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3-[(3-(Trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid: An efficient recyclable heterogeneous catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
⁎Corresponding author. Tel.: +91 734 2511321; fax: +91 734 2530962. srinujetti479@gmail.com (Srinivasa Rao Jetti)
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Received: ,
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This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
An efficient method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones through one-pot three-component reaction of ethyl acetoacetate, aryl aldehyde and urea or thiourea in ethanol using 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid as catalyst is described. The use of 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid as a catalyst offers several advantages such as high yields, short reaction times, mild reaction condition and a recyclable catalyst with a very easy work up.
Keywords
3-[(3-(Trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid
Heterogeneous catalysis
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-ones/thiones
1 Introduction
Dihydropyrimidinones (DHPMs) and their derivatives are well known heterocyclic units in the realm of natural and synthetic organic chemistry due to their wide spectrum of biological and therapeutic properties such as antibacterial, antiviral, antitumor and anti-inflammatory activities (Kappe, 1993, 2000; Kappe et al., 1997). Recently, functionalized DHPM analogs have emerged as integral backbones of several calcium channel blockers, antihypertensive agents and α-la-adrenergic receptor antagonists (Atwal et al., 1990; Nagarathnam et al., 1999; Patil et al., 1995). Moreover, several alkaloids containing the dihydropyrimidine core unit that has been isolated from marine sources also showed interesting biological properties, e.g. the batzelladine alkaloids have been found to be potent HIV gp-120-CD4 inhibitors (Patil et al., 1995; Snider et al., 1996).
Biginelli reaction has received renewed interest and several improved reaction protocols have recently been reported (Yu et al., 2011; Hajipour and Seddighi, 2012). Different acid catalysts including chiral phosphoric acids (Li et al., 2011), inorganic solid acids such as zeolite (Radha Rani et al., 2001), mesoporous silica (Choudhary et al., 2003) and Lewis acids as well as protic acids such as concentrated HCl (Saloutin et al., 2000), BF3 (Hu et al., 1998), polyphosphonate ester (Kappe and Falsone, 1998), montmorillonite (Bigi et al., 1999), InCl3 (Ranu et al., 2000), ceric ammonium nitrate (Yadav et al., 2001), Amberlyst 70 (Hemant Chandak et al., 2009) and many ionic salts (Shaabani et al., 2003) have been established as effective catalysts. However, in spite of their potential utility, many of these one-pot protocols suffer from drawbacks such as the use of expensive reagents, strong acidic conditions and long reaction times. Therefore, the methods with milder reaction conditions and higher yields are still needed.
Recently, solid-supported reagents like silica-supported acids, have gained considerable interest in organic synthesis because of their unique properties such as high efficiency due to more surface area, more stability and reusability, low toxicity, greater selectivity and ease of handling (Hajipour and Ruoho, 2005; Kantevari et al., 2007; Shaterian et al., 2009). Although, the catalytic applications of silica supported reagents for organic synthesis have been reported (Hitendra Karade et al., 2007), there seems to be no report in the literature on the use of 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid (TMSPTPOSA) as the catalyst in Biginelli reaction.
Therefore, herein we report the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones by the reaction of β-ketoester with urea (or thiourea) and aromatic aldehydes using TMSPTPOSA as heterogeneous catalyst. The preparation of catalyst IV is outlined in Scheme 1 with slight modification than the earlier reported method (Das et al., 2006).![Preparation of 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.12.012-fig1.png)
Preparation of 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid.
2 Experimental
2.1 Materials and methods
Products obtained are all known compounds and were identified by comparing their physical and spectral data (1H NMR, 13C NMR, IR, and Mass) with those reported in the literature. Melting points were obtained on an Electrothermal IA 9100 melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded in DMSO-d6 and CDCl3 on a Varian Mercury Plus 300 MHz and mass spectra were taken by Micromass Quattro LC–MS–MS instruments. Benzaldeyhde was purified by distillation. Other chemicals were of commercial grade and used without further purification.
2.2 Catalyst preparation
2.2.1 Synthesis of 3-mercaptopropylsilica (MPS) (II)
Silica (K100, 0.063–0.200 mm) was activated by refluxing in a mixture of conc. HCl and distilled water (1:1) for 24 h and then washed thoroughly with distilled water and dried at 110 °C for 12 h. The activated silica (10 g) was added to a solution of 3-mercaptopropyl (trimethoxy)silane (10 mmol) in dry toluene and refluxed for 18 h. The 3-mercaptopropyl silica (MPS) was filtered off, washed with hot toluene and dried at 110 °C for 5 h to give the surface bound thiol (MPS) groups.
