Neat synthesis and antioxidant activity of α-aminophosphonates

Guna Subba Reddy; Kunda Uma Maheswara Rao; Chereddy Syama Sundar; Sarva Santhi Sudha; Buchammagari Haritha; Sirasanagandla Swapna; Cirandur Suresh Reddy

doi:10.1016/j.arabjc.2013.01.004

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ORIGINAL ARTICLE

7 (

); 833-838

doi:

10.1016/j.arabjc.2013.01.004

Neat synthesis and antioxidant activity of α-aminophosphonates

Guna Subba Reddy^a, Kunda Uma Maheswara Rao^a, Chereddy Syama Sundar^a, Sarva Santhi Sudha^a, Buchammagari Haritha^a, Sirasanagandla Swapna^b, Cirandur Suresh Reddy^a,*

a Dept. of Chemistry, S.V University, Tirupati 517502, AP, India

b Dept. of Bio-Chemistry, S.V University, Tirupati 517502, AP, India

*Corresponding author. Tel.: +91 9849694958; fax: +91 877 2289555 csrsvu@gmail.com (Cirandur Suresh Reddy)

Received: 2011-11-2, Accepted: 2013-1-15, Published: 2013-11-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Available online 4 February 2013

Peer review under responsibility of King Saud University.

Abstract

A simple, efficient, and environmentally benign method for a three-component reaction of an amine, an aldehyde and diethyl phosphite catalyzed by Amberlyst-15 has been developed to afford α-amino phosphonates in high yields and short reaction times under solvent-free reaction conditions using microwave irradiation. The major advantages of the present method are inexpensive, ecofriendly and reusable catalyst and also studied their antioxidant activity of synthesized compounds.

Keywords

Multi-component reaction

Amberlyst-15

Microwave Irradiation

Antioxidant activity

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1 Introduction

α-Aminophosphonates are probably the most important substitutes for the corresponding amino acids in biological systems. (Giannousi and Bartlett, 1987) Indeed, a number of potent antibiotics, (Atherton et al., 1986) enzyme inhibitors, (Allen et al., 1989) and pharmacological agents (Kaboudin and Moradi, 2005) are α-aminophosphonates as well as their derivatives, notably peptides. α-Aminophosphonates are also found as constituents of natural products. These important compounds have been synthesized by various routes. Among the literature methods, (Abhimanyu and P., 2006; Heydari et al., 2009; Hou et al., 2011; Banik et al., 2010; Rao et al., 2008; Mitragotri et al., 2008 ) the Kabachnik–Fields reaction is one of the most convenient approaches to α-aminophosphonates. It is a one-pot, three-component reaction of carbonyl compound, amine, and dialkyl phosphite. The reaction usually needs Lewis acids such as SnCl₄, (Laschat and Kunz) BF₃.OEt₂ (Ha and Nam, 1992) and ZrCl₄. (Yadav and S., 2001) However, these reactions could not be carried out in a one-pot single step operation with a carbonyl compound, an amine and a dialkyl phosphite because the amine and water formed during imine formation decompose or deactivate the Lewis acid. (Atherton et al., 1986) This drawback has been partly overcome in some recent methods using lanthanide triflates/MgSO₄, (Li et al., 1999) InCl₃, (Ranu et al., 1999) TaCl₅–SiO₂, (Chandrasekhar et al., 2001) bismuth nitrate pentahydrate, (Bhattacharya and K., 2007) Mg(ClO₄)₂, Bhagat and Chakraborti, 2007 TiO₂, (Sarvari, 2008) Amberlite-IR120, (Bhattacharya and Rana, 2008) sulfamic acid, (Mitragotri et al., 2008) H₃PW₁₂O₄₀, (Heydari et al., 2007) trimethylanilinium chloride, (Heydari and Arefi, 2007) lithium perchlorate (Heydari et al., 1998) and Amberlyst-15. (Tajbakhsh et al., 2011) However, these catalysts have various other setbacks such as less accessibility of reagents, and require a long reaction time. Further, when the starting materials contain aliphatic amines, the reactions involving them usually give uncharacterizable products. In addition, some of these catalysts are expensive or are difficult to prepare. Hence the search continues for the development of a better and green synthetic protocol for them that is simple, efficient and cost effective and this remains an ever-challenging objective. In continuation of our program on the development of novel organic synthetic methodologies, (Rao et al., 2011) we have investigated the synthesis of α-aminophosphonate derivatives in the presence of amberlyst-15 using microwave irradiation.

The use of solid acidic catalysts has gained importance in organic synthesis due to several advantages such as, operational simplicity, nontoxicity, reusability, low cost and ease of isolation after completion of the reaction. Amberyst-15 resin has emerged as an efficient heterogeneous catalyst for various chemical transformations. (Yadav et al., 2005) Owing to the numerous advantages associated with this cheap and nonhazardous catalyst, we considered Amberyst-15 resin to be an ideal heterogeneous acid catalyst for the synthesis of α-amino phosphonates. Application of microwave irradiation to this reaction increases the efficiency, which otherwise requires long reaction time. Moreover, microwave-assisted reactions are believed to satisfy the demands of ‘green chemistry’ allowing for solvent-free conditions to be employed. Herein, we report a novel one-pot synthesis of a-amino phosphonates catalyzed by Amberyst-15 resin under solvent-free reaction conditions using microwave irradiation and also studied the anti oxidant activity of synthesized compounds.

