Potassium Hydroxide Impregnated Alumina (KOH-Alumina) as a Recyclable Catalyst for the Solvent-Free Multicomponent Synthesis of Highly Functionalized Substituted Pyridazines and/or Substituted Pyridazin-3(2<i>H</i>)-ones under Microwave Irradiation

Mecadon, Hormi; Myrboh, Bekington

doi:https://doi.org/10.5402/2011/406427

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Research Article | Open Access

Volume 2011 | Article ID 406427 | https://doi.org/10.5402/2011/406427

Potassium Hydroxide Impregnated Alumina (KOH-Alumina) as a Recyclable Catalyst for the Solvent-Free Multicomponent Synthesis of Highly Functionalized Substituted Pyridazines and/or Substituted Pyridazin-3(2H)-ones under Microwave Irradiation

Hormi Mecadon¹and Bekington Myrboh¹

Academic Editor: G. R. Cook, J. Perez-Castells, G. Kirsch

Received27 Jan 2011

Accepted03 Mar 2011

Published12 Apr 2011

Abstract

The work described herein employs potassium hydroxide impregnated alumina (KOH-alumina) as a mild, efficient, and recyclable catalyst for a one-pot solvent-free and environmentally safer synthesis of 3,4,6-triarylpyridazines and some substituted pyridazines from active methylene carbonyl species, 1,2-dicarbonyls, and hydrazine hydrate by microwave (MW) irradiation. The method offers highly convergent, inexpensive, and functionality-tolerable procedure for rapid access to important pyridazine compounds in good yields.

1. Introduction

Pyridazines have received considerable attention because of their important pharmacological and biological properties [1]. Several pyridazine compounds exhibit antimicrobial [2], potent analgesic [3], COX inhibitor [4], antidiabetic [5], antihypertensive [6], herbicidal [7], anticancer [8], and antifungal [9] activities. Further, various pyridazinones have been used as intermediates for drugs and agrochemicals [5] and blood platelet aggregation inhibitors [10].

The synthesis of pyridazine frameworks has been achieved primarily by the addition of hydrazine or its derivative to an appropriate 1,4-diketones and 1,4-ketoacids [11–13]. Other various pyridazines particularly amino-pyridazines have been prepared from polyfunctionalized nitriles, especially via the Jaap-Klingemaan reaction [14–18]. The literature also showed the preparation of pyridazines and pyridazinones involving active methylene species, benzil, and hydrazine. However, the methods employed harsh bases [19–21] or acids [22] in presence of hazardous solvents, and also the reactions require long period of time to complete. Therefore, there is a need for developing a milder and safer solvent-free procedure for the synthesis of substituted pyridazines especially because of the rise in demand for environmentally benign organic synthesis.

To address the challenge of green synthesis, multicomponent reactions (MCRs) provide a solution since they are more efficient, cost effective, and less wasteful than traditional methods. Such synthetic approach, however, when teamed with microwave (MW) irradiation, facilitates the reaction better as MW gives very efficient thermal management and atom efficiency thus resulting in faster reaction with an increased product yield. In another development, in recent years, the use of inorganic solid supports as catalysts for the synthesis of various biologically active molecules has increased tremendously. Among these inorganic solid supports, potassium hydroxide coated with alumina (KOH-alumina) has been a versatile reagent for various reactions and transformations such as in transesterification and biodiesel production [23–26], ester hydrolysis [27], selective alkylation [28–30], Michael addition [31], cyanoethylation [32], and gas phase dehydrogenations [33]. It has also been found that KOH-alumina exhibited the highest basicity and superior catalytic activity among the alumina-supported alkaline catalysts during transesterification processes [25]. Moreover, KOH-alumina can be prepared easily and is inexpensive. In view of these advantages in the applications of heterogeneous catalysts in the synthesis of heterocyclic compounds, we have chosen KOH-alumina (10% in alumina) for the synthesis of some substituted pyridazines.

Therefore, based on our previous work on pyridazine synthesis [21] and in conjunction with our current research aimed at development of synthetic methodologies using solid support catalysts through MCR’s [34–36], we report herein the three-component neat synthesis of 3,4,5-triarylpyridazines and other substituted pyridazines using KOH-alumina (10 mol%) by the microwave irradiation technique (Scheme 1).

