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Clean and Efficient One-Pot Synthesis of New 2-Oxo-2,3-Dihydro-1H-Pyrrole-3-Carboxylic Acid and 2-Oxo-1,2-Dihydro-Pyridine-3-Carboxylic Acid Derivatives through Ball Milling under Catalyst-Free and Solvent-Free Conditions

Mohamed Ould M’hamed*

Department of Chemistry, College of Sciences, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.

*Corresponding Author:
Mohamed Ould M’hamed
Department of Chemistry, College of Sciences
Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
Tel: 00966553379046
E-mail: mamhamed@imamu.edu.sa

Received date: 10/11/2015; Accepted date: 17/11/2015; Published date: 20/11/2015

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Abstract

A high-yielding one-pot ball milling method for the synthesis of new 2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid and 2-oxo-1,2-dihydropyridine- 3-carboxylic acid was developed under solvent-free and catalyst free conditions. The proposed method is simple and has environmental and economic advantages.

Keywords

Ball milling, Solvent-free, Catalyst-free, One-pot synthesis, Dihydro-1H-pyrrole-3-carboxylic acid, Dihydro-pyridine-3-carboxylic acid.

Introduction

Ball milling is a mechanical technique widely used for grinding solids with balls in a rotating vial to obtain fine particles [14]. Ball milling has recently attracted increasing attention from organic chemists because of its simplicity, low cost, environmental friendliness, and capability to achieve high yields.

Various organic reactions have been developed under ball milling conditions; these reactions include Knoevenagel condensation functionalization [5], phosphorus ylide preparation [6], functionalized indan-1,3-dione synthesis [7], coordination polymers [8], reductive benzylation of malononitrile [9], nitrone synthesis [10], fullerene functionalization [11], diol/diamine protection [12], Heck-type reactions [13,14], aldol reaction [15,16], Suzoku-type reaction [1720], pyrano pyrimidine-dione synthesis [21], symmetrical and unsymmetrical thioureas [22], and functionalized 2-amino-3-cyano-4H-pyrans [23]. Different reactions in organic chemistry under ball milling conditions have also been reviewed [2428].

Pyrrole and dihydropyridine derivatives are important heterocycles because of their different biological activities, including antibacterial, antiviral, anti-inflammatory, anticancer, antitumor, antianginal, analgesic, antitubercular, antithrombotic, and antioxidant activities [2941]; they are also used as conducting materials [4245]. Pyrrole and pyridine derivatives can be synthesized using different methods [4656]. However, these methods are generally performed under traditional conditions with long reaction times, different catalysts, and organic solvents that ultimately produce significant amounts of waste. The present study investigates a high-yielding one-pot three-component synthesis of new 2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid and 2-oxo-1,2-dihydropyridine- 3-carboxylic acid derivatives through simple ball milling under catalyst-free and solvent-free conditions (Schemes 1 and 2).

chemistry-carboxylic-acid

Scheme 1: Synthesis of 2-Oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid derivatives.

chemistry-Synthesis

Scheme 2: Synthesis of 4-Amino-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid derivatives.

Experimental

Materials and Techniques

The ball mill used in this study was a Planetary Micro Mill PULVERISETTE 7 classic line with 45 mL tempered steel vials and 10 mm tempered steel grinding balls. The melting points were determined using a Stuart Melting point apparatus SMP10. IR spectra were obtained with an FT-IR-Tensor 27 spectrometer in KBr pellets. 1H and 13C NMR spectra were determined with a BRUKER 500 NMR spectrometer in CDCl3 with TMS as the internal standard. Chemical shifts were expressed as δ ppm units. Elemental analysis was carried out on a Perkin Elmer 2400 CHN Elemental Analyzer. The progress of all reactions was monitored through TLC on silica gel 60 (Merck) using chloroform–ethanol.

General Procedure for the Synthesis of Pyrrole Compound 4a

An equimolar amount (0.02 mol) of phenacyl bromide (1a), malonic acid (2), and phenyl amine (3a) (total mass 7.90 g) was placed into tempered steel vials with 39.50 g of tempered steel balls (10 mm in diameter). The vials were closed and then placed in a Planetary Micro Mill PULVERISETTE 7. The pure form of pyrrole compound 4a was obtained after 30 min of milling without further purification.

