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A Facile and Microwave Assisted Solvent Free Synthesis of Novel Indole Pyrimidine Imide Derivatives

  • Mahesh Goud BakkollaEmail author
  • Ashok Kumar Taduri
  • Rama Devi Bhoomireddy
Original Article
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Abstract

A series of novel indole derivatives bearing pyrimidine and cyclic imide scaffolds such as phthalic and maleic anhydrides has been designed and synthesized using both conventional and microwave irradiation (MW) methods under solvent free conditions. The title compounds have been developed by the reaction of 2-aminoo-4-hydroxy-6-(5,1-substituted-indol-3-yl) pyrimidine-5-carbonitrile with phthalic and maleic anhydrides individually using MW method. In addition, these target compounds were also synthesised under conventional heating method. A considerable increase in the reaction rate has been observed with better yields (90–92%) within 2–6 min using microwave irradiation in comparison to conventional thermal treatment.

Graphic Abstract

Keywords

Indole-3-carbaldehyde Pyrimidine Phthalic anhydride Maleic anhydride Microwave irradiation Solvent free condition 

1 Introduction

One of the main aims of green chemistry is the reduction of the use of organic solvents because of the economical and environmental concerns associated with them, and therefore the development of solvent-free synthetic methods is of the utmost importance. Microwave irradiation (MW) has occurred as a powerful technique offering clean, fast, efficient and economical method for the synthesis of organic compounds with high yields when compare to conventional heating methods [1, 2, 3, 4]. The application of MW in organic synthesis has been the focus of considerable attention in recent years and is becoming a popular technology [5, 6, 7, 8, 9, 10, 11, 12]. Indole and other heterocyclic compounds containing indole moiety, have proven to be versatile intermediates for the synthesis of a wide range of bioactive drugs [13, 14, 15]. Furthermore, a literature survey demonstrates that a combination of two or more active structural moieties can possibly augment the bioactivity. A variety of N-based heterocycles, such as pyridine [16], quinolone [17] and quinazoline [18] have been integrated with the indole nucleus to obtain potent molecules. Among these moieties, the pyrimidine ring system was chosen because its today’s use in chemotherapy [19]. Over the years, pyrimidine ring systems have been widely explored for their wide range of biological activities [20, 21, 22, 23, 24, 25, 26] and were found to be potent as antitumor, [27, 28] antimicrobial [29, 30] and antioxidant agents [31]. According to the previously mentioned benefits, the combination of indole and pyrimidine moieties will greatly enhance the biological activity [32] of the compounds they present.

In addition to pyrimidines, N-arylphthalimides also are very important compounds which shows effective biological properties such as antifungal [33], antimicrobial [34], hypolipidemic [35, 36], antihistaminic [37], anticonvulsant [38, 39], histone-deacetylase-inhibitory [40] and HIV-1 transcriptase inhibitory [41] activities and some phthalimide derivatives are also used in tuberculosis therapy and growth healing for plants [42, 43]. The combination of indole and phthalimides were reported earlier such as N-phthaloyl derivatives of tryptophan possessing bielectrophoric activities [44] but there is not much work reported in the literature for the synthesis of indoles in combination with phthalimides and other imides.

N-arylphthalimides derivatives have been synthesized by many routes, including condensation of an anhydride and amine in acetic anhydride catalysed by acids [45], N-alkylation of imides in alcohol media [46] and N-alkylation of phthaloyl dichloride with azide in the presence of triphenylphosphine [47], cyclization in nitrobenzene [48] and toluene [49]. But these methods have some disadvantages like use of acids, longer reaction times, unstable organic solvents, noxious catalysts and recovery of yields in a very small amount. Phthalimide synthesis has also been reported using ionic liquids like [bmim] [BF4] [50] and [bmim] [PF6] [51] or non-ionic liquid solvents like PEG-400 [52]. Although all the above synthetic methods have showed better yields, but they still hold some limitations like longer reaction times, use of organic solvents during work-up etc.

