Facile and green synthesis of Hantzsch derivatives in deep eutectic solvent

1 Introduction

The Hantzsch reaction is an old but very famous reaction because it offers an effective way to construct 1,4-dihydropyridines (1,4-DHPs) which exhibit significant biological activities [1–4]. Up until now, several commercial, clinically important drugs such as amlodipine, nifedipin, nimodipine, felodipine, isradipine and nicardipine containing the 1,4-DHP parent nucleus have been manufactured and used worldwide (Figure 1).

Figure 1

Selective examples of 1,4-dihydropyridine derivatives.

Traditionally, 1,4-DHPs are prepared via the three-component condensation of aldehyde, β-ketoester and ammonia, namely the Hantzsch reaction [5]. However, this method suffers from some drawbacks such as long reaction time (∼20 h) and harsh reaction condition (in refluxing acetic acid or alcohol) while affords the products in low yields (low to moderate yields). Recently, numerous efficient methods have been developed for the synthesis of 1,4-DHP derivatives, including the use of microwave [6], solar thermal energy [7], ultrasound irritation [8], autoclave [9], ionic liquids [10], Lewis acids [11, 12], ceric ammonium nitrate (CAN) [13], organocatalyst [14] and Brønsted acids [15, 16]. Among them, polyhydroacridines (PHA) and polyhydroquinolines (PHQ) are two kinds of 1,4-DHPs that have received less attention than other 1,4-DHP derivatives. PHA are usually synthesized by one-pot condensation of dimedone, aldehydes and ammonium acetate under microwave irradiation [17, 18] and solvent-free condition [19]. Ionic liquid [20] and organocatalyst [21] were also employed for such transformation. PHQ are generally synthesized by an unsymmetrical Hantzsch reaction, which involves the one-pot, four-component condensation of dimedone, aldehydes, ethylacetoacetate and ammonium acetate, using various catalysts or reagents such as montmorillonite K-10 [22], Lewis acids [11, 23, 24], cerium (IV) ammonium nitrate [13] and trifluoroethanol [25]. Syntheses of these compounds using microwave irradiation [26], solar thermal energy [7] and grinding [27] have also been reported. Although great advances have been achieved, limitations including expensive reagents, unsatisfactory yields, long reaction time, tedious work-up as well as unrecyclability of the catalysts are still the major problems of the reported methods. Thus, a simple, efficient and eco-friendly protocol for such useful transformation is still in demand.

Recently, deep eutectic solvents (DES) have received wide attention as green solvents or catalysts in organic reactions due to their good properties such as low vapor pressure, low flammability and biodegradability [28]. Moreover, the DES are usually non-toxic and inexpensive. One of the most explicit examples is the mixing one mole of choline chloride (ChCl) with two moles of urea (with melting points of 247°C and 133°C, respectively), which results in a DES with a room temperature melting point [29]. It was worth noting that ChCl and urea are naturally occurring biocompatible compounds and they are also commercially produced on a large scale [30]. They also have shown potential applications as both solvents and catalysts in organic reactions such as epoxide hydrolysis [31], nitroaldol reaction [32], C-C bond formation reaction [33], alkylation of amines [34] and oxidative hydroxylation [35].

As a part of our program for green chemistry [35], herein, we wish to report a simple, efficient and reusable reaction system for one-pot synthesis of PHA and PHQ through the Hantzsch reaction (Scheme 1).

Scheme 1

One-pot synthesis of PHA and PHQ derivatives in ChCl/urea.

2 Materials and methods

3 Results and discussion

The DES ChCl/urea was readily prepared by mixing ChCl (1 mol) with urea (2 mol) at 100°C until a clear solution was obtained (30 min) which was directly used without any purification. Other DES could also be prepared in a similar way. Initially, a mixture of 5,5-dimethylcyclohexane-1,3-dione (1), benzaldehyde (2a) and ammonium acetate (3) was chosen as the model reaction to examine the reaction conditions. Results are summarized in Table 1. A 61% yield of product was obtained under solvent-free conditions. Other DES such as ChCl/p-TsOH (1:1), ChCl/malonic acid (1:2), ChCl/glycerol (1:2), ChCl/HFIP (1:1.5) and ChCl/ZnCl₂ (1:2) provided the products in low to moderate yields. ChCl/urea was found to be the best choice, giving the corresponding product 4a in 90% yield after 4 h (Table 1, entry 7). Other conventional solvents were also evaluated and low yields were obtained. A survey on the temperature also clearly showed that 80°C was the optimum temperature.