2-Oxo-1,5-diphenyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4a): Mp 123–125ºC; IR(KBr, ν, cm−1): 3276.23, 2953.91, 1697.64, 1684.28, 1593.10, 1453.25; 1H NMR (500 MHz, CDCl3) δ 9.63 (br, s, 1H , OH), 7,66-7.02 (m, 10H, Ar), 5.75 (s, 1H, CH=), 3.92 (s, 1H, CH); 13C NMR (125 MHz. CDCl3) δ 171.82, 170.40, 140.65, 137.59, 136.92, 129.87, 128.30, 128.11, 127.61, 126.67, 126.85, 115.67, 56.82; Anal. Calcd. For C17H13NO3 (279.30): C, 73.11; H, 4.69; N, 5.01. Found: C, 72.82; H, 4.75; N, 5.13.

1-Benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4b): Mp 125–127ºC; IR(KBr, ν, cm−1): 3280.20, 2950.71, 1698.33, 1688.21, 1584.02, 1463.12; 1H NMR (500 MHz, CDCl3) δ 9.62 (br, s, 1H , OH), 7,65-7.08 (m, 10H, Ar), 5.71 (s, 1H, CH=), 4.56 (s, 2H, CH2), 3.85 (s, 1H, CH); 13C NMR (125 MHz. CDCl3) δ 171.82, 170.40, 140.65, 137.59, 136.92, 129.87, 128.30, 172.05, 171.02, 145.72, 138.86, 137.86, 129,35, 128.62, 128.34, 127.95, 126.81, 126.21, 112.19, 57.72, 46.12; Anal. Calcd. For C18H15NO3 (293.33): C, 73.71; H, 5.15; N, 4.78. Found: C, 73.82; H, 5.25; N, 4.64.

2-Oxo-1-phenethyl-5-phenyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4c): Mp 129–131ºC; IR(KBr, ν, cm−1): 3272.06, 2956.70, 1694.13, 1682.11, 1586.10, 1433.18;1H NMR (500 MHz, CDCl3) δ 9.65 (br, s, 1H , OH), 7,64-7.06 (m, 10H, Ar), 5.54 (s, 1H, CH=), 3.94 (t, J=6.98 Hz, 2H, CH2), 3.79 (s, 1H, CH), 2.86 (t, J=6.98 Hz, 2H, CH2);13C NMR (125 MHz. CDCl3) δ 172.15, 171.13, 145.67, 138.36, 137.72, 129.16, 128.83, 128.12, 127.92, 127.48, 125.97, 111.05, 57,45, 42.83, 36.17; Anal. Calcd. For C19H17NO3 (307.35): C, 74.25; H, 5.58; N, 4.56. Found: C, 73.92; H, 5.63; N, 4.63.

1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4d): Mp 118–120ºC; IR(KBr, ν, cm−1): 3269.04, 2950.22, 1690.79, 1680.25, 1576.10, 1443.29; 1H NMR (500 MHz, CDCl3) δ 9.64 (br, s, 1H , OH), 7,78-7.18 (m, 5H, Ar), 5.57 (s, 1H, CH=), 3.87 (s, 1H, CH), 3.27 (s, 3H, CH3); 13C NMR (125 MHz. CDCl3) δ 171.17, 170.29, 146.92, 138.14, 129.13, 127.83, 127.46, 111.02, 56,11, 31.04; Anal. Calcd. For C12H11NO3 (217.23): C, 66.35; H, 5.10; N, 6.45. Found: C, 66.47; H, 5.15; N, 6.32.

5-(4-Bromo-phenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4e): Mp 140–142ºC; IR(KBr, ν, cm−1): 3274.01, 2958.11, 1688.19, 1669.15, 1546.18, 1440.14; 1H NMR (500 MHz, CDCl3) δ 9.64 (br, s, 1H , OH), 7,83-6.72 (m, 9H, Ar), 5.77 (s, 1H, CH=), 3.92 (s, 1H, CH); 13C NMR (125 MHz. CDCl3) δ 170.86, 170.17, 146.22, 139.84, 135.71, 131.14, 130.81, 130.43, 126.76, 126.32, 123.66, 115.42, 57,61; Anal. Calcd. For C17H12BrNO3 (358.19): C, 57.01; H, 3.38; N, 3.91. Found: C, 57.11; H, 3.35; N, 3.92.

