Three-component coupling reactions in ionic liquids: an improved protocol for the synthesis of 1,4-dihydropyridines

Abstract

Three-component condensation of aldehyde, β-ketoester and methyl 3-aminocrotonate proceeds smoothly in 1-n-butyl-3-methylimidazolium tetrafluoroborate [bmim]BF₄ or 1-n-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF₆ ionic liquids at room temperature under mild conditions to afford the corresponding 1,4-dihydropyridine derivatives in high yields. The recovered activated ionic liquids are recycled for four to five runs with no loss in activity.

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Green Context

Dihydropyridines are extremely versatile intermediates in the synthesis of numerous pharmaceuticals including those for the treatment of cardiovascular diseases and congestive heart failure. Their synthesis normally involves the use of organic solvents and wasteful work-up procedures. In this article a new synthetic procedure for these important compounds is described. This is based on the use of ionic liquid solvents that are shown to be recyclable. Organic solvents are still used in the work-up of the reaction mixture offering future scope for improvement but the avoidance of a VOC reaction solvent and general process simplicity give the process green chemistry credentials.

JHC

Introduction

Hantzsh 1,4-dihydropyridines are a biologically, medicinally and synthetically important class of compounds in the field of drugs and pharmaceuticals.¹ They act as potent vasodilators, antihypertensives, branchodilators, antiatherosclerotics, hepatoprotective, antitumor, antimutagenic, geroprotective and antidiabetic agents.² DHPs are commercially used as calcium channel blockers (such as Nifedifine, Nitrendifine and Nimodifine) for the treatment of cardiovascular diseases.³ A number of DHP calcium antagonists have been introduced, as potential drugs for the treatment of congestive heart failure.⁴ They are also useful as cognition enhancers, neuroprotectants and platelet antiaggregatory agents.⁵ Some of these 1,4-dihydropyridines acts as NADH mimics for the reduction of carbonyl compounds and their derivatives.⁶ 1,4-Dihydropyridines are generally synthesized by the Hantzsh method,⁷ which involves cyclocondensation of an aldehyde, β-ketoester and ammonia either in acetic acid or in refluxing ethanol.⁸ 1,4-Dihydropyridines have also been synthesized on a solid phase for making combinatorial libraries.⁹ The classical reactions are generally carried out in organic solvents such as methanol and acetic acid. Most of these methods often require tedious aqueous work-up to isolate the products and thus produce a large amount of waste. These organic solvents are often harmful to the environment and as a result are frequently subject to government restrictions and high waste disposal costs. Consequently, methods that successfully minimize their use are the focus of much attention. Thus use of solvents such as water, supercritical fluids and ionic liquids have received much attention in recent times in the area of green synthesis. In this respect, ionic liquids have emerged as a set of green solvents with unique properties such as tunable polarity, high thermal stability and immiscibility with a number of organic solvents, negligible vapor pressure and recyclability.¹⁰ Their high polarity and their ability to solubilise both inorganic and organic compounds can result in enhanced rates of chemical processes and can provide higher selectivities compared to conventional solvents. Accordingly, they are emerging as novel replacements for volatile organic solvents in organic synthesis. They are particularly promising as solvents for catalysis.¹¹ Ionic liquids however, have scarcely been used as both promoters and solvent although they provide advantages of easy recovery and reuse of the reaction media.¹² Moreover, ionic liquids are simple and inexpensive to prepare and easy to recycle and their properties can be fine-tuned by changing the anion or the alkyl group attached to the cation.

Because of distinct advantages of room-temperature ionic liquids as environmentally benign reaction media for catalytic processes, much attention has been currently focused on organic reactions promoted by ionic liquids.

Results and discussion

In view of the emerging importance of the imidazolium based ionic liquids as novel reaction media, we wished to explore the use of ionic liquids as environmentally friendly and recyclable solvent systems for the synthesis of 1,4-dihydropyridines under mild conditions (Scheme 1).