2 Experimental

2.1

2.1 Synthesis of diethyl(3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl) methyl phosphonate 4(d)

3,5-dichloro-4-hydroxy phenylamine (1 mmol), 3-nitro benzaldehyde (1 mmol), diethylphosphite (1 mmol) and Amberlyst-15 (100 mg) were added into a 25 mL three-necked flask and exposed to microwave irradiation (CATA-4R—Scientific Microwave oven, 490 W) for 4 min. After completion of the reaction (TLC), the reaction mixture was cooled and DCM (25 mL) was added. The catalyst was filtered from the reaction mixture and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (100–200 mesh) eluting with petroleum ether–ethyl acetate (4:1) to afford the corresponding pure α-amino phosphonate. The same procedure is successfully applied to remaining compounds. All the products were characterized from their spectral data.

2.2

2.2 Spectral data

2.2.1

2.2.1 Diethyl(3, 5-dichloro-4-hydroxyphenylamino)(1H-indol-3-yl)methylphosphonate 4(a)

Yield: 84 % IR (KBr) (ν_max cm⁻¹): 3300 (NH), 1260 (P⚌O), 750 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 1.18 (3H, t, J = 8.0 Hz, P-OCH₂CH₃), 1.25 (3H, t, J = 8.0 Hz, P-OCH₂CH₃), 3.64–3.72 (1H, m, P-OCH₂CH₃), 3.81–3.90 (1H, m, P-OCH₂CH₃), 3.99–4.10 (2H, m, P-OCH₂CH₃), 5.20 (1H, d, J = 20.0 Hz, P-CH), 5.32 (1H, s, Ar–OH), 6.06 (1H, s, NH), 6.60–7.83 (7H, m, Ar–H), 11.10 (1H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃) δ: 16.4 (d, J = 5.9 Hz, P-OCH₂CH₃), 16.6 (d, J = 5.6 Hz, P-OCH₂CH₃), 52.7 (d, J = 152.0 Hz, P-CH), 54.2 (d, J = 7.2 Hz, P-OCH₂CH₃), 62.9 (d, J = 7.0 Hz, P-OCH₂CH₃), 110.9 (C-1¹), 111.7 (C-5¹), 117.4 (C-8¹), 118.6 (C-2 & C-6), 120.5 (C-7¹), 121.0 (C-2¹), 123.0 (C-6¹), 127.3 (C-3 & C-5), 130.5 (C-9¹), 132.5 (C-4¹), 140.0 (C-4), 142.9 (C-1). ³¹P NMR (202.4, MHz, CDCl₃) δ: 23.48. EI-MS (m/z, %): 444 (M + 2, 60), 443 (M + 1, 60), 442 (M^+•, 100). Anal. Calcd for C₁₉H₂₁Cl₂N₂O₄P: C, 51.48; H, 4.78; N, 6.32. Found: C, 51.40; H, 4.71; N, 6.23.

2.2.2

2.2.2 Diethyl(3,5-dichloro-4-hydroxyphenylamino)(4-(dimethylamino)phenyl) methylphosphonate 4(b)

Yield: 86 %. IR (KBr) (ν_max cm⁻¹): 3333 (NH), 1263 (P⚌O), 748 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 1.07 (3H, t, J = 8.4 Hz, P-OCH₂CH₃), 1.21 (3H, t, J = 8.4 Hz, P-OCH₂CH₃), 3.09 (3H, s, –NCH₃), 3.18 (3H, s, –NCH₃), 3.78–3.92 (1H, m, P- OCH₂CH₃), 3.94–3.97 (1H, m, P-OCH₂CH₃), 3.99–4.18 (2H, m, P-OCH₂CH₃), 5.28 (1H, s, Ar–OH), 5.40 (1H, d, J = 24.0 Hz, P-CH), 6.55 (1H, s, NH), 6.60–8.42 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 16.9 (d, J = 6.2 Hz, P-OCH₂CH₃), 17.2 (d, J = 5.9 Hz, P-OCH₂CH₃), 41.8 (NC¹¹ & NC¹¹), 52.9 (d, J = 154.2 Hz, P-CH), 62.6 (d, J = 7.6 Hz, P-OCH₂CH₃), 62.9 (d, J = 7.0 Hz, P-OCH₂CH₃), 111.7 (C-3¹ & C-5¹), 114.7 (C-2 & C-6), 125.9 (C-1¹), 126.7 (C-2¹ & C-6¹), 129.7 (C-3 & C-5), 141.4 (C-4), 143.7 (C-1), 150.5 (C-4¹). ³¹P NMR (202.4, MHz, CDCl₃) δ: 22.20. EI-MS (m/z, %): 448 (M + 2, 60), 447 (M + 1, 60), 446 (M^+•, 100). Anal. Calcd for C₁₉H₂₅Cl₂N₂O₄P: C, 51.02; H, 5.63; N, 6.26. Found: C, 59.02; H, 5.60; N, 6.16.