1-Benzyl-5-(4-bromo-phenyl)-2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4f): Mp 144–146ºC; IR(KBr, ν, cm−1): 3265.47, 2947.46, 1690.63, 1672.82, 1530.48, 1436.22; 1H NMR (500 MHz, CDCl3) δ 9.66 (br, s, 1H , OH), 7,85-7.08 (m, 9H, Ar), 5.55 (s, 1H, CH=), 4.63 (s, 2H, CH2), 3.78 (s, 1H, CH); 13C NMR (125 MHz. CDCl3) δ 172.13, 171.32, 146.25, 138.44, 138.16, 130.66, 130.21, 128.37, 128.09, 123.21, 112.75, 57.66, 45.29; Anal. Calcd. For C18H14BrNO3 (372.22): C, 58.08; H, 3.79; N, 3.76. Found: C, 58.25; H, 3.68; N, 3.81.

5-(4-Bromo-phenyl)-2-oxo-1-phenethyl-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4g): Mp 141–143ºC; IR(KBr, ν, cm−1): 3260.32, 2949.61, 1696.17, 1670.65, 1537.37, 1431.41; 1H NMR (500 MHz, CDCl3) δ 9.55 (br, s, 1H , OH), 7,81-7.13 (m, 9H, Ar), 5.58 (s, 1H, CH=), 3.97 (t, J=6.99Hz, 2H, CH2), 3.82 (s, 1H, CH), 2.93 (t, J=6.99Hz, 2H, CH2); 13C NMR (125 MHz. CDCl3) δ 173.01, 172.09, 145.98, 139.02, 138.33, 131.05, 129.77, 129.42, 128.07, 125.92, 123.67, 111.05, 57.19, 45.06, 36.14; Anal. Calcd. For C19H16BrNO3 (386.25): C, 59.08; H, 4.18; N, 3.63. Found: C, 59.12; H, 4.22; N, 3.58.

5-(4-Bromo-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid (4h): Mp 130–132ºC; IR(KBr, ν, cm−1): 3260.54, 2953.27, 1692.85, 1675.71, 1541.29, 1429.63; 1H NMR (500 MHz, CDCl3) δ 9.68 (br, s, 1H , OH), 7,85-7.58 (m, 4H, Ar), 5.57 (s, 1H, CH=), 3.85 (s, 1H, CH), 3.28 (s, 3H, CH3); 13C NMR (125 MHz. CDCl3) δ 172.71, 171.08, 148.13, 138.01, 131.14, 130.77, 123.72, 111.12, 56.21, 31.04; Anal. Calcd. For C12H10BrNO3(296.12): C, 48.67; H, 3.40; N, 4.73. Found: C, 48.52; H, 3.45; N, 4.83.

4-Amino-2-oxo-1,6-diphenyl-1,2-dihydro-pyridine-3-carboxylic acid (6a): Mp 174–176ºC; IR(KBr, ν, cm−1): 3310.85, 3275.80, 2997.54, 1698.64, 1682.78, 1590.77, 1468.29; 1H NMR (500 MHz, CDCl3) δ 10.36 (br, s, NH2, OH, 3H), 7,51-7.22 (m, Ar, 7H), 7.18 (s, 1H, CH=), 7.11-6.98 (m, Ar, 3H); 13C NMR (125 MHz. CDCl3) δ 171.58, 165.61, 156.52, 147.79, 137.52, 137.27, 131.63, 129.24, 128.55, 128.20, 119.74, 117.95, 100.77, 99.83; Anal. Calcd. For C18H14N2O3 (306.32): C, 70.58; H, 4.61; N, 9.15. Found: C, 70.52; H, 4.65; N, 9.10.

4-Amino-1-benzyl-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (6b): Mp 179–181ºC; IR(KBr, ν, cm−1): 3307.48, 3270.83, 2992.46, 1697.75, 1681.72, 1598.61, 1466.18; 1H NMR (500 MHz, CDCl3) δ 10.37 (br, s, NH2, OH, 3H), 7.53-7.12 (m, Ar, 10H), 7.01 (s, 1H. CH=), 5.07 (s, 2H, CH2); 13C NMR (125 MHz. CDCl3) δ 171.60, 165.62, 158,78, 150.07, 141.85, 136.89, 128.76, 12842, 127.85, 127.64, 127.04, 99.72, 96.67, 48.36; Anal. Calcd. For C19H16N2O3 (320.35): C, 71.24; H, 5.03; N, 8.74. Found: C, 71.32; H, 4.98; N, 8.72.

