULVERISETTE 7 (Fritsch, Idar-Oberstein, Germany) classic line with 45 mL tempered steel vials and 10 mm tempered steel grinding balls. The melting points were determined with a Stuart SMP10 melting point apparatus (Bibby Scientific, Staffordshire, UK). All of the compounds used in this study were purchased from Aldrich (St. Louis, MO, USA). IR spectra were obtained with an FT-IR-Tensor 27 spectrometer in KBr pellets (Bruker, Ettlingen, Germany). 1 H and 13 C-NMR spectra were determined with a Bruker 400 NMR spectrometer (Bruker Biospin, Rheinstetten, Germany) in DMSO-d 6 with TMS as the internal standard. Chemical shifts were expressed as δ ppm units. The elemental analysis was performed on a PerkinElmer 2400 CHN Elemental Analyzer (Wellesley, MA, USA). The progress of all reactions was monitored through TLC on silica gel 60 with 1:1 hexane/ethyl acetate.

General Procedure for Synthesis of 3,4-Dihydropyrimidine Compound 4a
An equimolar amount (0.02 mol) of benzaldehyde (1a), ethyl acetoacetate (2), and urea (3a) (total mass 5.92 g) was placed into tempered steel vials with 47.36 g of tempered steel balls (22 balls of 10 mm in diameter). The vials were closed and then placed in a Planetary Micro Mill Pulverisette 7, which is set to 750 rpm. The 3,4-dihydropyrimidine compound 4a was obtained in pure form after 30 min of milling without further purification.
In this paper, we present an efficient one-pot, three-component solvent-free and catalyst-free approach to synthesize 3,4-dihydropyrimidine derivatives by direct condensation of equimolar quantities of benzaldehyde derivatives, ethyl acetoacetate, and urea/thiourea in a simple planetary ball mill at 750 rpm without adding any solvent or catalyst (Scheme 1). The progress of the reactions was monitored every 10 min of the milling cycle through thin-layer chromatography (TLC).
We examined different ball ratios (Table 1) to improve the efficiency of the ball milling approach for the Biginelli reaction. Equimolar quantities (0.02 mol) of benzaldehyde (1a), ethyl acetoacetate (2), and urea (3a) (with a total mass of 5.92 g) were introduced in the planetary ball milling, and several milling times and ball weights were tested [42]. Table 1. Milling parameters and the conversion rate for the synthesis of 3,4-dihydropyrimidines derivatives. Accordingly, our investigation showed that the reaction does not change even after 12 h of milling when the ratio (ball weight/reagent weight) is equal to 1. The increasing value of the ball weight causes the conversion rate to increase to the optimal value for the ball weight-to-reagent weight ratio, which is equal to 8 (47.36 g of balls) ( Table 1). The protocol also provides simple access to 3,4-dihydropyrimidine derivatives (4a-j) ( Table 2).

Entry * BRR (Balls-to-Reagents Weight Ratio) Time (min) Conversion (%)
This approach exhibits the advantages of high yield, short reaction time (30 min), and easy workup. It is also environmentally benign. All of the synthesized products have been characterized through NMR ( 1 H and 13 C), IR, and elemental analysis.

Conclusions
We developed a simple, green, and quick method for the one-pot Biginelli reaction. This technique is highly efficient. The important advantage of the present procedure, in addition to its simplicity, is its ability to obtain the synthesized 3,4-dihydropyrimidine derivatives in a short reaction time, in pure form, and with excellent yields.