Initially, the three-component synthesis was optimized by irradiating a mixture of acetophenone (2a) (0.2 mL, 1.50 mmol), benzil (1) (0.32 g, 1.50 mmol) and hydrazine hydrate (3) (0.10 mL, 2.00 mmol) in presence of 5 mol% KOH-alumina in a microwave reactor at 100°C for three minutes which afforded the product 4a in 57% yield. The same reaction when irradiated for ten minutes gave 4a in 64% yield. By varying the amount of the catalyst and irradiation time, optimization was finally arrived at 10 mol% of KOH-alumina which significantly resulted in 89% of the product 4a (Table 1). In another attempt, the catalyst recovered from the reaction after filtration, and washing with ethyl acetate was used further for the condensation of acetophenone (2a) (0.20 mL, 1.50 mmol), benzil (1) (0.32 g, 1.50 mmol), and hydrazine hydrate (3) (0.10 mL, 2.00 mmol). Interestingly, the reaction was observed to complete within 15 min of irradiation giving 4a in 61% yield. The results of the reactions using recycled KOH-alumina are shown in Table 1.

Thus, the present method was employed for the synthesis of a series of 3,4,5-triarylpyridazines involving different aromatic ketones (4a–g, Table 2). Irrespective of the presence of different substituents in the ortho and para positions on the ring of various aromatic aldehydes, the reactions proceeded well to furnish the desired products in good yields (4a–g, Table 2). Unfortunately, the reaction performed with meta substituted aromatic ketones gave only unisolable intermediates and failed to furnish the desired products. On the other hand, polyaromatic acetophenones such as 2-acetylnaphthalene (2h) underwent reaction smoothly with benzil (1) and hydrazine hydrate (3) to afford the desired product 4h in 77% yield (entry 9, Table 2).

Similarly, the scope of this methodology was extended to synthesize other substituted pyridazines involving different active methylene carbonyl compounds such as ethyl cyano acetate (5a), diethyl malonate (5b), ethyl acetoacetate (5c), and acetyl acetone (5d) (Scheme 2). In all the cases the reactions proceeded fairly well and afforded the desired products in good yields (6a–f), (Table 3).

The reactions were clean and all the products were purified by simple work-up and crystallization except for products 4d, 4g, 4h, and 6b which were purified by column chromatography using ethyl acetate and hexane. All the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, IR, Mass, and Elemental analyses which were found to be in good agreement with the expected data.

From the mechanistic point of view, the formation of the triarlpyridazines 4 probably takes place through the addition of hydrazine hydrate to the 1, 4-dicarbonyl species (8) formed in situ by reaction between the acetophenone (2) and 1,2-dicarbonyl compound (1) in a similar fashion as reported earlier [21]. The overall plausible mechanism for the formation of the triarylpyridazines is depicted in Scheme 3.

2. Conclusion

In summary, we have established a mild and efficient method for the synthesis of highly functionalized substituted pyridazines and other substituted pyridazinones using KOH-alumina (10 mol%). More importantly, the methodology presented here offers milder, more efficient, and particularly an environmentally friendly approach towards the synthesis of pyridazines by the use of potassium hydroxide impregnated on alumina as a recyclable catalyst.

3. Experimental Section

All the chemicals obtained commercially were directly used without further purification. KOH-alumina was prepared according to the procedure reported by Sukata [28], however, as 10% of KOH adsorbed on neutral alumina. Melting points were recorded by open capillary tube method and were uncorrected. The thin layer chromatography was performed on ACME’s silica or Merck precoated silica gel and the components were visualized in iodine chamber or by potassium permanganate spray technique. Flash column chromatography was performed on Merck silica gel (60–120 mesh) using ethyl acetate-hexane (3 : 7) as the eluent. IR spectra were recorded with Perkin-Elmer FT-IR spectrometer. The ¹H and ¹³C NMR were recorded with Bruker AVANCE II 400 FT-NMR machine with TMS as the internal standard. Mass spectra were recorded with Waters ZQ-4000 equipped with ESI and APCI mass detector, and CHN was analyzed on Perkin-Elmer PE 2400 Series II.

