Potassium carbonate as a green catalyst for Markovnikov addition of azoles to vinyl acetate in PEG

Abstract

A novel strategy to effect the Markovnikov addition between azoles and vinyl-acetate is described. The main attractive features of this process are a mild base catalyst, recyclability of solvent PEG, excellent yields of products, and easy workup procedure.

Keywords:

• Markovnikov addition
• K₂CO₃
• PEG
• N-heterocycles
• recyclability

Introduction

The current environmental concerns encourage the development of more efficient, economical and environmentally friendly reactions for chemical synthesis 1. In this context, a great deal of effort has gone into the development of efficient and environmentally acceptable alternatives for the synthesis of N-containing heterocyclic compounds. Markovnikov addition is one of the most useful carbon–carbon, carbon–oxygen, and carbon–nitrogen bond forming reactions. This method has been widely used for the synthesis of biologically active heterocyclic compounds in synthetic organic chemistry 2–8.

The N-heterocycle derivatives 1-[N-(N-heterocycle)]alkyl esters obtained are usually Pharmacological active 9, 10 and may be applied as potential therapeutic alternatives like acaricides 2 3, antimicrobials 4, antitumor drugs 5, and (H⁺–K⁺)-ATPase inhibitors 6. However, the above-mentioned methods were generally promoted by harsh bases, strong acids, and high temperature 11–13, which would lead to environmentally hazardous residues and low yield of products. Nevertheless, the replacement of these hazardous conditions with the environmentally benign methodologies is one of the key areas of green chemistry.

Recently, K₂CO₃ catalyst in polyethylene glycol (PEG) 14–17 has gained recognition as favorable environmentally benign alternatives. Over the past few years, potassium carbonate (K₂CO₃) has been widely used as mild base catalyst in many organic reactions such as monomethylation reactions 18, O-alkylation 19, synthesis of 2H-chromenes 20, thiolysis of epoxides 21, Knoevenagel and Nitroaldol Condensation 22. Using potassium carbonate as green catalyst, our group has successfully carried out the synthesis of substituted 2-amino-4H-chromenes 23, thieno-pyrimidines 24, organomercurials 25, fused pyrimido derivatives 26, and thiohydantoins 27. The various articles reported reactions of K₂CO₃ not only showing its essentiality for a particular reaction but also depicting its other characteristics like solubility in water, mild character 19, 28, easy availability, eco-friendly 29, 30, and nontoxic nature 18, 23. Thus potassium carbonate provides a mild basic medium for organic reactions to occur and get removed by easy separation by water.

During the past few years, the biologically compatible PEGs 31 were demonstrated to be a recyclable green reaction medium for various chemical reactions 32–34. Here, as an extension of this work, we discovered that K₂CO₃ in PEG could effectively catalyzed the C–N bond formation, namely the Markovnikov addition of N-heterocycles and vinyl acetate 35–37 to afford the corresponding N-heterocyclic derivatives in high yield under mild condition (Scheme 1).

short-legendScheme 1. Synthesis of Markonikov products using K2CO3 in PEG.

In pursuit of our recent efforts on developing green methodologies 38–47, we evaluated the feasibility of Markovnikov addition of 4-nitroimidazole to vinyl acetate in different conditions, which was shown in Table 1. Initially, the reaction was carried with 4-nitroimidazole (1 mmol) and vinyl acetate (4 mmol) at room temperature in PEG 400 using K₂CO₃ as catalyst for 5 h to evaluate the product. The formation of product was monitored by thin layer chromatography (TLC).

Table 1. Effect of solvents and catalysts on Markovnikov addition between azoles and vinyl acetate^a.

Entry	Solvent	Catalyst	Time (h)	Yield (%)^b
1	PEG 400	Catalyst-free	24	5
2	PEG 400	K2CO3	5	98
3	PEG 200	K2CO3	7	90
4	DMSO	K2CO3	15	72
5	DMF	K2CO3	10	85
6	Methanol	K2CO3	15	52
7	PEG 400	L-proline	14	20
8	PEG 400	NaOH	14	55
9	PEG 400	KOH	12	70
^aReaction conditions: 4-nitroimidazole (1.0 mmol), vinyl acetate (4.0 mmol), K2CO3 (0.3 mmol), solvent PEG 400 (3 mL); (room temperature).
^bIsolated yields.

To optimize the reaction conditions, the reaction was performed in a range of solvents such as DMSO, DMF, methanol, and various PEGs with K₂CO₃ in terms of both yield and reaction time (Table 1). We also tried different kind of bases such as L-proline, KOH, and NaOH but K₂CO₃ was found to be more effective (Table 1, entry 2). When the reaction was carried out in the absence of catalyst led to the Markovnikov adduct in very low yield (5%) even after longer reaction time.

Encouraged by these remarkable results, we tried the reaction with the imidazoles containing electron-withdrawing and electron-donating groups, high yield of product was obtained with the imidazole having electron-withdrawing groups. The reactivity decreases by the following order, 4-nitroimidazole, 4-methyl imidazole, and imidazole in agreement with their nucleophilicity (Table 2, entry 1, 6, and 7).