4-Amino-2-oxo-1-phenethyl-6-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (6c): Mp 185-187ºC; IR(KBr, ν, cm−1): 3304.76, 3267.64, 2990.55, 1694.81, 1683.72, 1595.24, 1462.39; 1H NMR (500 MHz, CDCl3) δ 10.38 (br, s, NH2, OH, 3H), 7.53-7.17 (m, Ar, 10H), 6.98 (s, 1H, CH=), 4.38 (t, J= 7Hz, 2H, CH2), 2.96 (t, J= 7Hz, 2H, CH2); 13C NMR (125 MHz. CDCl3) δ 168.66, 165.71, 158.72, 148.69, 141.17, 139.49, 128.76, 128.51, 128.06, 128.03, 127.66, 127.36, 100.81, 79.31, 48.14, 34.53; Anal. Calcd. For C20H18N2O3 (334.38): C, 71.84; H, 5.43; N, 8.38. Found: C, 71.72; H, 5.45; N, 8.32.

4-Amino-1-methyl-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (6d): Mp 164–166ºC; IR(KBr, ν, cm−1): 3301.41, 3262.73, 2986.74, 1691.79, 1680.20, 1590.76, 1466.32; 1H NMR (500 MHz, CDCl3) δ 10.39 (br, s, NH2, OH, 3H), 7.54-7.29 (m, Ar, 5H), 6.99 (s, 1H, CH=), 3.37 (s, 3H, CH3); 13C NMR (125 MHz. CDCl3) δ 171.67, 165.13, 158.36, 142.96, 137.37, 128.61, 128.14, 127.13, 99.64, 96.67, 32.54; Anal. Calcd. For C13H12N2O3 (244.25): C, 63.93; H, 4.95; N, 11.47. Found: C, 64.02; H, 4.98; N, 11.39.

4-Amino-6-(4-bromo-phenyl)-2-oxo-1-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (6e): Mp 179–181ºC; IR(KBr, ν, cm−1): 3315.33, 3276.84, 2996.77, 1698.25, 1685.11, 1597.06, 1472.02; 1H NMR (500 MHz, CDCl3) δ 10.38 (br, s, NH2, OH, 3H), 7.79- 7.21 (m, Ar, 6H), 7.18 (s, 1H, CH=), 7.11-6.98 (m, Ar, 3H); 13C NMR (125 MHz. CDCl3) δ 171.58, 164.67, 156.23, 147.64, 137.29, 135.84, 131.47, 130.21, 130.12, 123.03, 119.45, 117.65, 100.25, 97.19; Anal. Calcd. For C18H13BrN2O3 (385.22): C, 56.12; H, 3.40; N, 7.27. Found: C, 56.08; H, 3.45; N, 7.30.

4-Amino-1-benzyl-6-(4-bromo-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (6f): Mp 182–184ºC; IR(KBr, ν, cm−1): 3311.09, 3274.81, 2995.06, 1694.88, 1682.16, 1594.02, 1470.15; 1H NMR (500 MHz, CDCl3) δ 10.39 (br, s, NH2, OH, 3H), 7.75-7.11 (m, Ar, 9H), 6.98 (s, 1H, CH=), 5.07 (s, 1H, CH2); 13C NMR (125 MHz. CDCl3) δ 171.97, 165.32, 158.79, 149.83, 140.17, 138.06, 130.02, 129.17, 129.02, 127.28, 127.06, 123.11, 99.96, 94.15, 48.26; Anal. Calcd. For C19H15BrN2O3 (399.25): C, 57.16; H, 3.79; N, 7.02. Found: C, 57.13; H, 3.74; N, 7.04.

4-Amino-6-(4-bromo-phenyl)-2-oxo-1-phenethyl-1,2-dihydro-pyridine-3-carboxylic acid (6g): Mp 186–188ºC; IR(KBr, ν, cm−1): 3308.65, 3271.29, 2992.13, 1692.74, 1680.66, 1591.49, 1472.10; 1H NMR (500 MHz, CDCl3) δ 10.39 (br, s, NH2, OH, 3H), 7.71-7.15 (m, Ar, 9H), 6.99 (s, 1H, CH=), 4.28 (t, J= 6.99Hz, 2H, CH2), 2.98 (t, J= 6.99Hz, 2H, CH2); 13C NMR (125 MHz. CDCl3) δ 169.11, 165.39, 158.93, 148.89, 141.02, 140.85, 129.87, 128.27, 127.83, 127.62, 126.61, 123.16, 100.15, 94.86, 48.14, 34.23; Anal. Calcd. For C20H17BrN2O3 (413.27): C, 58.13; H, 4.15; N, 6.78. Found: C, 58.22; H, 4.18; N, 6.72.