3.1. General Procedure

3.1.1. Procedure for the Synthesis of 4(a–h)

A thoroughly mixed aromatic ketone (2) (1.50 mmol), 1,2-dicarbonyl compound (1) (1.50 mmol), hydrazine hydrate (3) (0.1 mL, 2.00 mmol) in presence of 10 mol% KOH-alumina was irradiated in a Chem Discover microwave reactor at 100°C (power 200 W) at regular intervals of 60 sec for 5–10 min. On completion of the reaction (monitored by thin layer chromatography), the reaction mixture was diluted with ethyl acetate and filtered on a sintered funnel. It was further washed down with ethyl acetate (5 mL × 4). The filtrate was then worked up with cold water, and the organic layer was separated and dried with anhydrous Na₂SO₄. The organic filtrate was evaporated in vacuo to afford the crude product which was crystallized from ethanol (4a, 4b, 4c, 4e, and 4f) or purified by flash column chromatography (4d, 4g, and 4h) over silica gel (60–120 mesh) using ethyl acetate-hexane (3 : 7) as the eluent to afford the 3,4,6-triarylpyridazines.

3.1.2. Procedure for the Synthesis of 6(a–f)

A thoroughly mixed 1,2-dicarbonyl compound (1) (1.50 mmol) and hydrazine hydrate (3) (2.00 mmol) was irradiated in a Chem Discover microwave reactor at 100°C (power 200 W) for 5 minutes. The mixture was cooled and then introduced therein the active methylene species (5) (1.50 mmol) and KOH-alumina (10 mol%). The components were mixed thoroughly and subjected to microwave irradiation at 100°C (power 200 W) for 3–6 minutes. On completion of the reaction (monitored by thin layer chromatography), the reaction mixture was diluted with ethyl acetate and filtered on a sintered funnel. It was further washed down with ethyl acetate (5 mL × 4). The filtrate was then worked up with cold water and the organic layer was separated and dried with anhydrous Na₂SO₄. The organic filtrate was evaporated in vacuo to afford the crude product which was crystallized from ethanol (6a, 6c, 6d, 6e, and 6f) or purified by flash column chromatography (6b) over silica gel (60–120 mesh) using ethyl acetate-hexane (3 : 7) as the eluent to afford the pure product.

3,4,6-triphenylpyridazine (4a, Table 2)
White solid; mp 182–184°C; ¹H NMR (400 MHz, CDCl₃): 7.27–7.89 (m, 13H, Ar-H), 8.20 (s, 1H, Ar-H), 8.20 (d, 2H, Hz, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 124.5, 126.6, 127.6, 128.3, 128.6, 129.5, 129.6, 135.4, 136.0, 136.6, 139.2, 157.2, 157.7 ppm; IR (KBr): 1075, 1177, 1394, 1444, 1488, 1582, 2854, 2924, 3063 cm⁻¹; MS (ES⁺) for C₂₂H₁₆N₂ 308.1 found 308.9 (M + H)⁺, 331.0 (M + Na)⁺; CHN calcd. for C₂₂H₁₆N₂ C, 85.69; H, 5.23; N, 9.08 found C, 85.71; H, 5.38; N, 9.32.

3,4-diphenyl-6-p-tolylpyridazine (4b, Table 2)
Light yellow solid; mp 160–162°C; ¹H NMR (400 MHz, CDCl₃): 2.43 (s, 3H, CH₃), 7.25–7.35 (m, 10H, Ar-H), 7.48 (d, 2H, Hz, Ar-H), 7.83 (s, 1H, Ar-H), 8.08 (d, 2H, Hz, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 21.4, 124.7, 126.9, 128.1, 128.7, 129.0, 129.8, 130.0, 133.0, 136.5, 137.1, 139.6, 140.4, 157.6, 157.9 ppm; IR (KBr): 1079, 1222, 1367, 1419, 1592, 2867, 2923, 3019 cm⁻¹; MS (ES⁺) for C₂₃H₁₈N₂ 322.1 found 323.0 (M + H)⁺, 345.0 (M + Na)⁺; CHN calcd. for C₂₃H₁₈N₂ C, 85.68; H, 5.63; N, 8.69 found C,85.55; H, 5.65; N, 8.44.