Table 2. K₂CO₃ catalyzed Markovnikov addition of azoles with vinyl acetate^a.

Entry	Nu–H	Products	Time (h)	Yield (%)^b
1			5	(3a) 98
2			8	(3b) 96
3			6	(3c) 92
4			5	(3d) 85
5			7	(3e) 81
6			9	(3f) 78
7			30	(3g) 75
8			6	(3h) 82
9			6	(3i) 88
10			10	(3j) 80
^aReaction conditions: azoles (1.0 mmol), vinyl acetate (4.0 mmol), K2CO3 (0.3 mmol), solvent PEG 400 (3 mL); (room temperature).
^bIsolated yields.

Apart from imidazole derivatives, other N-heterocycles such as pyrrole, benzotriazole, and benzimidazole also exhibited high Markovnikov addition activity.

Among these the benzotriazole reacted fairly faster due to its strong nucleophilicity (Table 2, entry 4).

It is important to stress that the solvent was recycled and reused for 3–4 runs. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with solvent ether, since PEG is immiscible with solvent ether. In PEG phase, ethanol (10 mL) was added and passed through a very short pad of silica gel and activated charcoal. The colorless organic layer was evaporated under reduced pressure. PEG was further dried under high vacuum and used for the next run (Table 3).

Table 3. Recycling of PEG 400^a.

No. of cycles^a	Fresh	Run 1	Run 2	Run 3	Run 4
Yield (%)^b	98	98	97	96	93
Time (h)	5	5	5	5	5
^aReaction conditions: 4-nitroimidazole (1.0 mmol), vinyl acetate (4.0 mmol), K2CO3 (0.3 mmol), solvent PEG 400; ( room temperature).
^bIsolated yields.

Experimental section

General

The materials were purchased from Sigma-Aldrich and Merk that used without any purification. All reactions and purity of N-heterocycles were monitored by TLC using aluminum plates coated with silica gel (merk) using hexane-ethylacetate (80:20) as an eluent. The isolated products were further purified by column chromatography using silica gel (100–200 meshes), purchased from RFCL Pvt. Ltd. New Delhi, India. ¹H NMR and ¹³C NMR (300 and 75 MHz, respectively) spectra were recorded on Bruker Avance Spectrospin 300 (300 MHz). All NMR samples were run in CDCl₃ and chemical shifts are expressed as δ relative to internal Me₄Si. IR spectra were obtained on Perkin Elmer FT-IR spectrometer spectrum-2000 using potassium bromide pellets or as liquid films.

Typical procedure for the Markovnikov addition:

A mixture of azoles (1 mmol), vinyl acetate (4 mmol), and K₂CO₃ (0.3 mmol) in PEG 400 (3 mL) was stirred at room temperature for the time indicated in Table 2. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with diethyl ether (10 mL) (PEG being insoluble in ether). The organic layer was washed with saturated solution of NaCl (20 mL) and dried over anhydrous sodium sulfate (Na₂SO₄), filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethylacetate: hexane (20:80) as an eluent. The structure of products was confirmed by IR, ¹HNMR, ¹³CNMR, and HRMS/mass spectral data. All the products are known compounds.

1-[1-(4-Nitroimidazole)]-ethyl acetate (3a): White solid; melting point 83–85^oC; IR (KBr): 3134, 1745, 1546, 1510 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz, δ, ppm): 7.99 (s, 1H), 7.71 (s, 1H), 6.74 (q, 1H, J=6.98Hz), 2.11 (s, 3H), 1.85 (d, 3H, J=6.15Hz). ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 169.28, 148.74, 135.27, 117.12, 77.52, 20.93, 20.16. HRMS: m/z calculated for C₇H₉N₃O₄ [M⁺]: 199.0593; found: 199.0386.

1-(1-Triazole)-ethyl acetate (3b): Yellowish oil. IR (film): 3120, 3005, 1750, 1490, cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 8.31 (s, 1H), 7.93(s, 1H), 6.84 (q, 1H, J=6.28 Hz), 2.10 (s, 3H), 1.87 (d, 3H, J=6.21Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.39, 150.91, 145.02, 76.6, 20.95, 19.22. HRMS: m/z calculated for C₆H₉N₃O₂ [M⁺]: 155.0695 found 156.1031.

1-(1-Pyrazole)-ethyl acetate (3c): Colorless oil. IR (film): 3125, 3000, 1748, 1495 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 7.90(s, 1H), 7.52 (s, 1H,), 6.77 (q, 1H, J=6.23Hz), 6.28 (t, 1H), 2.04 (s, 3H), 1.72 (d, 3H, J=6.25Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.63, 141.03, 130.58, 106.28, 79.42, 21.23, 19.62. HRMS: m/z calculated for C₇H₁₀N₂O₂ [M⁺]: 154.0742 found 154.0634.