Based on the above findings for the synthesis of indole based compounds in combination with pyrimidines, phthalimides and cyclic imides were not explored much by considering the inclusion of these scaffolds in a single molecular frame work. In view of this, a new class of indole pyrimidine cyclic imide hybrids i.e. 2-(1,3-dioxoisoindolin-2-yl)-4-hydroxy-6-(1,5-substituted-1H-indol-3-yl)pyrimidine-5-carbonitrile 6af and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(1,5-substituted-indol-3-yl)pyrimidine-5-carbonitrile 8af were synthesized under solvent free conditions using microwave irradiation (MW) technique as a rapid, convenient method which gave excellent yields and high purity of the products than conventional methods.

All newly synthesised compounds were characterised by 1H-NMR, 13C-NMR, LC–MS, spectroscopic methods.

2 Experimental Section

All chemicals were purchased from Sigma-Aldrich and used without further purification. Melting points of all newly synthesised compounds were determined in open capillaries using hot sulfuric acid bath. The progress of the reaction and purity of the compounds were checked by silica gel coated Thin Layer Chromatography (TLC) plate and visualization purpose we are using UV lamp. The MW method employed a multimode reactor (Synthos 3000, Aton Paar GmbH, and 1400 W maximum magnetron). 1H-NMR spectra were recorded in DMSO-d6 and tetramethylsilane (TMS) as an internal standard using Varian 400-MHz spectrometer instrument. 13C-NMR spectra were recorded in Avance 300-MHZ instrument. Mass spectra were recorded on Agilent LC–MS instrument.

2.1 General Procedure for the Synthesis of 2-Amino-4-hydroxy-6-(5,1-substituted-indol-3-yl)pyrimidine-5-carbonitrile 4a–f

A mixture of 1af (1 mmol), ethylcyanoacetate 2 (1 mmol) and guanidine hydrochloride 3 (2 mmol) taken into a 100 ml round bottom flask and added a catalytic amount of l-proline in ethanol (20 ml). This reaction mixture was refluxed with stirring for 2 h and the progress of the reaction monitored by Thin Layer Chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice cold water to get pure solid 4af.

2.2 General Procedure for the Preparation of 6a–f and 8a–f

A mixture of 4af and phthalic anhydride 5 (0.1 mmol), 4af and maleic anhydride 7 (0.1 mmol) individually taken into two separate 25 ml round bottom flasks. These reaction mixtures were allowed to heat on a mantle separately for 2 h. The progress of the reactions was monitored by Thin Layer Chromatography. After completion of the reactions, the reaction mixtures were poured into ice cold water individually, and the obtained products were filtered and dried to obtain target compounds 6af and 8af respectively.

2.3 General Procedure for the Preparation of 6a–f and 8a–f Under MW Method

A mixture of 4af and phthalic anhydride 5 (0.1 mmol) was charged into a microwave pressure vial and irradiated in a microwave reactor (Synthos 3000 Aton Paar, GmbH, 1400 W maximum magnetron) at 400 W and 140 °C for 4–6 min. In another setup, A mixture of 4af and maleic anhydride 7 (0.1 mmol) was charged into a separate microwave pressure vial and irradiated in the microwave reactor at 200 W and 60 °C for 2–5 min. After completion of the reaction, the purity and formation of the products were monitored by Thin Layer Chromatography. Both the reaction the mixtures were poured into ice cold water separately to obtain the solid precipitates which were filtered and dried to obtain crude products 6af and 8af respectively.

2.4 6a: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(1-methyl-1H-indol-3-yl)yrimidine-5-carbonitrile

White solid: yield 92%; M.P = 225–227 °C. 1H-NMR (DMSO-d6): δ 12.46 (s, 1H, OH, D2O exchangeable), 10.44 (s, 1H, NH, D2O exchangeable), 8.17–7.40 (m, 9H, Ar–H); 13C-NMR (100 MHZ; DMSO-d6): δ 176.55, 167.65, 167.61, 135.58, 133.03, 130.74, 130.51, 129.06, 129.03, 128.96, 128.57, 127.31, 123.26, 121.85, 120.36, 115.29, 88.36; MS: m/z 382.10 (M + 1). Anal. Calcd for C21H11N5O3 (381.09): C, 66.14; H, 2.91; N, 18.36; O, 12.59% Found: C, 65.92; H, 2.58; N, 17.98; O, 12.26%.

