Choline hydroxide promoted chemical fixation of CO₂ to quinazoline-2,4(1H,3H)-diones in water

Abstract

The efficient conversion of CO₂ to high value-added chemicals in water with cheap and non-toxic catalysts is a very attractive topic in green chemistry. In this work, the transformation of CO₂ and 2-aminobenzonitriles to quinazoline-2,4(1H,3H)-diones in water promoted by choline hydroxide has been studied. The effect of temperature, pressure, reaction time, and amount of catalyst on the reaction were investigated and the reaction conditions were optimized. It was demonstrated that choline hydroxide showed supernormal catalytic activity to promote this reaction as a biodegradable, environmentally friendly, green and cheap material showed supernormal catalytic activity to promote this reaction. Furthermore, the reaction mechanism was discussed.

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Introduction

CO₂ is not only a major greenhouse gas, but also an abundant, non-toxic, non-flammable, easily available, and renewable carbon source.^1–3 Considerable attention has been paid to the conversion of CO₂ into useful compounds during the past few decades.^4–8 Many chemicals have been synthesized using CO₂ as a raw material such as dimethyl carbonate,^9,10 cyclic carbonates,^11,12 N,N′-disubstituted ureas,^13,14 urethanes,¹⁵ formic acid,¹⁶ methyl formate,¹⁷ etc.

Quinazoline-2,4(1H,3H)-diones, as pharmaceutical intermediates and biologically active additives, are an important class of pharmaceutical intermediates and have a wide range of applications.^18–21 In recent years, the synthesis of quinazoline-2,4(1H,3H)-diones from CO₂ and 2-aminobenzonitriles (Scheme 1) has attracted considerable interest. In this case, not only value-added quinazoline-2,4(1H,3H)-diones are synthesized but CO₂ is also utilized effectively as the raw material. Up to now, numerous catalysts have been developed to catalyze the reaction of CO₂ and 2-aminobenzonitriles such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),^22,23 Cs₂CO₃,²⁴ ionic liquids 1-butyl-3-methylimidazolium hydroxide²⁵ and 1-butyl-3-methylimidazolium acetate,²⁶ MgO–ZrO₂,²⁷ 1,1,3,3-tetramethylguanidine,²⁸ N-methyltetrahydropyrimidine,²⁹ and TBA₂[WO₄] (TBA = tetra-n-butylammonium).^30,31 However, in most cases, organic solvents are used in the reactions. Recently, our group has reported that this kind of reaction could proceed in water without any catalyst at higher pressure and temperature.³² Although the reaction of CO₂ with 2-aminobenzonitriles to produce quinazoline-2,4(1H,3H)-diones has been studied extensively, the design of highly effective and cheap catalysts is still desirable.

Scheme 1 Reactions of CO₂ and 2-aminobenzonitriles (1) to form quinazoline-2,4(1H,3H)-dione (2).

In this work, we used choline hydroxide (Fig. 1) to catalyze the formation of quinazoline-2,4(1H,3H)-diones from CO₂ and 2-aminobenzonitriles in water (Scheme 1). It was found that this abundant, natural, environmentally benign and cheap material could promote the reaction very efficiently in water. Further study showed that the HCO₃⁻, formed from hydroxyl group in choline hydroxide and carbonic acid (H₂CO₃), was crucial for the very high efficiency of the catalyst.

Fig. 1 Structure of choline hydroxide.

Experimental

Materials

2-Aminobenzonitrile (1a) (purity >99%), L-arginine (purity >99%) and L-histidine (purity >98%) were provided by J&K Scientific Ltd. 2-amino-4,5-dimethoxybenzonitrile (1b) (purity >99%) was purchased from Matrix Scientific. 2-amino-5-chlorobenzonitrile (1c) (purity >99%) and 2-amino-5-bromobenzonitrile (1e) (purity >98%) were obtained from Fluorochem Ltd. 2-amino-4-chlorobenzonitrile (1d) (purity >99%) and choline hydroxide 20 wt% in water were supplied by Sigma-Aldrich Co. Betaine (anhydrous, purity >98%) was purchased from Alfa-Aesar Co. Analytical grade Cs₂CO₃ and KF·2H₂O were provided by Sinopharm Chemical Reagent Beijing Co., Ltd. Analytical grade Et₃N was purchased by Beijing Chemical Reagents Company. CO₂ was supplied by Beijing Analytical Instrument Factory with a purity of 99.99%. The deuterated solvent (DMSO-d₆) was provided by Cambridge Isotope Laboratories, Inc.