2.2.3

2.2.3 Diethyl(3,5-dichloro-4-hydroxyphenylamino)(2-hydroxyphenyl)methylphosphonate 4(c)

Yield: 89 %. IR (KBr) (ν_max cm⁻¹): 3328 (NH), 1268 (P⚌O), 744 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 1.09 (3H, t, J = 8.2 Hz, P-OCH₂CH₃), 1.18 (3H, t, J = 8.0 Hz, P-OCH₂CH₃), 3.72–3.88 (1H, m, P-OCH₂CH₃), 3.95–4.08 (1H, m, P-OCH₂CH₃), 4.14–4.28 (2H, m, P-OCH₂CH₃), 5.28 (1H, s, Ar–OH), 5.92 (1H, d, J = 22.0 Hz, P-CH), 6.14 (1H, s, NH), 6.54–8.70 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 16.2 (d, J = 6.8 Hz, P-OCH₂CH₃), 16.8 (d, J = 6.0 Hz, P-OCH₂CH₃), 52.0 (d, J = 152.2 Hz, P-CH), 62.0 (d, J = 7.2 Hz, P-OCH₂CH₃), 62.6 (d, J = 7.2 Hz, P-OCH₂CH₃), 111.5 (C-2 & C-6), 114.7 (C-3¹), 119.8 (C-5¹), 125.9 (C-1¹), 127.7 (C-3 & C-5), 128.2 (C-6¹), 128.5 (C-4¹), 140.4 (C-4), 144.5 (C-1), 156.7 (C-2¹). ³¹P NMR (202.4, MHz, CDCl₃) δ: 21.82. EI-MS (m/z, %): 420 (M + 2, 18), 421 (M + 1, 55), 420 (M^+•, 100). Anal. Calcd for C₁₇H₂₀Cl₂NO₅P: C, 48.59; H, 4.80; N, 3.33. Found: C, 48.50; H, 4.72; N, 3.28.

2.2.4

2.2.4 Diethyl (3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl)methylphosphonate 4(d)

Yield: 92 %. IR (KBr) (ν_max cm⁻¹): 3319 (NH), 1260 (P⚌O), 752 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 1.12 (3H, t, J = 7.8 Hz, P-OCH₂CH₃), 1.19 (3H, t, J = 7.6 Hz, P-OCH₂CH₃), 3.64–3.72 (1H, m, P-OCH₂CH₃), 3.78–3.94 (1H, m, P-OCH₂CH₃), 4.02–4.20 (2H, m, P-OCH₂CH₃), 5.34 (1H, s, –OH), 5.42 (1H, s, Ar–OH), 5.48 (1H, d, J = 20.0 Hz, P-CH), 6.08 (1H, s, NH), 6.17–8.48 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 16.2 (d, J = 6.8 Hz, P-OCH₂CH₃), 16.8 (d, J = 6.0 Hz, P-OCH₂CH₃), 52.0 (d, J = 152.2 Hz, P-CH), 62.0 (d, J = 7.2 Hz, P-OCH₂CH₃), 62.6 (d, J = 7.2 Hz, P-OCH₂CH₃), 111.5 (C-2 & C-6), 125.9 (C-1¹), 125.7 (C-3 & C-5), 126.7 (C-2¹), 128.2 (C-6¹), 131.5 (C-4¹), 133.8 (C-5¹), 140.4 (C-4), 142.5 (C-1), 147.7 (C-3¹). ³¹P NMR (202.4, MHz, CDCl₃) δ: 22.64. EI-MS (m/z, %): 450 (M + 2, 60), 448 (M^+•, 100). Anal. Calcd for C₁₇H₁₉Cl₂N₂O₆P: C, 45.45; H, 4.26; N, 6.24. Found: C, 45.34; H, 4.21; N, 6.19.

2.2.5

2.2.5 Diethyl(2-(benzyloxy)phenyl)(3,5-dichloro-4-hydroxyphenylamino) methylphosphonate 4(e)

Yield: 83%. IR (KBr) (ν_max cm⁻¹): 3320 (NH), 1268 (P⚌O), 745 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 1.09 (3H, t, J = 8.6 Hz, P-OCH₂CH₃), 1.18 (3H, t, J = 8.4 Hz, P-OCH₂CH₃), 3.24–3.36 (1H, m, P-OCH₂CH₃), 3.42–3.64 (1H, m, P-OCH₂CH₃), 3.86–4.18 (2H, m, P-OCH₂CH₃), 5.12 (1H, s, –OCH₂), 5.40 (1H, s, Ar–OH), 5.32 (1H, d, J = 24.0 Hz, P-CH), 6.28 (1H, s, NH), 6.14–8.62 (11H, m, Ar–H). ³¹P NMR (202.4, MHz, CDCl₃) δ: 24.12. EI-MS (m/z, %): 511 (M + 2, 60), 510 (M + 2, 20), 509 (M^+•, 100). Anal. Calcd for C₂₄H₂₆Cl₂NO₅P: C, 56.48; H, 5.14; N, 2.74. Found: C, 56.40; H, 5.10; N, 2.66.