6-(2-methoxyphenyl)-3,4-diphenylpyridazine (4c, Table 2)
White solid; mp 137–139°C; ¹H NMR (400 MHz, CDCl₃): 3.85 (s, 3H, OCH₃), 7.00–7.30 (m, 12H, Ar-H), 7.43 (s, 1H, Ar-H), 8.03 (d, 2H, Hz, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 55.8, 111.4, 121.4, 124.7, 128.2, 128.7, 128.9, 129.2, 130.1, 131.5, 131.6, 136.3, 137.0, 139.1, 156.9, 157.3, 157.7 ppm; IR (KBr): 1076, 1199, 1206, 1371, 1496, 1509, 2877, 2943, 3016 cm⁻¹; MS (ES⁺) for C₂₃H₁₈N₂O 338.1 found 339.0 (M + H)⁺, 361.0 (M + Na)⁺; CHN calcd. for C₂₃H₁₈N₂O C, 81.63; H, 5.36; N, 8.28 found C, 81.59; H, 5.16; N, 8.35.

6-(4-methoxyphenyl)-3,4-diphenylpyridazine (4d, Table 2)
Yellow solid; mp 164–166°C; ¹H NMR (400 MHz, CDCl₃): 3.87 (s, 3H, OCH₃), 7.04 (d, 2H, Hz, Ar-H), 7.21–7.35 (m, 8H, Ar-H), 7.47 (d, 2H, Hz, Ar-H), 7.79 (s, 1H, Ar-H), 8.15 (d, 2H, Hz, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 55.39, 114.4, 124.2, 128.2, 128.3, 128.4, 128.6, 128.7, 129.0, 130.0, 136.7, 137.2, 139.5, 157.2, 157.6, 161.3 ppm; IR (KBr): 1067, 1208, 1310, 1487, 1562, 2877, 2931, 3012 cm⁻¹; MS (ES⁺) for C₂₃H₁₈N₂O 338.1 found 339.0 (M + H)⁺, 361.0 (M + Na)⁺; CHN calcd. for C₂₃H₁₈N₂O C, 81.63; H, 5.36; N, 8.28 found C, 81.58; H, 5.29; N, 8.11.

6-(4-bromophenyl)-3,4-diphenylpyridazine (4e, Table 2)
White solid; mp 147–149°C; ¹H NMR (400 MHz, CDCl₃): 7.05–7.45 (m, 12H, Ar-H), 7.74 (s, 1H, Ar-H), 8.08 (d, 2H, Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): 122.6, 125.2, 126.9, 127.2, 128.2, 128.8, 128.9, 129.1, 130.1, 130.2, 131.6, 131.8, 135.8, 136.4, 137.0, 139.9, 157.7, 158.2 ppm; IR (KBr): 1075, 1296, 1400, 1488, 1571, 2934, 3011 cm⁻¹; MS (ES⁺) for C₂₂H₁₅BrN₂ 386.0 found 387.0 (M + H)⁺, 409.0 (M + Na)⁺; CHN calcd. for C₂₂H₁₅BrN₂ C, 68.23; H, 3.90; N, 7.23 found C, 68.21; H, 3.73; N, 7.11.

6-(4-chlorophenyl)-3,4-diphenylpyridazine (4f, Table 2)
Light yellow solid; mp 179–181°C; ¹H NMR (400 MHz, CDCl₃): 7.06–7.44 (m, 12H, Ar-H), 7.73 (s, 1H, Ar-H), 8.08 (d, 2H, Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): 125.1, 126.4, 126.5, 127.1, 127.2, 128.2, 128.6, 128.9, 129.1, 129.5, 129.7, 130.1, 130.2, 135.9, 136.5, 139.8, 157.7, 158.2 ppm; IR (KBr): 1076, 1200, 1301, 1481, 1546, 2879, 2932, 3088 cm⁻¹; MS (ES⁺) for C₂₂H₁₅ClN₂ 342.1 found 343.0 (M + H)⁺, 365.0 (M + Na)⁺; CHN calcd. for C₂₂H₁₅ClN₂ C, 77.08; H, 4.41; N, 8.17 found C, 77.26; H, 4.59; N, 8.06.