Scheme 1

The condensation of benzaldehyde and ethyl acetoacetate with methyl-3-aminocrotonate in 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid afforded the corresponding 1,4-dihydropyridine in 90% yield. In a similar fashion, a variety of aldehydes reacted smoothly with ethyl acetoacetate and 3-aminocrotonate to give the corresponding 1,4-dihydropyridines in excellent yields. The reactions proceeded efficiently at ambient temperature with high selectivity. Enolizable and acid sensitive aldehydes such as cyclohexane carbaldehyde and furfural, worked well under these reaction conditions. This method is compatible with highly acid sensitive protecting groups such as THP ethers, acetals, aminoacetals and carbamates present in the substrate. This method is equally effective for both electron rich as well as electron deficient aldehydes. All the products were characterized by ¹H NMR, IR and mass spectral analysis and also by comparison with authentic samples.⁸ In this reaction, the efficiency of ionic liquid was strongly influenced by the nature of the anion. The reactions of various aldehydes, β-ketoesters and methyl 3-aminocrotonate were examined in hydrophilic 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) and hydrophobic 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆) ionic liquids and the results are presented in Table 1. Among these ionic liquids, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) was found to be superior in terms of yields and reaction rates. Since the products were weakly soluble in the ionic phase, they were easily separated by simple extraction with diethyl ether. The remaining oily ionic liquid was thoroughly washed with diethyl ether and recycled in subsequent reactions. Second and third reactions using recovered ionic liquid afforded similar yields to those obtained in the first run. In the fourth and fifth runs, the yields were gradually decreased. For example, benzaldehyde, ethyl acetoacetate and methyl-3-aminocrotonate in [bmim]BF₄ afforded 90, 90, 89, 85 and 82% yields of the 1,4-dihydropyridine over five cycles. However, the activity of ionic liquid was consistent in runs and no decrease in yield was obtained when the recycled ionic liquid was activated at 80 °C under vacuum in each cycle. Furthermore, the products obtained were of the same purity as in the first run. However, the products were obtained in low to moderate yields (55–67%) after a long reaction period (15–24 h) when the reaction was carried out in refluxing ethanol. In further reactions the efficiency of various quaternary ammonium salts was studied. The three-component condensation was not successful when the reaction was carried out in other molten salts such as n-tetrabutylammonium chloride (n-Bu₄NCl) or 1-n-butyl-3-methylimidazolium chloride ([bmim]Cl). The simple experimental and product isolation procedures combined with ease of recovery and reuse of these novel reaction media is expected to contribute to the development of a green strategy for the synthesis of 1,4-dihydropyridines. The scope and generality of this process is illustrated with respect to various aldehydes and ionic liquids and the results are presented in Table 1. The use of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) ionic liquid as reaction medium for this transformation allows avoiding the use of additives or acidic promoters and also eliminating aqueous work-up to isolate the products.

Table 1 Hantzsch synthesis of 1,4-dihydropyridines in ionic liquids

			[bmim]BF4		[bmim]PF6
Entry	Aldehyde	Product	Time/h	Yield^a (%)	Time/h	Yield^b (%)
a All products were characterized by ^1H NMR, IR and mass spectra.b Isolated and unoptimized yields after purification.
a		4a	5.0	90	8.0	84
b		4b	6.5	85	9.0	81
c		4c	6.0	93	9.5	80
d		4d	5.0	91	8.0	83
e		4e	5.0	90	8.0	85
f		4f	7.0	88	11.0	81
g		4g	6.5	85	10.0	78
h		4h	5.0	91	8.0	87
i		4i	4.5	90	7.5	83
j		4j	7.0	87	12.0	79
k		4k	5.0	85	9.0	80
l		4l	8.0	80	10.0	72
m		4m	7.0	82	8.0	75
n		4n	5.0	89	7.0	84

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Conclusion

In summary, this paper describes a convenient and efficient process for the synthesis of 1,4-dihydropyridines through the three-component coupling of aldehydes, β-ketoester and 3-aminocrotonate using imidazolium based ionic liquids as novel reaction media. This method is very useful for the synthesis of 1,4-dihydropyridines especially from acid sensitive aldehydes. The notable features of this procedure are mild reaction conditions, simplicity in operation, improved yields and reaction rates, cleaner reaction profiles and recyclability of ionic liquids which make it a convenient, economic and user-friendly process for the synthesis of 1,4-dihydropyridines of biological and medicinal importance.