2.2.6

2.2.6 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(1H-indol-3-yl) methylphosphonate 4(f)

Yield: 89%. IR (KBr) (ν_max cm⁻¹): 3331 (NH), 1257 (P⚌O), 741 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 3.12 (3H, s, P-OCH₃), 3.28 (3H, s, P-OCH₃), 5.22 (1H, d, J = 20.0 Hz, P-CH), 5.32 (1H, s, Ar–OH), 6.06 (1H, s, NH), 6.56–7.98 (7H, m, Ar–H), 10.10 (1H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃) δ: 52.7 (d, J = 152.0 Hz, P-CH), 55.4 (d, J = 5.9 Hz, P-OCH₃), 55.9 (d, J = 5.6 Hz, P-OCH₃), 110 .9 (C-1¹), 112.2 (C-5¹), 116.4 (C-7¹), 117.9 (C-2 & C-6), 118.7 (C-8¹), 121.8 (C-6¹), 122.7 (C-2¹), 127.8 (C-3 & C-5), 128.9 (C-9¹), 134.4 (C-4¹), 137.7 (C-4), 140.7 (C-1). ³¹P NMR (202.4, MHz, CDCl₃) δ: 22.52. EI-MS (m/z, %): 416 (M + 2, 60), 415 (M + 1, 18), 414 (M^+•, 100). Anal. Calcd for C₁₇H₁₇Cl₂N₂O₄P: C, 49.18; H, 4.13; N, 6.75. Found: C, 49.08; H, 4.05; N, 6.64.

2.2.7

2.2.7 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(4-(dimethylamino)phenyl) methylphosphonate 4(g)

Yield: 90 %. IR (KBr) (ν_max cm⁻¹): 3320 (NH), 1268 (P⚌O), 753 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 3.10 (3H, s, –NCH₃), 3.20 (3H, s, –NCH₃), 3.72 (3H, s, P-OCH₃), 3.94 (3H, s, P-OCH₃), 5.32 (1H, s, Ar–OH), 5.46 (1H, d, J = 24.0 Hz, P-CH), 6.55 (1H, s, NH), 6.63–8.52 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 42.7 (NC¹¹ & NC¹¹), 52.0 (d, J = 153.8 Hz, P-CH), 52.9 (d, J = 6.2 Hz, P-OCH₃), 53.8 (d, J = 5.9 Hz, P-OCH₃), 110.8 (C-3¹ & C-5¹), 113.9 (C-2 & C-6), 124.7 (C-2¹ & C-6¹), 128.8 (C-1¹), 130.8 (C-3 & C-5), 139.8 (C-4), 142.8 (C-1), 151.8 (C-4¹), ³¹P NMR (202.4, MHz, CDCl₃) δ: 22.80. EI-MS (m/z, %): 420 (M + 2, 60), 419 (M + 1, 15), 418 (M^+•, 100). Anal. Calcd for C₁₇H₂₁Cl₂N₂O₄P: C, 48.70; H, 5.05; N, 6.68. Found: C, 48.70; H, 5.05; N, 6.68.

2.2.8

2.2.8 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(2-hydroxyphenyl) methylphosphonate 4(h)

Yield: 83 %. IR (KBr) (ν_max cm⁻¹): 3327 (NH), 1264 (P⚌O), 750 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 3.48 (3H, s, P-OCH₃), 3.62 (3H, s, P-OCH₃), 5.34 (1H, s, Ar–OH), 5.84 (1H, d, J = 22.8 Hz, P-CH), 6.20 (1H, s, NH), 6.45–8.72 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 52.8 (d, J = 152.0 Hz, P-CH), 54.2 (d, J = 6.8 Hz, P-OCH₃), 54.8 (d, J = 6.0 Hz, P-OCH₃), 111.9 (C-2 & C-6), 115.5 (C-3¹), 120.5 (C-5¹), 125.9 (C-3 & C-5), 126.5 (C-1¹), 127.2 (C-4¹), 127.6 (C-6¹), 140.0 (C-4), 144.7 (C-1), 155.5 (C-2¹), ³¹P NMR (202.4, MHz, CDCl₃) δ: 21.82. EI-MS (m/z, %): 420 (M + 2, 60), 419 (M + 1, 15), 418 (M^+•, 100). Anal. Calcd for C₁₇H₂₁Cl₂N₂O₄P: C, 48.70; H, 5.05; N, 6.68. Found: C, 48.60; H, 4.98; N, 6.57.

2.2.9

2.2.9 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl) methylphosphonate 4(i)

Yield: 88 %. IR (KBr) (ν_max cm⁻¹): 3319 (NH), 1260 (P⚌O), 752 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 3.42 (3H, s, P-OCH₃), 3.64 (3H, s, P-OCH₃), 5.30 (1H, s, –OH), 5.38 (1H, s, Ar–OH), 5.52 (1H, d, J = 22.2 Hz, P-CH), 6.12 (1H, s, NH), 6.20–8.32 (6H, m, Ar–H). ¹³C NMR (125.7 MHz, CDCl₃) δ: 16.2 (d, J = 6.8 Hz, P-OCH₃), 16.8 (d, J = 6.0 Hz, P-OCH₃), 52.0 (d, J = 152.2 Hz, P-CH), 110.6 (C-2 & C-6), 124.7 (C-1¹), 125.5 (C-3 & C-5), 127.7 (C-2¹), 128.9 (C-6¹), 133.5 (C-4¹), 135.7 (C-5¹), 141.7 (C-4), 143.8 (C-1), 148.8 (C-3¹). ³¹P NMR (202.4, MHz, CDCl₃) δ: 21.52. EI-MS (m/z, %): 422 (M + 2, 60), 420 (M^+•, 100). Anal. Calcd for C₁₅H₁₅Cl₂N₂O₆P: C, 42.78; H, 3.59; N, 6.65. Found: C, 42.68; H, 3.50; N, 6.58.