2.2.2 3-(3-Silicapropylthio)-1-propanol (III)
3-Chloro-1-propanol (5 mmol, 0.473 g) was added to a magnetically stirred solution of 3-mercaptopropylsilica (10 g) in toluene (30 ml) followed by few drops of triethyl amine. The resulting mixture was refluxed for 24 h. Then the mixture was filtered and the solid was washed with ethanol (20 ml × 3) and then dried in an oven at 110 °C. 3-(3-Silicapropylthio)-1-propanol (III) was obtained as a cream powder (10.3 g).
2.2.3 3-[(3-(Trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid (TMSPTPOSA) (IV)
To a mixture of 3-(3-silicapropylthio)-1-propanol (5 g) in chloroform (20 ml), chlorosulfonic acid (0.19 g, 1.65 ml) was added dropwise at 0 °C over 2 h. After the addition was complete the mixture was stirred for 2 h until HCl gas evolution stopped. The solid obtained was filtered and washed with ethanol (30 ml) and dried at room temperature to give 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid as a cream powder (5.13 g). The sulfur content of the samples by conventional elemental analysis was 15.51%.
2.3 General procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones 4a–m using TMSPTPOSA as catalyst
A mixture of ethyl acetoacetate 1 (5 mmol), aryl aldehyde 2 (5 mmol), urea or thiourea 3 (6 mmol), TMSPTPOSA (0.3 g) and ethanol (15 mL) was heated under reflux for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered immediately. A solid was precipitated in the filtrate on cooling which was filtered and recrystallized from ethanol to give 4a–m in good to excellent yields (see Scheme 2).
TMSPTPOSA catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones.
3 Results and discussion
3-[(3-(Trimethoxysilyl)propyl)thio]propane-1-oxy-sulfonic acid IV was prepared by the reaction of 3-(3-silicapropylthio)-1-propanol with chlorosulfonic acid in chloroform. Elemental analysis showed the S content to be 15.51%. Typically a loading at approximately 0.35 mmol/g is obtained. On the other hand, when the washed sulfonated product IV was placed in an aqueous NaCl solution, the solution pH dropped virtually instantaneously to pH ∼1.93, as ion exchange occurred between protons and sodium ions’ proton exchange capacity: 0.33 mmol/g of sulfonic acid IV.
The thermo gravimetric analysis (TGA) seems to indicate two-stage decomposition which is considered to be due to the removal of physically absorbed water (100–130 °C) or basic silica sulfonic acid (150–230 °C), respectively, and is involved with a total overall weight loss of catalyst 43.1%. The BET surface area and total pore volume of 3-[(3-(trimethoxysilyl)propyl) thio]propane-1-oxy-sulfonic acid were found to be 4.35 m2g−1 and 0.63 cm3g−1, respectively.
In the FT-IR spectrum of catalyst, the major peaks for silica (SiO2) are broad non-symmetric Si–O–Si stretching from 1300 to 1010.6 cm−1 and symmetric Si–O–Si stretching near 880–852.5 cm−1. For the sulfuric acid functional group, the FT-IR absorption range of the O–S–O asymmetric and symmetric stretching modes lies in 1170 and 1060 cm−1, respectively, the S–O stretching model lies around 574.7 cm−1. The FT-IR spectrum shows the overlap asymmetric and symmetric stretching bands of SO2 with Si–O–Si stretching bands in the silica functionalized alkyl-sulfuric acid. The spectrum also shows a broad OH stretching absorption around 3600–2520 cm−1.