Synthesis of quinazoline-2,4(1H,3H)-diones

All the reactions were conducted in a stainless steel reactor with a capacity of 22 mL equipped with a magnetic stirrer. As an example, the procedure using 1a as the substrate is described, which is similar to those used for other substrates. In a typical experiment, 1a (5 mmol) and a suitable amount of choline hydroxide aqueous solution of 20 wt% were added into the reactor. The air in the reactor was removed using a flow of CO₂ through the reactor. CO₂ was charged into the reactor until the desired pressure was achieved. After sealing, the reactor was placed in an oil bath at the desired temperature and the reaction mixture was stirred. After a certain period of time, the reactor was placed in an ice-water bath for 20 min and CO₂ was released slowly. Then, water was added into the reactor. The mixture was centrifuged to precipitate the product. The aqueous solution of choline hydroxide was removed. The product was washed with water (ethyl alcohol when the catalyst was Et₃N) (3 × 25 mL) to remove the choline. Then, the precipitate was washed with tert-butyl methyl ether 3 times (25 mL each time) to remove the remnant reactants from the product. Finally, the mass of the product was determined by an electronic balance (Mettler-Toledo) with an accuracy of 0.1 mg after drying at 95 °C for 3 hours. The purity and structure of the products were characterized by NMR spectroscopy and elemental analysis. ¹H NMR and ¹³C NMR was carried out using a Bruker AV400 (400 MHz, 100 MHz) NMR spectrometer with DMSO-d₆ as the solvent. Elemental analyses for C, H and N were carried out with a Flash EA 1112 elemental analyzer. Characterization data of the products (2a–2e) are reported below.

Quinazoline-2,4(1H,3H)-dione (2a). ¹H NMR (400 MHz, DMSO-d₆) δ = 11.25 (s, 1H), 11.11 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.21–7.04 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ = 162.83, 150.26, 140.82, 134.78, 126.89, 122.24, 115.20, 114.35. C₈H₆N₂O₂: calcd C 59.26, H 3.73, N 17.28; found C 59.13, H 3.78, N 17.30.

6,7-Dimethoxyquinazoline-2,4(1H,3H)-dione (2b). ¹H NMR (400 MHz, DMSO-d₆) δ = 11.09 (s, 1H), 10.92 (s, 1H), 7.23 (s, 1H), 6.68 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ = 162.43, 154.87, 150.35, 145.06, 136.58, 107.09, 106.20, 97.72, 55.75, 55.65. C₁₀H₁₀N₂O₄: calcd C 54.05, H 4.54, N 12.61; found C 54.21, H 4.60, N 12.51.

6-Chloroquinazoline-2,4(1H,3H)-dione (2c). ¹H NMR (400 MHz, DMSO-d₆) δ = 11.30 (s, 2H), 7.77 (s, 1H), 7.62 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ = 161.91, 150.08, 139.83, 134.75, 126.22, 125.94, 117.51, 115.81. C₈H₅N₂O₂Cl: calcd C 48.88, H 2.56, N 14.25; found C 48.91, H 2.63, N 14.16.

6-Bromoquinazoline-2,4(1H,3H)-dione (2d). ¹H NMR (400 MHz, DMSO-d₆) δ = 11.29 (s, 2H), 7.90 (s, 1H), 7.74 (d, J = 5.9 Hz, 1H), 7.10 (d, J = 6.5 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ = 161.78, 150.05, 140.03, 137.50, 128.86, 117.71, 116.22, 113.83. C₈H₅N₂O₂Br: calcd C 39.86, H 2.09, N 11.62; found C 39.96, H 2.06, N 11.68.