2.2.10

2.2.10 Dimethyl(2-(benzyloxy)phenyl)(3,5-dichloro-4-hydroxyphenylamino) methylphosphonate 4(j)

Yield: 85 %. IR (KBr) (ν_max cm⁻¹): 3320 (NH), 1268 (P⚌O), 745 (P-C_aliphatic). ¹H NMR (400 MHz, CDCl₃) δ: 3.34 (3H, s, P-OCH₃), 3.56 (3H, s, P-OCH₃), 5.08 (1H, s, –OCH₂), 5.42 (1H, s, Ar–OH), 5.60 (1H, d, J = 20.8 Hz, P-CH), 6.12 (1H, s, NH), 6.15–8.50 (11H, m, Ar–H). ³¹P NMR (202.4, MHz, CDCl₃) δ: 21.12. EI-MS (m/z, %): 511 (M + 2, 60), 510 (M + 1, 20), 509 (M^+•, 100). Anal. Calcd for C₂₂H₂₂Cl₂NO₅P: C, 54.79; H, 4.60; N, 2.90. Found: C, 54.71; H, 4.54; N, 2.81.

2.3

2.3 Antioxidant activity

The antioxidant activity of 4a–j was performed according to three methods. All the synthesized compounds show good activity against DPPH, NO and reducing power scavenging. Among the synthesized compounds 4 h, exhibited high activity when compared with other compounds.

2.3.1

2.3.1 DPPH Radical Scavenging Activity

The scavenging activity of α-aminophosphonates against DPPH radical was performed in accordance with Choi et al. Choi et al. (2002) 85 μM of DPPH was added to a medium containing different α-aminophosphonates. The medium was incubated for 30 min at room temperature. The decrease in absorbance was measured at 518 nm. Ascorbic acid was used as standard reference to record maximal decrease in DPPH radical absorbance. The values are expressed in percentage of inhibition of DPPH radical absorbance with those of the standard control values without the title compounds (ascorbic acid maximal inhibition was considered 100% of inhibition). $DPPH Scavenged (%) = \frac{(A_{cont} - A_{test})}{A_{cont}} \times 100$ where A_cont is the absorbance of the control reaction and A_test is the absorbance in the presence of the sample.

In the case of α-aminophosphonates 4a–j (Fig. 1) derivatives, 4h showed the highest DPPH radical scavenging activity with IC₅₀ at 49.35 μg/mL when compared with other compounds. The remaining compounds exhibited DPPH radical scavenging activity in the following order: 4e (IC₅₀ 52.7 μg/mL), 4b (IC₅₀ 59.8 μg/mL), 4j (IC₅₀ 60.16 μg/mL), 4i (IC₅₀ 62.1 μg/mL), 4c (IC₅₀ 62.2 μg/mL), 4f (IC₅₀ 63.4 μg/mL), 4g (IC₅₀ 66.5 μg/mL), 4a (IC₅₀ 68.2 μg/mL), 4d (IC₅₀ 70.8 μg/mL) and when compared with ascorbic acid (IC₅₀ 50.06 μg/mL).

2.3.2

2.3.2 Nitric Oxide (NO) scavenging activity

The scavenging activity of α-aminophosphonates against nitric oxide radical was performed in accordance with A Shirwaiker et al. Shirwaiker et al. (2004) Sodium nitropruside (5 μM) in phosphate buffer pH 7.4 was incubated with 100 μM concentration of test compounds dissolved in a suitable solvent (dioxane/methanol) and tubes were incubated at 25 °C for 120 min. Control experiment was conducted with equal amount of solvent in an identical manner. At intervals, 0.5 ml of incubation solution was taken and diluted with 0.5 ml of griess reagent (1% Sulfanilamide, 0.1% N-naphthylethylenediamine dihydrochloride and 2% o-phosphoric acid dissolved in distilled water). The absorbance of the chromophore formed during diazotization of nitrite with sulfanilamide and subsequent N-naphthylethylenediamine dihydrochloride was read at $λ$ 546 nm. The experiment was repeated in triplicate.

In the case of α-aminophosphonates 4a–j (Fig. 2) derivatives, 4e showed the highest NO scavenging with IC₅₀ of 53.09 μg/mL when compared with other compounds. The remaining compounds exhibited reducing power activity in the following order: 4h (IC₅₀ 53.7 μg/mL), 4g (IC₅₀ 56.2 μg/mL), 4f (IC₅₀ 59.46 μg/mL), 4j (IC₅₀ 65.8 μg/mL), 4b (IC₅₀ 65.9 μg/mL), 4i (IC₅₀ 67.7 μg/mL), 4d (IC₅₀ 74.8 μg/mL), 4c (IC₅₀ 76.5 μg/mL), 4a (IC₅₀ 81.9 μg/mL) and when compared with ascorbic acid (IC₅₀ 64.9 μg/mL).

2.3.3

2.3.3 Reducing power assay

The reducing power of synthesized compounds 4a–j was determined according to the method of Oyaizu et.al. Saha et al. (2008) The compounds having 50–100 μM were mixed with 2.5 mL of phosphate buffer (0.2 M, pH 6.6) and 2.5 mL of 1% potassium ferricyanide and incubated at 50 °C for 20 min. To this mixture 2.5 mL of 10% trichloroacetic acid (TCA) was added and the mixture was centrifuged at 3000 rpm for 20 min. The upper layer (2.5 mL) was mixed with 2.5 mL of deionized water and 0.5 mL of 0.1% ferric chloride and the UV absorbance was measured at 700 nm using a spectrophotometer. Increase of absorbance of the reaction mixture indicates higher reducing power. Mean values from three independent samples were calculated for each compound and standard deviations were less than 5 %.