4-Amino-6-(4-bromo-phenyl)-1-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (6h): Mp 173–175ºC; IR(KBr, ν, cm−1): 3310.60, 3272.07, 2994.18, 1694.89, 1685.24, 1593.59, 1475.07; 1H NMR (500 MHz, CDCl3) δ 10.38 (br, s, NH2, OH, 3H), 7.75-7.60 (m, Ar, 4H), 7.01 (s, 1H, CH=), 3.35 (s, 3H, CH3); 13C NMR (125 MHz. CDCl3) δ 171.68, 165.83, 158.92, 143.13, 135.84, 129.96, 129.75, 123.17, 99.98, 94.36, 32.77; Anal. Calcd. For C13H11BrN2O3 (323.15): C, 48.32; H, 3.43; N, 8.67. Found: C, 48.39; H, 3.41; N, 8.72.

Results and Discussion

In continuation of our interest in ball milling applications for organic synthesis [54-56], this article introduced a green and efficient three-component synthesis of 2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acid and 2-oxo-1,2-dihydro-pyridine-3-carboxylic acid derivatives. In this technique, equimolar quantities of phenacyl bromide/phenacyl cyanide derivatives, malonic acid, and primary amine were directly condensed through simple planetary ball milling without adding any solvent or catalyst (Schemes 1 and 2). The progress of the reactions was monitored every 10 min milling cycle using thin-layer chromatography (TLC).

To study the effect of different rotation speeds on the reactions, equimolar quantities (0.02 mol) of phenacyl bromide (1a), malonic acid (2), and phenyl amine (3a) were used in planetary ball milling with a ball weight-to-reagent weight ratio of 5 [54]. Pyrrole (4a) yield was low at a low rotation speed of 250 rpm, whereas pyrrole (4a) yield was high after a short reaction time at 750 rpm (Table 1). The protocol also provides a facile access to new different functional pyrroles (4a-h) and dihydropyridines (6a-h) (Table 2).

chemistry-Comparison-effect

Table 1: Comparison of the effect of different rotation speeds conditions for the condensation of phenacyl bromide (1a), malonic acid (2) and phenyl amine (3a).

chemistry-derivatives-using

Table 2: Synthesis of 2-oxo-2,3-dihydro-1-H-pyrrole-3-carboxylic acid and 2-oxo-1,2-dihydro-pyridine-3-carboxylic acid derivatives using ball mill.

Spectroscopic data of the newly synthesized products agreed with the proposed chemical structures. An interesting signal was detected in the 1H-NMR spectra of 4a–h (2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylic acids); this signal was located at approximately 5.54–5.77 and 3.78–3.92 ppm, which corresponded to the vinylic and allylic protons in the pyrrole rings, respectively. Products 6a–h (2-oxo-1,2-dihydro-pyridine-3-carboxylic acids) showed a characteristic single peak in the 1H-NMR spectra at approximately 6.98-7.18 ppm, which corresponded to the vinylic proton in the pyridine rings.

The plausible reaction mechanism for pyrrole synthesis is described as an example in Scheme 3. The primary amine 3 reacted with malonic acid 2 to provide the corresponding malonic acid anion, which subsequently reacted with phenacyl bromide 1 to form phenacyl malonic acid. The primary amine again reacted with phenacyl malonic acid to produce an intermediate that underwent internal cyclization, which yielded pyrrole 4.

chemistry-Reaction-mechanism

Scheme 3: Reaction mechanism for the synthesis of pyrroles (4a-h).

Conclusion

In conclusion, we have developed a green, easy, and facile approach to new different 2-oxo-2,3-dihydro-1H-pyrrole-3- carboxylic acids and 2-oxo-1,2-dihydro-pyridine-3-carboxylic acids (Table 2) using ball milling technique. This economical and ecofriendly process afforded all synthesized compounds in high yields and in pure form without further purification.

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