7-Chloroquinazoline-2,4(1H,3H)-dione (2e). ¹H NMR (400 MHz, DMSO-d₆) δ = 11.26 (s, 2H), 7.84 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ = 162.13, 150.21, 141.95, 139.25, 129.03, 122.51, 114.64, 113.29. C₈H₅N₂O₂Cl: calcd C 48.88, H 2.56, N 14.25; found C 48.97, H 2.65, N 14.19.

Results and discussion

Activity of various catalysts

The activity of various catalysts was tested using the reaction of 1a and CO₂ to produce 2a at 90 °C and 2 MPa, and the results are summarized in Table 1. Clearly, without the catalyst, the reaction of 1a and CO₂ did not occur with or without solvent (entry 1 to 3). It is well-known that bases can act as an effective catalyst for CO₂-based transformations if the basicity is appropriate. Hence, the activity of some basic compounds, such as Cs₂CO₃, KF·2H₂O, and Et₃N, were investigated. It was shown that the alkali carbonate Cs₂CO₃ could catalyze the reaction in water giving an isolated yield of 48% (entry 4) and the inorganic base KF·2H₂O gave only an 8% isolated yield of 2a (entry 5). Et₃N also had moderate catalytic activity, and the yield of 2a was 66%. In addition, some other environmentally friendly and biocompatible catalysts were investigated. L-Arginine could produce a yield of 59% (entry 7), while L-histidine was not active in this reaction (entry 8) under the same reaction conditions. Entry 9 shows an isolated yield of 3%, which indicates that the catalytic activity of betaine was very low to promote the reaction of CO₂ and 1a. However, a satisfactory isolated yield (92%) of 2a was obtained in the presence of choline hydroxide solution (20 wt% in water), which acted as the catalyst and reaction medium (entry 10). The catalytic activity of choline hydroxide was significantly better than that of the other investigated catalysts. Furthermore, this natural material is non-toxic, cheap and abundant. Therefore, from a viewpoint of efficiency and green chemistry, choline hydroxide/water was chosen to be the catalyst/solvent for promoting the reaction of CO₂ and 2-aminobenzonitriles.

Table 1 Influence of various catalysts on the synthesis of 2a from 1a and CO₂^a

Entry	Catalyst	Solvent	Yield^b (%)
a Reaction conditions: 1a 5 mmol, catalyst 5 mmol, CO2 2.0 MPa, 24 h, 90 °C. The volume of the catalyst aqueous solution was 3 mL in all the experiments.b Isolated yield.
1	—	None	0
2	—	Water	0
3	—	DMF	0
4	Cs2CO3	Water	48
5	KF·2H2O	Water	8
6	Et3N	Water	66
7	L-Arginine	Water	59
8	L-Histidine	Water	0
9	Betaine	Water	3
10	Choline hydroxide	Water	92

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The effect of the catalyst amount

In this work, an aqueous solution containing 20 wt% choline hydroxide was used as the catalyst. Hereafter, the amount of the catalyst refers to the mass of the solution. Fig. 2 shows the effect of the amount of catalyst on the yield of the target product 2a. The yield increased with an increasing amount of catalyst. The yield reached 92% using a catalyst amount of 3.0 g. Further increases in the amount of catalyst did not notably affect the yield.

Fig. 2 Effect of the amount of catalyst (20 wt% choline hydroxide solution) on the isolated yield of 2a. Reaction conditions: 1a (5 mmol), CO₂ (2.0 Mpa), 90 °C, 24 h.

The influence of CO₂ pressure

Fig. 3 shows the effect of CO₂ pressure on the yield of 2a at 90 °C with a reaction time of 24 h. CO₂ pressure had a considerable effect on the yield of the product. At the beginning, the yield of the product increased dramatically with an increase in the pressure, and then increased gradually with further increasing pressure. The yield became independent of the pressure above 2 MPa.

Fig. 3 Effect of CO₂ pressure on the isolated yield of 2a. Reaction conditions: 1a (5 mmol), catalyst (3.0 g, 20 wt% choline hydroxide solution), 90 °C, 24 h.

Effect of temperature

As shown in Fig. 4, the yield of 2a strongly depended on reaction temperature. At lower temperatures, the yield increased with increasing temperature. The yield reached 92% at 90 °C, and then remained unchanged with further increasing temperature.