6-(4-nitrophenyl)-3,4-diphenylpyridazine (4g, Table 2)
White solid; mp 164–166°C; ¹H NMR (400 MHz, CDCl₃): 7.16–7.44 (m, 11H, Ar-H), 7.56 (t, 1H, Hz, Ar-H), 7.79 (s, 1H, Ar-H), 8.07 (d, 2H, Hz, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 123.0, 123.6, 126.1, 127.3, 128.2, 128.9, 129.0, 129.1, 129.3, 129.6, 134.4, 135.6, 140.9, 148.1, 157.6, 158.1 ppm; IR (KBr): 1076, 1230, 1309, 1441, 1541, 2877, 2932, 3081 cm⁻¹; MS (ES⁺) for C₂₂H₁₅N₃O₂ 353.1 found 354.0 (M + H)⁺, 376.0 (M + Na)⁺; CHN calcd. for C₂₂H₁₅N₃O₂ C, 74.78; H, 4.28; N, 11.89 found C, 74.53; H, 4.40; N, 11.76.

6-(naphthalen-2-yl)-3,4-diphenylpyridazine (4h, Table 2)
White solid; mp 190–192°C; ¹H NMR (400 MHz, CDCl₃): 7.10–7.73 (m, 18H, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 124.2, 125.4, 125.8, 126.1, 127.3, 127.9, 128.3, 128.8, 129.0, 129.1, 130.2, 130.3, 133.1, 135.6, 136.9, 157.7, 158.2 ppm; IR (KBr): 1080, 1234, 1290, 1438, 1521, 2861, 2932, 2995, 3043 cm^-1; MS (ES⁺) for C₂₆H₁₈N₂ 358.1 found 359.0 (M + H)⁺, 381.0 (M + Na)⁺; CHN calcd. for C₂₆H₁₈N₂ C, 87.12; H, 5.06; N, 7.82 found C, 87.31; H, 5.21; N, 7.71.

2,3-dihydro-3-oxo-5,6-diphenylpyridazine-4-carbonitrile (6a, Table 3)
White solid; mp 270–272°C; ¹H NMR (400 MHz, CDCl₃ + DMSO-): 6.91–7.94 (m, 10H, Ar-H), 11.58 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃ + DMSO-): 110.3, 116.5, 127.8, 128.9, 129.1, 129.6, 130.2, 131.4, 132.7, 133.6, 135.3, 146.9, 158.2 ppm; IR (KBr): 1010, 1089, 1210, 1464, 1511, 1693, 2256, 2868, 2932, 3412 cm⁻¹; MS (ES⁺) for C₁₇H₁₁N₃O 273.1 found 274.0 (M + H)⁺, 296.0 (M + Na)⁺; CHN calcd. for C₁₇H₁₁N₃O C, 74.71; H, 4.06; N, 15.38 found C, 74.86; H, 4.21; N, 15.12.

2,3-dihydro-3-oxopyridazine-4-carbonitrile (6b, Table 3)
White solid; mp 182–184°C; ¹H NMR (400 MHz, CDCl₃ + DMSO-): 7.24 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 11.57 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃ + DMSO-): 110.4, 118.3, 138.7, 152.3, 168.8 ppm; IR (KBr): 1089, 1212, 1400, 1526, 1676, 2247, 2881, 2932, 3310 cm⁻¹; MS (ES⁺) for C₅H₃N₃O 121.0 found 122.0 (M + H)⁺, 144.0 (M + Na)⁺; CHN calcd. for C₅H₃N₃O C, 49.59; H, 2.50; N, 34.70 found C, 49.53; H, 2.41; N, 34.62.