2.5 6b: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(1-methyl-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 90%; M.P = 218–220 °C; 1H-NMR (DMSO-d6): δ 12.40 (s, 1H, –OH, D2O exchangeable), 8.01–7.39 (m, 9H, Ar–H), 3.24 (s, 3H, CH3); 13C-NMR (100 MHZ; DMSO-d6): δ 177.93, 168.98, 168.79, 136.78, 134.19, 131.96, 130.78, 129.98, 129.93, 128.56, 128.32, 127.33, 124.25, 121.86, 121.25, 114.59, 85.33, 34.05; MS: m/z 396.04 (M + 1). Anal. Calcd for C22H13N5O3 (395.10): C, 66.83; H, 3.31; N, 17.71; O, 12.59% Found: C, 66.72; H, 3.34; N, 17.68; O, 12.42%.

2.6 6c: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(5-nitro-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 92%; M.P = 234–236 °C, 1H-NMR (DMSO-d6): δ 12.29 (s, 1H, OH, D2O exchangeable), 10.44 (s, 1H, NH, D2O exchangeable), 8.69–7.50 (m, 8H, Ar–H);13C-NMR (100 MHZ; DMSO-d6): δ 178.13, 168.92, 168.56, 136.84, 132.32, 130.83, 130.03, 129.46, 129.23, 128.82, 128.46, 127.33, 123.35, 121.96, 120.03, 115.09, 85.42; MS: m/z 427.03 (M + 1). Anal. Calcd for C21H10N6O5 (426.07): C, 59.16; H, 2.36; N, 19.71; O, 18.76% Found: C, 59.06; H, 2.24; N, 19.64; O, 18.72%.

2.7 6d: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(1-methyl-5-nitro-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 92%; M.P = 230–232 °C; 1H-NMR (DMSO-d6): δ 12.19 (s, 1H, OH, D2O exchangeable), 8.91–7.32 (m, 8H, Ar–H), 3.61 (s, 3H, CH3); 13C-NMR (100 MHZ; DMSO-d6): δ 178.07, 168.95, 168.85, 136.82, 132.30, 130.87, 130.04, 129.56, 129.23, 128.82, 128.56, 127.33, 123.33, 121.96, 120.03, 115.09, 85.60, 34.30; MS: m/z 441.13 (M + 1). Anal. Calcd for C22H12N6O5 (441.13): C, 60.00; H, 2.75; N, 19.08; O, 18.17% Found: C, 60.02; H, 2.72; N, 18.92; O, 17.96%.

2.8 6e: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(5-methoxy-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 90%; M.P = 220–224 °C; 1H-NMR (DMSO-d6): δ 12.36 (s, 1H, OH, D2O exchangeable), 10.48 (s, 1H, NH, D2O exchangeable), 8.10–7.48 (m, 8H, Ar–H), 3.89 (s, 3H, OCH3); 13C-NMR (100 MHZ; DMSO-d6): δ 175.56, 168.37, 168.36, 151.10, 135.38, 133.35, 130.77, 130.76, 129.51, 129.32, 128.63, 128.32, 127.20, 123.65, 121.81, 120.15, 115.36, 85.33, 56.35; MS: m/z 412.10 (M + 1). Anal. Calcd for C22H13N5O4 (411.10): C, 64.23; H, 3.19; N, 17.02; O, 15.56% Found: C, 64.02; H, 3.18; N, 17.00; O, 15.42%.

2.9 6f: 2-(1,3-Dioxoisoindolin-2-yl)-4-hydroxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 90%; M.P = 226–228 °C; 1H-NMR (DMSO-d6): δ 12.23 (s, 1H, OH, D2O exchangeable), 8.37–7.38 (m, 8H, Ar–H), 3.82 (s, 3H, OCH3), 3.67 (s, 3H, CH3); 13C-NMR (100 MHZ; DMSO-d6): δ 176.50, 167.55, 167.50, 150.90, 135.30, 133.30, 130.77, 130.56, 129.55, 129.22, 128.95, 128.52, 127.20, 123.65, 121.81, 120.26, 115.37, 85.39, 55.50, 34.95; MS: m/z 426.10 (M + 1). Anal. Calcd for C22H13N5O3 (395.10): C, 64.94; H, 3.55; N, 16.46; O, 15.04% Found: C, 65.02; H, 3.48; N, 16.38; O, 14.92%.