Fig. 4 Dependence of the isolated yield of 2a on temperature. Reaction conditions: 1a (5 mmol), catalyst (3.0 g, 20 wt% choline hydroxide solution), CO₂ (2.0 Mpa), 24 h.

Influence of reaction time

Fig. 5 shows the effect of reaction time on the yield of 2a. The results in the figure indicates that the isolated yield of product 2a increased gradually as the reaction time was prolonged. When the reaction time was 24 h, the isolated yield was 92%, and there was no change in the yield with further extension of time. The yield was below 100% because some product was lost in the separation and purification process.

Fig. 5 Dependence of the isolated yield of 2a on reaction time. Reaction conditions: 1a (5 mmol), catalyst (3.0 g, 20 wt% choline hydroxide solution), CO₂ (2.0 Mpa), 90 °C.

Different substrates

Using choline hydroxide as the catalyst, reactions of CO₂ with other substituted 2-aminobenzonitriles in water were also examined at 90 °C and 2 MPa. The results showed that choline hydroxide was active for all the investigated substrates. The reaction of 1a with CO₂ provided 92% yield of 2a under the selected reaction conditions (Table 2, entry 1). The presence of electron-donating group has a slight influence on the reaction, and the yield of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione (2b) was 94% (entry 2). The reactivity of meta-halogen substituted 2-aminobenzonitriles was also investigated. Experimental results showed that 2-amino-5-chlorobenzonitrile (1c) and 2-amino-5-bromobenzonitrile (1d) could react smoothly with CO₂ giving a yield of 91% and 88%, respectively (entries 3, 4). Whereas, 2-amino-4-chlorobenzonitrile (1e) provided only 79% yield of 7-chloroquinazoline-2,4(1H,3H)-dione (2e) under the experimental conditions (entry 5), which was partly due to the electron-withdrawing effect on basicity.

Table 2 Synthesis of various quinazoline-2,4(1H,3H)-diones (2a–e)^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: reactant 5 mmol, catalyst 3.0 g (20 wt% choline hydroxide solution), CO2 2.0 MPa, 24 h, 90 °C.b Isolated yield.c Reaction time 50 h.
1			92
2			94
3			91
4			88
5			79^c

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Reaction mechanism

Based on the reaction mechanism of these kind of reactions discussed previously,³³ we proposed the probable catalytic cycle for the reaction of CO₂ with 1a to yield 2a using choline hydroxide as a catalyst, which is depicted in Scheme 2. It is well-known that CO₂ can form carbonic acid (H₂CO₃) in water, which can further react with the hydroxide group of the choline to form an ion-pair A (choline bicarbonate) easily. After the formation of choline bicarbonate, the hydroxyl H of HCO₃⁻ migrates to the N atom of the nitrile group of 1a, accompanied by the nucleophilic attack of the carbonyl O atom of HCO₃⁻ on the C atom of the nitrile group, and the structure B is formed. Following a series of rearrangement steps, the intermediate C is formed. Finally, with the insertion of CO₂ molecule and the removal of HCO₃⁻ anion, the target product 2a is formed. At the same time, the choline bicarbonate regenerates and participates in the next catalytic cycle.

Scheme 2 Plausible mechanism for the reaction of CO₂ and 1a catalyzed by choline hydroxide aqueous solution.

Conclusions

A series of quinazoline-2,4(1H,3H)-diones can be synthesized in high isolated yields via the reaction of CO₂ with 2-aminobenzonitriles catalyzed by choline hydroxide in water under mild conditions. In this case, the use of an organic solvent is avoided and the catalyst choline hydroxide is cheap and abundant. We believe that this efficient and green catalytic system has potential applications for synthesizing quinazoline-2,4(1H,3H)-diones from CO₂ and 2-aminobenzonitriles.

Acknowledgements

The authors thank the National Natural Science Foundation of China (21303224, 21173239, 21133009), the Chinese Academy of Sciences (KJCX2.YW.H30) and the Institute of Chemistry, Chinese Academy of Sciences (CMS-PY-201318).

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