2,3-dihydro-5,6-dimethyl-3-oxopyridazine-4-carbonitrile (6c, Table 3)
White solid; mp 209–211°C; ¹H NMR (400 MHz, CDCl₃ + DMSO-): 2.33 (s, 3H, CH₃), 2.50 (s, 3H, CH₃), 11.25 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃ + DMSO-): 9.9, 27.6, 116.7, 126.2, 152.8, 157.4, 167.9 ppm; IR (KBr): 1046, 1287, 1412, 1547, 1671, 2219, 2931, 3349 cm⁻¹; MS (ES⁺) for C₇H₇N₃O 149.1 found 150.0 (M + H)⁺, 172.0 (M + Na)⁺; CHN calcd. for C₇H₇N₃O C, 56.37; H, 4.73; N, 28.17 found C, 56.21; H, 4.68; N, 28.32.

Ethyl 2,3-dihydro-3-oxo-5,6-diphenylpyridazine-4-carboxylate (6d, Table 3)
White solid; mp 217–219°C; ¹H NMR (400 MHz, CDCl₃): 0.90 (t, 3H, Hz, CH₃), 4.05 (q, 2H, Hz, CH₂), 7.03–7.27 (m, 10H, Ar-H), 12.56 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): 13.7, 62.0, 128.0, 128.3, 128.7, 129.1, 129.2, 133.7, 133.8, 134.7, 143.3, 147.7, 158.7, 163.6 ppm; IR (KBr): 1101, 1200, 1432, 1500, 1672, 1768, 2867, 2931, 3401 cm⁻¹; MS (ES⁺) for C₁₉H₁₆N₂O₃ 320.1 found 321.0 (M + H)⁺, 343.0 (M + Na)⁺; CHN calcd. for C₁₉H₁₆N₂O₃ C, 71.24; H, 5.03; N, 8.74 found C, 71.43; H, 5.17; N, 8.68.

Ethyl 3-methyl-5,6-diphenylpyridazine-4-carboxylate (6e, Table 3)
White solid; mp 77–79°C; ¹H NMR (400 MHz, CDCl₃ + DMSO-): 0.95 (t, 3H, Hz, CH₃), 2.65 (s, 3H, CH₃), 4.05 (q, 2H, Hz, CH₂), 7.14–7.46 (m, 10H, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃ + DMSO-): 14.6, 23.7, 61.4, 126.7, 126.9, 127.5, 128.3, 128.8, 129.3, 130.1, 132.1, 132.7, 134.6, 137.8, 139.5, 141.0, 152.6, 196.3 ppm; IR (KBr): 1087, 1100, 1280, 1434, 1510, 1769, 2862, 2932, 3084 cm⁻¹; MS (ES⁺) for C₂₀H₁₈N₂O₂ 318.1 found 319.0 (M + H)⁺, 341.0 (M + Na)⁺; CHN calcd. for C₂₀H₁₈N₂O₂ C, 75.45; H, 5.70; N, 8.80 found C, 75.57; H, 5.69; N, 8.82.

1-(3-methyl-5,6-diphenylpyridazin-4-yl)ethanone (6f, Table 3)
White solid; mp 132–134°C; ¹H NMR (400 MHz, CDCl₃): 1.82 (s, 3H, CH₃), 2.59 (s, 3H, CH₃), 7.18–7.47 (m, 10H, Ar-H) ppm; ¹³C NMR (100 MHz, CDCl₃): 21.9, 27.6, 126.7, 126.8, 128.5, 129.3, 129.7, 130.0, 134.6, 135.8, 136.6, 138.4, 138.8, 151.2, 152.3, 186.9 ppm; IR (KBr): 1201, 1240, 1433, 1520, 1692, 2888, 2932, 3100 cm⁻¹; MS (ES⁺) for C₁₉H₁₆N₂O 288.1 found 289.0 (M + H)⁺, 311.0 (M + Na)⁺; CHN calcd. for C₁₉H₁₆N₂O C, 79.14; H, 5.59; N, 9.72 found C, 79.33; H, 5.51; N, 9.77.

Acknowledgments

H. Mecadon thanks the University Grants Commission (UGC), India for the Financial Assistance under the RGNF scheme, and the SAIF, NEHU for the data analyses.

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Copyright © 2011 Hormi Mecadon and Bekington Myrboh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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