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“Solvent-Less” Mechanochemical Approach to the Synthesis of Pyrimidine Derivatives Tilak Raj,† Hemant Sharma,† Mayank,† Ajnesh Singh,† Thammarat Aree,‡ Navneet Kaur,*,§ Narinder Singh,*,† and Doo Ok Jang*,∥ †

Department Department § Department ∥ Department

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‡

of of of of

Chemistry, Chemistry, Chemistry, Chemistry,

Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand Panjab University, Chandigarh160014, India Yonsei University, Wonju 26493, Korea

S Supporting Information *

ABSTRACT: Modified ZnO NPs were synthesized through a sol−gel route with an aromatic capping agent to provide a highly efficient catalyst, NS-5, for the one-pot multicomponent synthesis of various pyrimidine derivatives using a solvent-free ball milling technique. Greenness of the present method was evaluated by calculating an Ecoscale score and E-factor. Characteristics of the method include use of a recyclable catalyst, scale-up to a multigram scale, and ease of product isolation. KEYWORDS: Nanoparticle, Green chemistry, Multicomponent reaction, Radical reaction, Nitrogen heterocycle

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INTRODUCTION Pyrimidine derivatives constitute the central core of adenine, cytosine, xanthine alkaloids, and other important biologically active biomolecules.1 The pyrimidine skeleton is a part of many pharmaceutically interesting drugs that exhibit a variety of biological activities including antibacterial,2−5 antifungal,6,7 antileishmanial,8 anti-inflammatory,9,10 analgesic,11 antihypertensive,12,13 antipyretic,14 antiviral,15 antidiabetic,16 antiallergic,17 anticonvulsant,18 antioxidant,19,20 antihistaminic,21 herbicidal,22 anticancer activities,23,24 central nervous system depressant properties,25,26 and calcium channel blockers.27,28 Examples of important pyrimidine core containing biologically active molecules include afloqualone and epirizole as antiinflammatory and analgesic agents,29 lamivudine as an anti-HIV agent,30 minoxidil as an antihypertensive agent,31 and [11C]SCH-442416 for mapping cerebral A2A receptors (Figure 1).32 In earlier decades, various synthetic methodologies have been developed and utilized for the synthesis of pyrimidine analogues;33−37 however, tedious, low yielding procedures have supplied the impetus for better methods. Multicomponent reactions (MCRs) have provided new prospects for advancement in the synthesis of pyrimidine analogues. © 2017 American Chemical Society

Among MCRs, the Biginelli (condensation of aldehydes and ß-keto carbonyls with urea or thiourea)38−41 and Traube− Schwarz42−48 (condensation of α,β-unsaturated carbonyl compounds with amino heterocycles or amidines) reactions have served as powerful tools for the synthesis of 3,4dihydropyrimidin-2(1H)-ones and tricyclic 1,6-dihydropyrimidine derivatives42−48 under different reaction conditions such as with base,38 microwave irradiation,39 tetrabutylammonium hydrogen sulfate,41 thiamine hydrochloride,49 boric acid,50 melamine trisulfonate,51 ionic liquid,44,52 N,N′-dichlorobis(2,4,6-trichlorophenyl) urea,53 α-zirconium sulfophenylphosphonate,54 sulphamic acid,55 and zinc perchlorate hexahydrate.56 Recently, the utility of nanoparticles (NPs) such as copper NPs,57 a magnetic (Fe3O4)-NP supported nickel(II) complex,58 and nickel NPs for MCRs was recognized.59 However, some of the reported methodologies require harsh reaction conditions and the use of toxic reagents for the syntheses and purification of products, which potentially could harm the environment. Received: August 25, 2016 Revised: December 8, 2016 Published: January 6, 2017 1468

DOI: 10.1021/acssuschemeng.6b02030 ACS Sustainable Chem. Eng. 2017, 5, 1468−1475

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ACS Sustainable Chemistry & Engineering