2.10 8a: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 92%; M.P = 225–227 °C; 1H-NMR (DMSO-d6): δ 12.86 (s, 1H, OH, D2O exchangeable), 10.43 (s, 1H, NH, D2O exchangeable), 8.53–7.22 (m, 7H, Ar–H); 13C-NMR (100 MHZ; DMSO-d6): δ 175.90, 165.98, 165.53, 134.19, 131.91, 130.90, 129.91, 129.52, 128.36, 128.02, 127.38, 124.22, 121.63, 114.62, 84.60: MS: m/z 322.19 (M + 1). Anal. Calcd for C17H9N5O3 (331.07): C, 61.63; H, 2.74; N, 21.14; O, 14.49% Found: C, 61.56; H, 2.68; N, 21.15; O, 14.40%.

2.11 8b: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(1-methyl-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 88%; M.P = 216–218 °C; 1H-NMR (DMSO-d6): δ 12.58 (s, 1H, OH, D2O exchangeable), 8.25–7.12 (m, 7H, Ar–H), 3.58 (s, 3H, CH3);13C-NMR (100 MHZ; DMSO-d6): δ 175.55, 166.78, 166.00, 133.18, 130.76, 129.09, 129.08, 128.96, 128.35, 127.70, 123.37, 121.86, 115.46, 84.66, 34.59; MS: m/z 346.10 (M + 1). Anal. Calcd for C18H11N5O3 (345.09): C, 66.83; H, 3.31; N, 17.71; O, 12.59% Found: C, 66.72; H, 3.34; N, 17.68; O, 12.42%.

2.12 8c: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(5-nitro-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 90%; M.P = 234–236 °C; 1H-NMR (DMSO-d6): δ 12.58 (s, 1H, OH, D2O exchangeable), 10.84 (s,1H, NH, D2O exchangeable), 8.86–7.14 (m, 5H, Ar–H); 13C-NMR (100 MHZ; DMSO-d6): δ 176.66, 165.66, 165.36, 136.69, 132.29, 130.89, 130.07, 129.50, 129.38, 128.88, 128.50, 127.25, 123.38, 115.36, 84.36. MS: m/z 377.06 (M + 1). Anal. Calcd for C17H8N6O5 (376.06): C, 54.26; H, 2.14; N, 22.33; O, 21.26% Found: C, 54.15; H, 2.12; N, 22.24; O, 21.22%.

2.13 8d: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(1-methyl-5-nitro-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 88%; M.P = 232–236 °C; 1H-NMR (DMSO-d6): δ 12.02 (s, 1H, OH, D2O exchangeable), 8.88–7.42 (m, 6H, Ar–H), 3.69 (s, 3H, CH3); 13C-NMR (100 MHZ; DMSO-d6): δ 176.50, 165.68, 165.53, 136.62, 132.73, 130.82, 130.27, 129.53, 129.38, 128.88, 128.50, 127.30, 123.38, 115.36, 85.39, 36.69; MS: m/z 391.17 (M + 1). Anal. Calcd for C18H10N6O5 (390.07): C, 55.39; H, 2.58; N, 21.53; O, 20.50% Found: C, 55.30; H, 2.52; N, 21.51; O, 20.48%.

2.14 8e: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(5-methoxy-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 92%; M.P = 228–230 °C; 1H-NMR (DMSO-d6): δ 12.46 (s, 1H, OH, D2O exchangeable), 10.84 (s, 1H, NH, D2O exchangeable), 8.62–6.99 (m, 6H, Ar–H), 3.82 (s, 3H, OCH3); 13C-NMR (100 MHZ; DMSO-d6): δ 175.30, 163.95, 163.56, 154.55, 136.63, 132.25, 130.89, 130.10, 129.50, 129.38, 128.82, 128.63, 127.25, 123.68, 115.95, 85.00, 55.23; MS: m/z 362.09 (M + 1). Anal. Calcd for C18H11N5O4 (361.08): C, 59.84; H, 3.07; N, 19.38; O, 17.71% Found: C, 59.78; H, 3.02; N, 19.26; O, 17.70%.