In the case of α-aminophosphonates 4a–j (Fig. 3) derivatives, 4h showed the highest reducing power with IC₅₀ of 1.75 μg/mL when compared with other compounds. The remaining compounds exhibited reducing power activity in the following order: 4e (IC₅₀ 1.86 μg/mL), 4j (IC₅₀ 2.09 μg/mL), 4f (IC₅₀ 2.21 μg/mL), 4g (IC₅₀ 2.35 μg/mL), 4i (IC₅₀ 2.63 μg/mL), 4b (IC₅₀ 2.81 μg/mL), 4d (IC₅₀ 3.03 μg/mL), 4a (IC₅₀ 3.12 μg/mL), 4c (IC₅₀ 3.38 μg/mL) and when compared with ascorbic acid (IC₅₀ 2.42 μg/mL).

3 Results and discussion

The conventional method for this three component one pot reaction requires high temperatures and long reaction times to afford the corresponding phosphonates. A new method is developed for the preparation of α-aminophosphonates from a mixture of amine, aldehydes and diethyl phosphite in the presence of amberlyst-15 as catalyst under solvent free conditions by microwave irradiation. (see Scheme 1.)

One pot synthesis of α-aminophosphonates using Amberlyst-15 under MWI.

To optimize the reaction conditions, the reaction of 3,5-dichloro-4-hydroxy phenyl amine (1 mmol), 3-nitro benzaldehyde (1 mmol), and diethylphosphite (1 mmol) was selected as a model. This reaction has been performed in different organic solvents such as toluene, methanol, dioxane, tetrahydrofuran, acrylonitrile, chloroform, dichloromethane, diethyl ether in the presence of Amberlyst-15 at room temperature and a low yield (<75%) of the α-aminophosphonates was obtained in all these experiments. Use of a higher amount of catalyst also did not lead to a significant change in the reaction yields. The best result was obtained (91 %) when the same reaction was done under solvent free conditions with a small amount of (0.1 g) catalyst in one hour at room temperature. To increase the rate of reaction the same experiment was done at different temperatures (Table 1) in the presence of amberlyst-15 as catalyst. In all the cases the reaction time was decreased but the low yield of product was obtained. When the same experiment was done by microwave irradiation in the presence of amberlyst-15 as catalyst, surprisingly the reaction was completed in 4 min with 92 % yield.

Table 1 Influence of temperature on the synthesis of 4d.

S.No	Temp(°C)	Time (min)	Yield^a (%)
1	RT	60	81
2	50	50	72
3	70	50	69
4	90	50	70
5	120	35	68
6	MWI	4	92

a Isolated yield.

Based on the optimized reaction conditions, a group of α-aminophosphonates were synthesized by the reaction of aromatic amine, aromatic/heterocyclic aldehydes and diethyl phosphite. In all the cases the reaction was completed within 4 min in good to excellent yields. In these experiments, the catalyst was isolated by filtration and could be reloaded with fresh reagents for further runs, thus, recyclization of the catalyst is possible without significant loss of activity (Table 2, entry 4d). The products were obtained as solids and purified by column chromatography using silica gel as adsorbent and petroleum ether-ethyl acetate (3:1) as eluent. The chemical structures of 4a–j were confirmed by elemental analysis, IR, ¹H–, ¹³C–, ³¹P– NMR and mass spectral data.

4 Conclusion

A simple, efficient, and environmentally benign method for the synthesis of α-aminophosphonates was developed and also studied their antioxidant activity.

Acknowledgments

The authors thank Prof. C.D. Reddy, Dept. of Chemistry, S.V. University, Tirupati for helpful discussions and for CSIR [01(2347)/09/EMR-II] New Delhi for providing financial assistance.

References

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Ranu B.C., Hajra A., Jana U., . General procedure for the synthesis of α-amino phosphonates from aldehydes and ketones using Indium(III) chloride as a catalyst. Org. Lett.. 1999;1:1141-1143.
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Rao X., Song Z., He L., . Synthesis and antitumor activity of novel α-aminophosphonates from diterpenic dehydroabietylamine. Heteroat. Chem.. 2008;19:512-516.
[Google Scholar]
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Sarvari M.H., . TiO₂ as a new and reusable catalyst for one-pot three-component syntheses of α-aminophosphonates in solvent-free conditions. Tetrahedron. 2008;64:5459-5466.
[Google Scholar]
Shirwaiker A., Rajendran K., Dinesh kumar C., . In vitro antioxidant studies of Annona squamosa Linn Leaves. Indian J. Expl. Biol.. 2004;42:803-807.
[Google Scholar]
Tajbakhsh M., Heydari A., Alinezhad H., Ghanei M., Khaksar S., . Coupling of aldehydes, amines and trimethyl phosphite promoted by Amberlyst-15: highly efficient synthesis of α-amino phosphonates. Synthesis 2008:352-354.
[Google Scholar]
Yadav J.S., Reddy B.V.S., Raj S., Reddy K.B., Prasad A.R., . Zr4+-Catalyzed efficient synthesis of α-aminophosphonates. Synthesis 2001:2277-2280.
[Google Scholar]
Yadav J.S., Subbareddy B.V., Vishnumurthy P., . Amberlyst-15 as a novel and recyclable solid acid for the coupling of aromatic aldehydes with homopropargyl alcohol. Tetrahedron Lett.. 2005;46:1311-1313.
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Introduction