cetate was placed in a tungsten carbide milling jar along with 0.4 mol % ZnO NPs, and the mixture was milled for 40 min at 600 rpm. After completion of the reaction, the crude mixture was analyzed by 1H NMR, and the results are presented in Table 1. The yield of product 7 was higher in the presence of a catalyst (entries 2−7) compared to the noncatalytic reaction (entry 1). Particularly, NS-4, NS-5, and NS-6 afforded good yields of product 7 (entries 5−7), and among these catalysts, NS-5 gave the highest yield (entry 6). The syntheses of these catalysts differed only in the capping agent. Capping agents can arrange the inorganic units into a particular topology, acting as base to promote further growth of crystals and leading to a particular shape with different sizes.74 ZnO NPs NS-5 and NS6 were obtained using capping agents prepared from aromatic amines, which generally serve as good capping agents due to their rigidity, thermal stability, and hydrophobicity.74 Moreover, it was reported that aromatic rings form self-assembled systems through π−π type interactions, providing a better template for the growth of NPs.74 SEM imaging analysis and a DLS study showed that NS-5 possessed uniform needle-shaped nanoparticles, and exhibited the best catalytic activity (Figures S1 and S2).75 Although the other ZnO NPs had a broader size range, NS-5 was selected as the lead catalyst for further MCRs because the reaction afforded the highest yield of the desired product in its presence. To optimize the amount of NS-5 in order to achieve the maximum conversion, the turnover number (TON) and turnover frequency (TOF) were determined for the reaction of 2-aminobenzimidazole, 2-nitrobenzaldehyde, and ethyl acetoacetate. As shown in Figure 3, the maximum yield of 7 and the highest values of TON and TOF were obtained with 0.4 mol % of NS-5. Further increases in the amount of NS-5 resulted in a slight decrease in TON, TOF, and product yield. Additionally, the yield of the product was further optimized by varying the reaction conditions including reaction time, speed of ball milling (rpm), and number of balls (Figure S4). The progress of the reaction was monitored through recording the 1H NMR of the crude reaction mixture at different time intervals. In ball milling, three parameters are most important: milling speed (rpm), time of milling, and number of balls.61 The highest yield was attained when the reaction was milled using 20 balls with a size of 5 mm at 600 rpm for 45 min. Any change in these parameters resulted in a lowering of the reaction yield. The scope of the present methodology was investigated by synthesizing structurally different pyrimidine derivatives using the optimized reaction conditions. Various benzo[4,5]imidazo[1,2-a]pyrimidine derivatives were obtained in high yields by MCRs of 2-aminobenzimidazole, aldehydes, and acetoacetates under the optimal reaction conditions, and the results are presented in Table 2. Benzaldehyde or aromatic aldehydes with an electron-withdrawing substituent gave high yields of the products (7−9). Somewhat lower yields were obtained with aromatic aldehydes with an electron-donating group (10−12) or bulky aromatic aldehydes (13−15). MCRs of heteroaromatic aldehydes afforded the corresponding pyrimidine derivatives in high yields (16−20). Aliphatic aldehydes were also good substrates in the reaction, affording the corresponding products in high yields (21 and 22). Overall, the reaction was not significantly affected by changing the structure of the aldehydes, which shows the generality of the substrates. The structure of compound 16 was further confirmed by single crystal X-ray analysis. Compound 16 crystallized in the

Figure 1. Some biologically active pyrimidine derivatives.

Ball milling is an eco-friendly and economical technique that has been used for the grinding of large particles into small particles. Recently, the ball milling technique has found utility in the field of organic synthesis. Various reports advocate the high efficiency and eco-friendly nature of ball milling.60−68 We have explored the application of this methodology to the synthesis of benzimidazole, benzothiazole, and benzoxazole derivatives under solvent-free conditions.69,70 Herein, we report a MCR for the synthesis of pyrimidine derivatives with ZnO NPs using a solvent-free ball milling technique.

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RESULTS AND DISCUSSION The synthesis of ZnO NPs was carried out using a sol−gel method with in situ decoration of organic ligands on the surface of the ZnO.71,72 The ligands guided the growth of ZnO NPs in a particular direction, according to the so-called templating effect due to the nonbonding interactions between ZnO NPs and organic ligands.73,74 Six different capping agents were used to prepare different ZnO NPs (Figure 2). All of the capping

Figure 2. Capping agents used for the synthesis of ZnO NPs.

agents were removed by heating at 500 °C to obtain ZnO NPs, NS-1 to NS-6, which were characterized using dynamic light scattering (DLS) for size determination and scanning electron microscopy (SEM) to analyze morphology (Figures S1 and S2). Powder X-ray diffraction (PXRD) analysis confirmed a wurtzite-type structure for the ZnO NPs (Figure S3). The reaction of 2-aminobenzimidazole, 2-nitrobenzaldehyde, and ethyl acetoacetate was chosen as a model reaction to screen the catalytic activity of ZnO NPs. A reaction mixture containing 2-aminobenzimidazole, 2-nitrobenzaldehyde, and ethyl acetoa1469


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Table 1. Screening of ZnO NPs Catalysts for the MCR of 2-Aminobenzimidazole, 2-Nitrobenzaldehyde and Ethyl Acetoacetatea

entry

capping agent

ZnO NPs

yield (%)b

1 2 3 4 5 6 7

1 2 3 4 5 6

no catalyst NS-1 NS-2 NS-3 NS-4 NS-5 NS-6

29 38 40 45 70 82 79

a

Reaction conditions: 2-aminobenzimidazole (3 mmol), 2-nitrobenzaldehyde (3 mmol), and ethyl acetoacetate (3 mmol), ZnO NPs (0.4 mol %), 600 rpm, 20 milling balls (5 mm) in a milling jar (80 mL) for 40 min at room temperature. bYield was calculated by integration of 1H NMR peaks.