Experimental

Melting points were recorded on Buchi R-535 apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectrophotometer using KBr optics. ¹H, ¹³C NMR spectra were recorded on a Gemini-200 spectrometer in CDCl₃ using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV. 1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) and 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆) ionic liquids were prepared according to the procedures reported in the literature.¹³

General procedure

A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol) and methyl 3-aminocrotonate in 1-butyl-3-methylimidazolium tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate (1 mL) was stirred at ambient temperature for an appropriate time (Table 1). After completion of the reaction, as indicated by TLC, the reaction mixture was washed with diethyl ether (3 × 10 mL). The combined ether extracts were concentrated in vacuo and the resulting product was directly charged on a small silica gel column and eluted with a mixture of ethyl acetate–n-hexane (1∶9) to afford the pure 1,4-dihydropyridine. The remainder of the viscous ionic liquid was further washed with ether and dried at 80 °C under reduced pressure to retain its activity in subsequent runs. Solid products were purified by recrystallization in ethanol.

Recycling of ionic liquid

In the case of the hydrophilic ionic liquid, i.e. [bmim]BF₄, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were washed with water, dried over anhydrous Na₂SO₄ and concentrated in vacuo and the resulting product was purified either by column chromatography or by recrystallization to afford pure product. The ionic liquid can be recovered either by extracting the aqueous phase with ethyl acetate or by vaporating the aqueous layer in vacuo. The ionic liquid thus obtained was further dried at 80 °C under reduced pressure for use in subsequent runs.

Spectral data for selected products

4a: 3-Ethyl 5-methyl 2,6-dimethyl-1,4-dihydropyridine-3-5-dicarboxylate: liquid, IR (KBr) :ν 3328, 2925, 1743, 1542, 1233, 1041, 760 cm⁻¹. ¹H NMR (CDCl₃): δ 1.20 (t, 3H, J = 6.9 Hz), 2.18 (s, 6H), 3.20 (s, 2H), 3.80 (s, 3H), 4.20 (q, 2H, J = 6.9 Hz), 5.20 (br s, 1H). EIMS: m/z: 239 (M⁺), 225, 195, 167, 138, 109, 81.

4b: 3-Ethyl 5-methyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate: solid, mp 156–158 °C, IR (KBr): ν 3073, 2960, 1449, 1375, 1263, 1149, 1042, 974, 702 cm⁻¹. ¹H NMR (CDCl₃): δ 1.30 (t, 3H, J = 6.8 Hz), 2.50 (s, 6H), 3.80 (s, 3H), 4.20 (q, 2H, J = 6.8 Hz), 5.05 (s, 1H), 5.70 (br s, 1H), 7.25–7.35 (m, 5H). EIMS: m/z: 315 (M⁺), 301, 271, 243, 213, 185, 157, 81, 77.

4h: 3-Ethyl 5-methyl 4-(2-furyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate: solid, mp 163–165 °C, ¹H NMR (CDCl₃): δ 1.30 (t, 3H, J = 6.8 Hz), 2.40 (s, 6H), 3.80 (s, 3H), 4.30 (q, 2H, J = 6.8 Hz), 5.30 (s, 1H), 5.80 (br s, 1H), 6.80–7.05 (m, 3H). EIMS: m/z: 305 (M⁺), 246, 208, 174, 146, 99, 75, 43. ¹³C NMR (CDCl₃, 50 MHz): δ 14.5, 19.3, 19.4, 33.4, 51.0, 59.6, 96.2, 100.0, 104.4, 110.0, 140.8, 144.9, 145.3, 158.5, 167.1, 167.5.

4i: 3-Ethyl 5-methyl 4-(2-phenyl-1-ethenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate: solid, mp 149–150 °C, IR (KBr): ν 3027, 29298, 1679, 1449, 1263, 964, 754 cm⁻¹. ¹H NMR (CDCl₃): δ 1.20 (t, 3H, J = 7.0 Hz), 2.40 (s, 6H), 3.80 (s, 3H), 4.20 (q, 2H, J = 6.8 Hz), 5.10 (d, 1H, J = 5.5 Hz), 5.70 (br s, 1H), 6.10 (dd, 1H, J = 5.5, 16.8 Hz), 7.20 (d, 1H, J = 16.8 Hz), 7.25–7.35 (m, 5H). EIMS: m/z: 341 (M⁺), 327, 297, 269, 211, 183, 104, 81, 77.

Acknowledgments

B. V. S. and A. K. B. thank CSIR, New Delhi for the award of fellowships.

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