Experimental

Synthesis of diethyl(3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl) methyl phosphonate 4(d)
Spectral data
Antioxidant activity

Results and discussion

Conclusion

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[1] Abhimanyu S.P., Arumugam S., . A novel Cu(OTf)₂ mediated three component high yield synthesis of α-aminophosphonates. Arkivoc. (x) 2006:183-189.
[Google Scholar]

[2] Allen M.C., Fuhrer W., Tuck B., Wade R., Wood J.M., . Renin inhibitors. Synthesis of transition-state analogue inhibitors containing phosphorus acid derivatives at the scissile bond. J. Med. Chem.. 1989;32:1652-1661.
[Google Scholar]

[3] Atherton F.R., Hassal C.H., Lambert R.W., . Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl)phosphonic acid and (aminomethyl)phosphonic acid. J. Med. Chem.. 1986;29:29-40.
[Google Scholar]

[4] Atherton F.R., Hassal C.H., Lambert R.W., . Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (l-aminoethyl) phosphonic acid and (aminomethy1)phosphonic acid. J. Med. Chem.. 1986;29:29-40.
[Google Scholar]

[5] Banik A., Batta S., Bandyopadhyay D., Banik B.K., . A highly efficient Bismuth Salts-catalyzed route for the synthesis of α-aminophosphonates. Molecules. 2010;15:8205-8213.
[Google Scholar]

[6] Bhagat S., Chakraborti A.K., . An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites for the synthesis of α-aminophosphonates catalyzed by magnesium perchlorate. J. Org. Chem.. 2007;72:1263-1270.
[Google Scholar]

[7] Bhattacharya A.K., Tanpreet Kaur T., . An efficient one-pot synthesis of α-amino phosphonates catalyzed by bismuth nitrate pentahydrate. Synlett 2007:745-748.
[Google Scholar]

[8] Bhattacharya A.K., Rana K.C., . Amberlite-IR 120 catalyzed three-component synthesis of α-amino phosphonates in one-pot. Tetrahedron Lett.. 2008;49:2598-2601.
[Google Scholar]

[9] Chandrasekhar S., Prakash S.J., Jagadeshwar V., Narsihmulu C., . Three component coupling catalyzed by TaCl₅–SiO2: synthesis of α-aminophosphonates. Tetrahedron Lett.. 2001;42:5561-5563.
[Google Scholar]

[10] Choi C.W., Kim S.C., Hwang S.S., Choi B.K., Ahn H.J., Lee M.Y., Park S.H., Kim S.K., . Antioxidant activity and free radical scavenging capacity between Korean medicinal plants and flavonoids by assay-guided comparison. Plant Sci.. 2002;153:1161-1168.
[Google Scholar]

[11] Giannousi P.P., Bartlett P.A., . Phosphorus amino acid analogues as inhibitors of leucine aminopeptidase. J. Med. Chem.. 1987;30:1603-1609.
[Google Scholar]

[12] Ha H.J., Nam G.S., . An efficient synthesis of anilinobenzylphosphonates. Synth. Commun.. 1992;22:1143-1148.
[Google Scholar]

[13] Heydari A., Arefi A., . One-pot three-component synthesis of α-aminophosphonate derivatives. 2007;8:1023-1026.

[14] Heydari A., Karimian A., Ipaktschi J., . Lithium perchlorate/diethylether catalyzed aminophosphonation of aldehydes. Tetrahedron Lett.. 1998;39:6729-6732.
[Google Scholar]

[15] Heydari A., Hamadi H., Pourayoubi M., . A new one-pot synthesis of α-amino phosphonates catalyzed by H₃PW₁₂O₄₀. Catal. Commun.. 2007;8:1224-1226.
[Google Scholar]

[16] Heydari A., Khaksar S., Tajbakhsh M., . Trifluoroethanol as a metal-free, homogeneous and recyclable medium for the efficient one-pot synthesis of α-amino nitriles and α-amino phosphonates. Tetrahedron Lett.. 2009;50:77-80.
[Google Scholar]

[17] Hou J.T., Gao J.W., Zhang Z.H., . NbCl₅: an efficient catalyst for one-pot synthesis of α-aminophosphonates under solvent-free conditions. Appl. Organomet. Chem.. 2011;25:47-53.
[Google Scholar]

[18] Kaboudin B., Moradi K., . A simple and convenient procedure for the synthesis of 1-aminophosphonates from aromatic aldehydes. Tetrahedron Lett.. 2005;46:2989-2991.
[Google Scholar]

[19] Laschat S., Kunz H., . Carbohydrates as chiral templates: stereoselective synthesis of (R) - and (S)-α-aminophosphonic acid derivatives. Synthesis 1992:90-95.
[Google Scholar]

[20] Li G., Wei H.X., Hook J.D., . Ytterbium (III) triflate-catalyzed asymmetric nucleophilic addition of functionalized lithium (α-carbalkoxyvinyl)cuprates to chiral p-toluenesulfinimines (thiooxime S-oxides) Tetrahedron Lett.. 1999;40:4611-4614.
[Google Scholar]