(23−27) in good yields, regardless of the structure of the aromatic aldehyde. The method was also applied to the synthesis of 2-oxo-tetrahydropyrimidine (28 and 29) and 2thioxo-tetrahydropyrimidine derivatives (30 and 31), which have wide applications in the pharmaceutical industry due to their biological activities. To examine the recyclability of NS-5, the reaction of 2aminobenzimidazole, 2-nitrobenzaldehyde, and ethyl acetoacetate was chosen as a model reaction. The crude product was dissolved in methanol, and the catalyst was allowed to settle out. To ensure catalyst purity, NS-5 was filtered and then washed three times with methanol. It was observed that the recovered catalyst sustained its activity up to the fifth cycle, after which the catalytic activity of NS-5 decreased, as shown in Table 4. To understand the reasons for the decrease in catalytic efficiency, DLS analysis and SEM of the recycled catalyst were performed, and the results were compared with freshly prepared catalyst. Large aggregates of NS-5 formed after the sixth cycle. The morphological analysis by SEM revealed that the catalyst tended to aggregate with recycling (Figures S6).69,70 The formation of aggregates of NS-5 was also supported by the DLS studies (Figure S7). For industrial applications, a MCR was performed on the gram scale. The reaction of 2-aminobenzimidazole (60 mmol), benzaldehyde (60 mmol), and ethyl acetoacetate (60 mmol) was performed in the presence of 0.4 mol % NS-5 in an 80 mL tungsten carbide jar containing 20 milling balls (5 mm) for 45 min at 600 rpm to afford 16.4 g (82% yield) of the corresponding benzoimidazopyrimidine 8, demonstrating that the present methodology could be utilized for multigram scale syntheses. It was observed that reactions with liquid reactants gave lower yields as compared to reactions with solid reactants. This result is attributed to hindrance of free rotation of the milling balls due to the viscosity of liquid reactants. The ecological effect of the present methodology was monitored by calculating an Ecoscale score and E-factor.79,80 The reaction of 2-aminobenzimidazole, benzaldehyde, and ethyl acetoacetate was selected to calculate these parameters. This methodology had an Ecoscale score of 67 (Table S4) and an E-factor of 0.28 (Table S5). As shown in Table S6, comparison with literature values illustrates that the present methodology reflects a good combination of Ecoscale score and E-factor. Although other methodologies have a low Ecoscale

Figure 3. Effect of NS-5 catalyst loading on TON, TOF, and yield of 7.

triclinic P1̅ space group with one molecule in the asymmetric unit. An ORTEP plot along with atom numbering scheme is shown in Figure 4A. The detailed analysis of the bond lengths is summarized in Tables S1 and S2.76−78 In the structure, the benzimidazole moiety adheres to its usual planar nature and is approximately orthogonal to the 2-pyridine moiety with a dihedral angle of 81.59° between the least-squares planes containing the 2-pyridine and benzimidazole moieties. The molecules are arranged in the form of dimers through N−H···N hydrogen bonds (N3−H3A···N1 = 2.089 Å), as shown in Figure 4B. These dimers extend along the b-axis and are connected to each other by C−H···O hydrogen bonding interactions (C4−H4B···O1 = 2.083 Å). The different layers of compound 16 are stacked over one another and held together by weak C−H···π interactions between the hydrogen atoms of the pyridyl group and the benzene ring of the benzimidazole moiety, as shown in Figure S5. The hydrogen bonding parameters are given in Table S3. The present method was extended to the construction of various heterocyclic skeletons, and the results are presented in Table 3. Reactions with 2-aminobenzothiazole instead of 2aminobenzimidazole gave benzothiazolopyrimidine derivatives 1470


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Table 2. Synthesis of Various Pyrimidine Derivatives Using the ZnO NP Catalyst in MCRs of 2-Aminobenzimidazole, Aromatic aldehydes, and Acetoacetatesa,b

a

Reaction conditions: 2-aminobenzimidazole (3 mmol), acetoacetate (3 mmol), aromatic aldehyde (3 mmol), ZnO NPs (0.4 mol %), 600 rpm, 20 milling balls (5 mm) in a milling jar (80 mL) at room temperature. bIsolated yield.