1-(1-Benzotriazolyl)-ethyl acetate (3d): Colorless oil. IR (film): 3130, 2998, 1752, 1501 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 8.01 (d, 1H, J=8.23Hz). 7.77 (d, 1H, J=8.3), 7.50 (m, 1H), 7.43 (m, 2H), 2.09 (d, 3H, J=6.4Hz), 2.04 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 168.20, 130.63, 124.48, 117.56, 91.71, 19.12, 15.84. HRMS: m/z calculated for C₁₀H₁₁N₃O₂ [M⁺]: 205.0851 found 205.0764.

1-(1-Benzimidazolyl)-ethyl acetate (3e): Colorless oil. IR (film): 3095, 1744, 1640, 1490 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 8.07 (s, 1H), 7.83 (m, 1H), 7.57 (m, 1H), 7.30 (m, 2H), 6.97 (q, 1H, J=6.35Hz), 2.02 (s, 3H), 1.91 (d, 3H, J=6.41Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 168.72, 140.21, 139.46, 132.35, 120.17, 108.56, 20.28, 16.90. HRMS: m/z calculated for C₁₁H₁₂N₂O₂ [M⁺]: 204.0899 found 204.1476.

1-(1-4-Methylimidazole)-ethyl acetate (3f): Light yellowish oil. IR (film): 3095, 1744, 1640, 1490 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 7.69 (s, 1H), 7.10 (s, 1H), 6.61 (q, 1H, J=6.21 Hz), 2.04 (s, 3H), 2.01 (s, 3H), 1.63 (d, 3H, J=6.12 Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.98, 136.91, 136.12, 114.01, 76.25, 21.35, 20.60, 14.21. HRMS: m/z calculated for C₈H₁₂N₂O₂ [M⁺]: 168.0899 found 168.0301.

1-(1-Imidazole)-ethyl acetate (3g): Yellow oil. IR (film): 3116, 1743, 1493 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 7.79 (s, 1H), 7.23 (d, 1H, J=5.11 Hz), 7.12 (d, 1H, J=6.73 Hz,), 6.67 (q, 1H, J=6.45 Hz), 2.48 (s, 3H), 1.75 (d, 3H, J=6.51 Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.78, 135.01, 128.31, 117.62, 76.20, 21.06, 20.17. HRMS: m/z calculated for C₇H₁₀N₂O₂ [M⁺]: 154.0742 found 155.0112.

1-(1-Indole)-ethyl acetate (3h): Colorless oil. IR (film): 3110, 1742, 1570, 1498 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 7.68 (m, 1H), 7.51 (m, 1H), 7.46 (m, 2H), 7.18 (d, 1H, J=6.28 Hz), 6.78 (d, 1H, J=6.30 Hz), 6.52 (q, 1H, J=6.32 Hz), 2.03(s, 3H), 1.73 (d, 3H, J=6.42 Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 163.32, 131.21, 126.73, 124.15, 118.63, 107.24, 85.33, 18.72, 15.25. HRMS: m/z calculated for [M⁺]: C₁₂H₁₃NO₂ 203.0946 found 203.0472.

1-(1-2-Methyl-5-nitroimidazole)-ethyl acetate (3i): White solid. melting point 137–138^oC. IR (KBr): 3138, 1753, 1540, 1508 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 7.91 (s, 1H), 6.68 (q, 1H, J=6.32 Hz), 2.49 (s, 3H), 2.10 (s, 3H,), 1.73 (d, 3H, J=6.33 Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.61, 148.57, 147.01, 119.82, 76.39, 21.12, 20.49, 13.48. HRMS: m/z calculated for C₈H₁₁N₃O₄ [M⁺]: 213.0750 found 213.0295.

1-(1-Pyrrole)-ethyl acetate (3j): Colorless oil. IR (film): 3110, 1742, 1570, 1498 cm⁻¹. ¹H NMR (CDCl₃, 300 MHz_, δ, ppm): 6.72 (d, 2H, J=2.5 Hz), 6.29 (q, 1H, J=6.23 Hz), 6.11 (d, 2H, J=6.35 Hz), 2.08 (s, 3H), 1.69 (d, 3H, J=6.25 Hz). ¹³C NMR (CDCl₃, 75 MHz_, δ, ppm): 169.71, 121.32, 120.08, 110.19, 108.25, 79.11, 21.15, 19.12. HRMS: m/z calculated for C₈H₁₁NO₂ [M⁺]: 153.0790 found 153.2031.

Conclusion

In conclusion, we have developed a novel and efficient protocol for the Markovnikov addition using K₂CO₃ as catalyst in PEG 400 under mild reaction conditions with excellent yields. This strategy is quite general and it works with a broad range of azoles. Furthermore, this method exhibits a simple and green procedure to avoid the use of toxic solvents and catalysts. The ease of mildness of this method provides an attractive route to the synthesis of N-heterocycle derivatives which may use as pharmacological alternatives.

Acknowledgements

The authors (Manohar Lal, Neeraj Kumar Mishra and Anwar Jahan) thank to UGC and CSIR, New Delhi, India for the grant of Junior and Senior Research Fellowship.