[21] Mitragotri S.D., Pore D.M., Desai U.V., Wadgaonkar P.P., . Sulfamic acid: an efficient and cost-effective solid acid catalyst for the synthesis of α-aminophosphonates at ambient temperature. Catal. Commun.. 2008;9:1822-1826.
[Google Scholar]

[22] Mitragotri S.D., Pore D.M., Desai U.V., Wadgaonkar P.P., . Sulfamic acid: an efficient and cost-effective solid acid catalyst for the synthesis of α-aminophosphonates at ambient temperature. Catal. Commun.. 2008;9:1822-1826.
[Google Scholar]

[23] Ranu B.C., Hajra A., Jana U., . General procedure for the synthesis of α-amino phosphonates from aldehydes and ketones using Indium(III) chloride as a catalyst. Org. Lett.. 1999;1:1141-1143.
[Google Scholar]

[24] Rao X., Song Z., He L., . Synthesis and antitumor activity of novel α-aminophosphonates from diterpenic dehydroabietylamine. Heteroat. Chem.. 2008;19:512-516.
[Google Scholar]

[25] Uma Maheswara Rao K., Syama Sundar Ch., Siva Prasad S., Nayak S.K., Suresh Reddy C., . Neat synthesis and anti-oxidant activity of α-hydroxyphosphonates. Bull. Korean Chem. Soc.. 2011;32:3343-3347.
[Google Scholar]

[26] Saha M.R., Hasan S.M.R., Akter R., Hossain M.M., Alam M.S., Alam M.A., Mazumder M.E.H., . In vitro free radical scavenging activity of methanol extract of the leaves of mimusops elengi linn. Bangl. J. Vet. Med.. 2008;6:197-202.
[Google Scholar]

[27] Sarvari M.H., . TiO₂ as a new and reusable catalyst for one-pot three-component syntheses of α-aminophosphonates in solvent-free conditions. Tetrahedron. 2008;64:5459-5466.
[Google Scholar]

[28] Shirwaiker A., Rajendran K., Dinesh kumar C., . In vitro antioxidant studies of Annona squamosa Linn Leaves. Indian J. Expl. Biol.. 2004;42:803-807.
[Google Scholar]

[29] Tajbakhsh M., Heydari A., Alinezhad H., Ghanei M., Khaksar S., . Coupling of aldehydes, amines and trimethyl phosphite promoted by Amberlyst-15: highly efficient synthesis of α-amino phosphonates. Synthesis 2008:352-354.
[Google Scholar]

[30] Yadav J.S., Reddy B.V.S., Raj S., Reddy K.B., Prasad A.R., . Zr4+-Catalyzed efficient synthesis of α-aminophosphonates. Synthesis 2001:2277-2280.
[Google Scholar]

[31] Yadav J.S., Subbareddy B.V., Vishnumurthy P., . Amberlyst-15 as a novel and recyclable solid acid for the coupling of aromatic aldehydes with homopropargyl alcohol. Tetrahedron Lett.. 2005;46:1311-1313.
[Google Scholar]

Entry	R₁	Time (Min)	Yield (%)
4a	Et	4	84
4b	Et	4	86
4c	Et	6	89
4d	Et	5	92(91,90,90,89)^a
4e	Et	6	83
4f	Me	5	89
4 g	Me	6	90
4 h	Me	5	83
4i	Me	4	88
4j	Me	6	85

Neat synthesis and antioxidant activity of α-aminophosphonates

Abstract

Keywords

Multi-component reaction

Amberlyst-15

Microwave Irradiation

Antioxidant activity

1 Introduction

2 Experimental

2.1 Synthesis of diethyl(3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl) methyl phosphonate 4(d)

2.2 Spectral data

2.2.1 Diethyl(3, 5-dichloro-4-hydroxyphenylamino)(1H-indol-3-yl)methylphosphonate 4(a)

2.2.2 Diethyl(3,5-dichloro-4-hydroxyphenylamino)(4-(dimethylamino)phenyl) methylphosphonate 4(b)

2.2.3 Diethyl(3,5-dichloro-4-hydroxyphenylamino)(2-hydroxyphenyl)methylphosphonate 4(c)

2.2.4 Diethyl (3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl)methylphosphonate 4(d)

2.2.5 Diethyl(2-(benzyloxy)phenyl)(3,5-dichloro-4-hydroxyphenylamino) methylphosphonate 4(e)

2.2.6 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(1H-indol-3-yl) methylphosphonate 4(f)

2.2.7 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(4-(dimethylamino)phenyl) methylphosphonate 4(g)

2.2.8 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(2-hydroxyphenyl) methylphosphonate 4(h)

2.2.9 Dimethyl(3,5-dichloro-4-hydroxyphenylamino)(3-nitrophenyl) methylphosphonate 4(i)

2.2.10 Dimethyl(2-(benzyloxy)phenyl)(3,5-dichloro-4-hydroxyphenylamino) methylphosphonate 4(j)

2.3 Antioxidant activity

2.3.1 DPPH Radical Scavenging Activity

2.3.2 Nitric Oxide (NO) scavenging activity

2.3.3 Reducing power assay

3 Results and discussion

4 Conclusion

Acknowledgments

References

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