Figure 4. (A) ORTEP plot of the asymmetric unit of compound 16. (B) Dimers of compound 16 held together by N−H···N hydrogen bonds and repeated along the b-axis by C−H···O interactions.

score and high E-factor, the Liu et al. methodology, which also exhibits a high Ecoscale score and low E-factor, requires long reaction times and high temperature that adversely affect its importance. The present method has several advantages including a high Ecoscale score, low E-factor, short reaction time, high yield, and ease of purification. These parameters indicate the present methodology is a clean and green synthetic route for the

synthesis of benzoimidazopyrimidine, 2-oxo-tetrahydropyrimidine, and 2-thioxo-tetrahydropyrimidine derivatives. A plausible mechanism for the reaction is shown in Scheme 1. Due to their high surface defects, ZnO NPs have high affinity for imine groups,71 and the milling energy promotes electron transitions from the valence (VB) to the conduction band (CB).81,82 Thus, interaction of 2-aminobenzimidazole or 2aminobenzothiazole with ZnO NPs affords a radical anion I, 1471


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ACS Sustainable Chemistry & Engineering Table 3. Synthesis of Various Pyrimidine Derivativesa,b

a

Reaction conditions: 2-aminobenzothiazole (urea, or thiourea) (3 mmol), aromatic aldehyde (3 mmol), acetoacetate (3 mmol), ZnO NPs (0.4 mol %), 600 rpm, 20 milling balls (5 mm) in a milling jar (80 mL) at room temperature. bIsolated yield.

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CONCLUSION Different ZnO NPs were prepared using directing agents. Among the ZnO NPs, NS-5 afforded the highest yield of the desired product in MCRs of 2-aminobenzimidazole, aromatic aldehydes, and acetoacetates using a solvent-less ball milling technique. Catalyst NS-5 was recyclable up to five times without a decrease in catalytic activity. The present method was applied to the construction of various heterocyclic skeletons including benzoimidazopyrimidine, benzothiazolopyrimidine, 2-oxo-tetrahydropyrimidine, and 2-thioxo-tetrahydropyrimidine. Assessment of the method in terms of Ecoscale and Efactor showed that the present methodology provides a clean and green synthetic route for the synthesis of various pyrimidine derivatives. In addition, the present method could be performed on a multigram scale. Thus, the present method should find industrial applications.

Table 4. Physical Properties and Efficiency of the Recovered Catalyst entry 1 2

catalyst c

NS-5 NS-5d

size (nm)a

yield (%)b

15 90

82 45

a

Measured by DLS. bYield was determined by integration of the 1H NMR spectrum. cFreshly prepared NS-5. dNS-5 after the sixth catalytic reaction cycle.

Scheme 1. Plausible Mechanism for the Catalytic Synthesis of Pyrimidine Derivatives

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EXPERIMENTAL SECTION

Synthesis of Structural Directing Agents and ZnO NPs. Capping agents were prepared using a literature method.83 ZnO NPs were prepared in the presence of structural directing agents using a sol−gel method.71,72 A solution of Zn(ClO4)2 (529 mg, 2 mmol) and NaOH (120 mg, 3 mmol) along with the respective structural directing agent (7 mmol) in MeOH (20 mL) was heated to reflux for 2 h. After filtration, a yellow product was obtained. The capping agent was removed from the nanoparticle surface by heating at 500 °C for 6 h. The presence of a wurtzite type structure for ZnO NPs was confirmed by PXRD analysis. Morphology and size measurements of ZnO NPs were carried out using SEM and DLS analyses. General Procedure for MCRs. A mixture of acetoacetate (3 mmol), aromatic aldehyde (3 mmol), amine (3 mmol), and NS-5 (0.4 mol %) in a milling jar (80 mL) was milled with 20 milling balls (5 mm) at 600 rpm for 40 min at room temperature under argon. The product was recrystallized from an acetone/water mixture. Spectroscopic data of products were in agreement with those previously reported.56,84−87

which undergoes Michael addition with an intermediate produced by Knoevenagel condensation44 of the aldehyde and β-ketoester, to give the radical anion II. Intermediate II expels an electron and undergoes intramolecular condensation to generate the final product.45 To confirm the formation of radical intermediates, a reaction was performed in the presence of a radical scavenger, 2,2,6,6-tetramethylpiperidinyloxyl. In the presence of radical scavenger, no reaction took place. 1472


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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b02030. DLS studies, SEM images, crystallographic data for compound 16 (CCDC 1044213) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*N. Kaur. E-mail: [email protected]. *N. Singh. E-mail: [email protected]. *D. O. Jang. E-mail: [email protected]. ORCID

Thammarat Aree: 0000-0002-7298-7401 Navneet Kaur: 0000-0002-0012-6151 Narinder Singh: 0000-0002-8794-8157 Doo Ok Jang: 0000-0003-3234-955X Author Contributions

T.R. and H.S. contributed equally. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS H.S. is thankful to IIT Ropar for a fellowship. REFERENCES

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