In order to optimize the reaction conditions, the synthesis of compound 4a was used as a model reaction. Therefore, a mixture of ethyl acetoacetate (5 mmol), benzaldehyde (5 mmol), and urea (6 mmol) in different amounts of TMSPTPOSA was taken (Table 1). The efficiency of the reaction is mainly effected by the amount of the catalyst. No product could be detected in the absence of the catalyst even after 10 h (entry 1), while good results were obtained in the presence of TMSPTPOSA. The optimal amount of the catalyst was 0.3 g (entry 4); the higher amount of the catalyst did not increase the yield noticeably (entries 5, 6). It is clearly evident from Table 1 that the reaction is catalyzed by TMSPTPOSA and the maximum yield of the product is obtained with 0.3 g of the catalyst.
| Entry | Catalyst | Catalyst loading (g) | Time (h) | Yielda (%) |
|---|---|---|---|---|
| 1 | No Catalyst | – | 10.0 | – |
| 2 | TMSPTPOSA | 0.1 | 6.5 | 70 |
| 3 | TMSPTPOSA | 0.2 | 5.0 | 78 |
| 4 | TMSPTPOSA | 0.3 | 3.0 | 95 |
| 5 | TMSPTPOSA | 0.4 | 3.0 | 93 |
| 6 | TMSPTPOSA | 0.5 | 4.0 | 94 |
Reaction conditions: ethyl acetoacetate (5 mmol), benzaldehyde (5 mmol), urea (6 mmol), in ethanol under reflux.
The effect of temperature on the same model reaction to synthesize 4a has also been investigated. The reaction was carried out by changing the temperature from 50 to 100 °C. Yields of the product at different temperatures are listed in Table 2. From the Table 2 it is evident that the reaction is more efficient at 80 °C and gave 95% of the yield.
| Entry | Amount of catalyst (gm) | Reaction temperature (°C) | Yields (%) |
|---|---|---|---|
| 1 | 0.3 | 50 | 65 |
| 2 | 0.3 | 60 | 79 |
| 3 | 0.3 | 70 | 87 |
| 4 | 0.3 | 80 | 95 |
| 5 | 0.3 | 90 | 94 |
| 6 | 0.3 | 100 | 93 |
Reaction conditions: ethyl acetoacetate (5 mmol), benzaldehyde (5 mmol), urea (6 mmol), in ethanol under reflux.
Based on the above optimized results, i.e. 0.3 g amount of TMSPTPOSA as a catalyst and the reaction temperature being 80 °C we further examined the effects of the reaction time on the same model reaction. The results are summarized in Table 3. It was found that with the increase of reaction time from 1 h to 3 h the yield of 4a increased from 86% to 95% (Table 3, entries 1–3) but by the reaction time more than 3 h the yield of the product gradually decreased due to the decomposition of the product (Table 3, entries 4,5).
| Entry | Amount of catalyst (g) | Reaction temperature (°C) | Reaction time (H) | Yields (%) |
|---|---|---|---|---|
| 1 | 0.3 | 80 | 1 | 86 |
| 2 | 0.3 | 80 | 2 | 90 |
| 3 | 0.3 | 80 | 3 | 95 |
| 4 | 0.3 | 80 | 4 | 94 |
| 5 | 0.3 | 80 | 5 | 92 |
Reaction conditions: ethyl acetoacetate (5 mmol), benzaldehyde (5 mmol), urea (6 mmol), TMSPTPOSA (0.3 g) in ethanol under 800C reflux temperature.
This work has also been extended to observe the effect of solvent on the reaction (Table 4 entries 1–6) and ethanol was found to be the best solvent when considering the reaction yields and environmental damage (Table 4 entry 3).
| Entry | Catalyst | Solvent | Time (h) | Yield (%) |
|---|---|---|---|---|
| 1 | TMSPTPOSA | CH3OH | 4 | 73 |
| 2 | TMSPTPOSA | CH3CN | 5 | 82 |
| 3 | TMSPTPOSA | C2H5OH | 3 | 96 |
| 4 | TMSPTPOSA | CH2Cl2 | 7 | 68 |
| 5 | TMSPTPOSA | CHCl3 | 10 | 57 |
| 6 | TMSPTPOSA | THF | 10 | 48 |
An additional important feature of the present protocol is the ability to tolerate variation in the components simultaneously as compared to the classical Biginelli reaction. Most importantly, many of the pharmacological relevant substitution patterns on the aromatic ring could be introduced without any interruption in efficiency. Aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents afforded high yields of products in high purity. Thiourea has been used with similar success to provide the corresponding dihydro pyrimidin-2(1H)-thiones, which are also of much interest with regard to the biological activity (Table 5).