Table 1

Survey on the solvent effect on the model reaction.^a

Entry	DES	Temperature (°C)	Yield (%)b
1	–	80	61
2	ChCl/p-TsOH (1:1)	80	76
3	ChCl/malonic acid (1:2)	80	30
4	ChCl/glycerol (1:2)	80	Trace
5	ChCl/HFIP (1:1.5)	80	41
6	ChCl/ZnCl2 (1:2)	80	65
7	ChCl/urea (1:2)	80	90
8	EtOH	80	40
9	Water	80	Trace
10	CH3CN	80	32
11	CH2Cl2	Reflux	Trace
12	EtOAc	Reflux	20
13	ChCl/urea (1:2)	60	70
14	ChCl/urea (1:2)	40	53
15	ChCl/urea (1:2)	25	30

^aReaction conditions: 1 (2 mmol), benzaldehyde 2a (1 mmol), ammonium acetate 3 (1 mmol), DES or other solvents (4 ml), 4 h.

^bIsolated yields.

Then, the scope and limitations of the current procedure were examined, and a series of aromatic aldehydes were evaluated under the optimized reaction conditions (Table 1, entry 7). The results are summarized in Table 2. Generally, the reactions proceeded smoothly to give the corresponding products in good to excellent yields (81–92%). Aromatic aldehydes bearing both electron-withdrawing and electron-donating groups showed good activities, while aromatic aldehydes with nitro group at para position afforded slightly higher yield (Table 3, entry 8). The steric hindrance was also examined and ortho-substituted aldehydes gave relatively lower yield (Table 3, entry 10).

Table 2

Synthesis of PHA derivatives in ChCl/urea.^a

Entry	Ar	Time (h)	Yield (%)b
1	C6H5	4	4a (90)
2	4-CH3C6H4	4	4b (88)
3	4-CH3OC6H4	4	4c (85)
4	4-OHC6H4	6	4d (84)
5	2-OHC6H4	6	4e (82)
6	4-ClC6H4	6	4f (90)
7	3-ClC6H4	4	4g (83)
8	4-NO2C6H4	4	4h (92)
9	3-NO2C6H4	6	4i (83)
10	2-NO2C6H4	6	4j (81)
11	3-CH3O-4-OHC6H3	6	4k (87)

^aReaction conditions: dimedone 1 (2 mmol), aldehyde 2 (1 mmol), ammonium acetate 3 (1 mmol), ChCl/urea (4 ml), 80°C.

^bIsolated yield.

Table 3

Synthesis of PHQ derivatives in ChCl/urea.^a

Entry	Ar	Time (h)	Yield (%)b
1	C6H5	4	6a (91)
2	4-CH3C6H4	4	6b (88)
3	4-CH3OC6H4	4	6c (87)
4	4-OHC6H4	6	6d (85)
5	4-ClC6H4	3	6e (90)
6	4-NO2C6H4	3	6f (92)

^aReaction conditions: dimedone 1 (1 mmol), aldehyde 2 (1 mmol), ammonium acetate 3 (1 mmol), acetoacetate (1 mmol), ChCl/urea (4 ml), 80°C.

^bIsolated yield.

The good results obtained for the reaction shown in Table 2 prompted us to extend this protocol to the synthesis of PHQ (Table 3). As seen from the table, the above protocol was also suitable for the synthesis of PHQ, providing the products 6a–6f in excellent yields.

The recyclability of ChCl/urea was also investigated using the model reaction in Table 2. After completion of the reaction, ethyl acetate and water were added and the mixture was stirred for 5 min. The ethyl acetate layer containing the starting substrates and product was separated. After removing the water, the deep eutectic solvent was dried under vacuum at 80°C and then reused for the next cycle. The results showed that the DES could be reused for several runs with a gradual decrease in the yield (Table 4).

4 Conclusion

In summary, we have developed a simple, efficient and green procedure for the one-pot synthesis of PHA and PHQ derivatives using ChCl/urea as a reaction medium. Mild conditions, good to excellent yields as well as wide substrate compatibility are the major advantages of this protocol. Moreover, this deep eutectic solvent was environmentally benign, easily available and could be recycled and reused for several runs.