| Entry | Ar | X | Time (h) | Product | Yield (%)b | M.p (found) (°C) | M.p (lit.) (°C) |
|---|---|---|---|---|---|---|---|
| 1 | C6H5 | O | 3 | 4a | 95 | 202–204 | 201–204e |
| 2 | 4-Cl-C6H4 | O | 3 | 4b | 76 | 215–217 | 214–217e |
| 3 | 3-HO-C6H4 | O | 4 | 4c | 77 | 168–171 | 167–170c |
| 4 | 4-HO-C6H4 | O | 4 | 4d | 71 | 236–238 | 237–238d |
| 5 | 4-CH3O-C6H4 | O | 3 | 4e | 94 | 201–203 | 202–204e |
| 6 | 4-CH3-C6H4 | O | 4 | 4f | 87 | 216–218 | 215–217e |
| 7 | 3-NO2-C6H4 | O | 3 | 4g | 79 | 224–226 | 225–228e |
| 8 | 4-NO2-C6H4 | O | 5 | 4h | 83 | 206–208 | 205–209e |
| 9 | C6H5 | S | 4 | 4i | 85 | 208–210 | 209–211e |
| 10 | 4-Cl-C6H4 | S | 3 | 4j | 92 | 192–193 | 191–195e |
| 11 | 3-HO-C6H4 | S | 4 | 4k | 84 | 182–184 | 183–184c |
| 12 | 4-HO-C6H4 | S | 4 | 4l | 91 | 201–204 | 202–203d |
| 13 | 4-CH3O-C6H4 | S | 3 | 4m | 73 | 154–156 | 155–156c |
In order to show the merit of the present work in terms of time, yield and reaction conditions in comparison to the earlier reported works, the results of the present study were compared with those of the earlier studies (Table 6). As can be seen from Table 6, the present method is simpler, more efficient for the synthesis of dihydropyrimidinone derivatives.
| Catalyst | Conditions | Yield (%) | Time (h) | References |
|---|---|---|---|---|
| Montmorillonit KSF | Solvent-free/130 °C | 70–88 | 48 | Bigi et al. (1999) |
| Yb(III)-resin | Solvent-free/120 °C | 63–80 | 48 | Dondoni and Massi (2001) |
| Ceric ammonium nitrate | Sonication/MeOH | 84–92 | 5–7 | Yadav et al. (2001) |
| ZrCl4 | Reflux EtOH | 83–94 | 5–6 | Reddy et al. (2002) |
| In(OTf)3 | Reflux EtOH/N2 | 82–95 | 4–13.5 | Ghosh et al. (2004) |
| TMSPTPOSA | Reflux EtOH | 90–95 | 3 | Present work |
The following mechanism has been proposed for the formation of DHPs illustrating the role of TMSPTPOSA in its formation (Scheme 3). Thus the catalyst makes the nitrogen electro positive by protonation thereby making it more reactive toward enolate ion. The reactions were carried out using different aldehydes and the results are reported in Table 5. The results show that introduction of the electron withdrawing group in the aldehyde decreases the yield of the product while introduction of the electron donating group increases the yield. This may be because of the fact that the electron withdrawing group decreases the electron availability on nitrogen whereas the electron donating group increases the electron availability for protonation. This observation supports the proposed mechanism.
Proposed mechanism for the formation of pyrimidine derivative.
3.1 Recycling and reusing the catalyst
The reusability of the catalyst was also investigated. For this purpose, the same model reaction to synthesize compound 4a was studied by the reaction of ethyl acetoacetate (5 mmol), benzaldehyde (5 mmol), urea (6 mmol) and TMSPTPOSA (0.3 g) under optimized reaction conditions. After completion of the reaction the catalyst, recovered by filtration was washed with diethyl ether, dried at 100 °C under vacuum for 2 h and reused in another reaction. The catalyst was reused twelve times and a variable catalytic activity was observed which may be due to the incorporation of impurities (Fig. 1).
Reusability of TMSPTPOSA.
4 Conclusion
The synthesis of dihydropyrimidin-2(1H)-ones and thiones through one-pot three-component reaction of ethyl acetoacetate, aryl aldehyde and urea or thiourea using TMSPTPOSA as catalyst is a green method with high yields and mild reaction conditions. The catalyst can be reused after a simple work-up. Thus TMSPTPOSA is a better catalyst than the earlier reported ones due to good to excellent yields, relatively short reaction times, simple operation and easy work-up of this protocol.
Acknowledgments
The authors are thankful to the Madhya Pradesh Council of Science & Technology (MPCOST, Bhopal) for the financial support.
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