2.15 8f: 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-hydroxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carbonitrile

White solid: yield 90%; M.P = 222–226 °C; 1H-NMR (DMSO-d6): δ 12.42 (s, 1H, OH, D2O exchangeable), 8.72–6.99 (m, 8H, Ar–H), 3.86 (s, 3H, OCH3), 3.58 (s, 3H, CH3);13C-NMR (100 MHZ; DMSO-d6): δ 175.26, 163.90, 163.63, 154.24, 136.52, 132.55, 130.99, 130.23, 129.53, 129.28, 128.87, 128.73, 127.25, 123.69, 115.95, 84.00, 54.03, 34.53; MS: m/z 376.16 (M + 1). Anal. Calcd for C19H13N5O4 (375.10): C, 60.80; H, 3.49; N, 18.66; O, 17.05% Found: C, 60.78; H, 3.38; N, 18.62; O, 16.96%.

3 Results and Discussions

Microwave irradiation (MW) method is highly efficient for the synthesis of various types of organic compounds. The major advantages of these methods are shorter reaction times, higher yields, no by-products and solvent free methods. In the present study, we synthesised 4af according to literature [53], from 5-substituted indole-3-carbaldehyde 1ac, ethyl cyanoacetate 2 and guanidine 3 refluxing in ethanol with catalytic amount of l-proline under reflux condition (Scheme 1).
Scheme 1

One pot Synthesis of compounds 4 (af)

A mixture of 4af reacts individually with 5 and 7 under conventional solvent free condition at 130 °C for 1–2 h (Scheme 2). The same reaction was repeated using MW for 2–6 min using a multimode reactor (Synthos 3000 Aton Paar, GmbH, 1400 W maximum magnetron) (Scheme 3) gave novel target compounds 6af and 8af derivatives with good yields compare to conventional method. The MW afforded the products in less reaction time, higher yield and purity than conventional heating method (Table 2).
Scheme 2

Synthesis of compounds 6af and 8af under solvent free condition

Scheme 3

Synthesis of compounds 6af and 8af under MW method

To optimize the reaction conditions, earlier various solvents were used for the synthesis of 6a and 8a. 4a reacts phthalic anhydride and maleic anhydride individually in water under reflux condition for about 2–5 h obtained 6a and 8a in lower yields i.e. 42% (Table 1, entry 01). Here we tried to improve the reaction conditions using different solvents, without using any catalyst. Various solvents such as ethanol, methanol, PEG-600, acetonitrile, acetic acid and dioxane have been used under reflux conditions along with solvent free method for the synthesis of target compounds of 6a and 8a (Table 1, entry 2–7). In these optimisation conditions, acetic acid gave the best yield of 78% (Table 1, entry 6), but the solvent free method stood as the most suitable for the synthesis of 6a and 8a with maximum amount of yield i.e. 84% in shorter reaction time (Table 1, entry 8). Hence, from the above optimization conditions, here we prepared the target compounds 6a and 8a under conventional method without using any solvent and catalyst resulted good yields (Scheme 2).
Table 1

Optimization of reaction condition of the compound 6a and 8a

S. no

Solvent

Temp (°C)

Time (h)

Yield (%)

1

Water

Reflux

3–5

42

2

Ethanol

Reflux

3–5

60

3

Methanol

Reflux

3–5

62

4

PEG-600

Reflux

1–3

66

5

Acetonitrile

Reflux

8–10

38

6

Acetic acid

Reflux

1–3

78

7

Dioxane

Reflux

8–10

42

8

Solvent free

Reflux

1–2

84

Alternatively, in order to achieve higher yields in an eco-friendly manner, MW method has been chosen for the synthesis of tittle compounds 6a and 8a and compared the obtained results with the conventional method.

In this protocol, compound 4a was treated with 5 and 7 individually under solvent free conditions, using MW method for 2–6 min yielded tittle compounds 6a and 8a (Scheme 3) with excellent yields. Based on above results, it is observed that both conventional and MW methods are effective under solvent free conditions, but the MW method has the advantage like shorter reaction times with higher yields, without the formation of any side products and neat reaction conditions. To keep it in view, we synthesised 6af and 8af derivatives under solvent-free conditions in both conventional and MW method and the yields were calculated (Table 2).
Table 2

Synthesis of 6af and 8af derivatives in different conditions

On the basis of the above results, it has been observed that the formation of target compounds in conventional method took 1–2 h. But in MW method, the reactions were completed just within 2–6 min and the yields have been extraordinarily improved. The major role of MW techniques was well studied and reasonably explained in reaction conditions. Microwave heating system doubles the rate of the chemical reactions due to its capability to significantly increase the temperature of the reaction about 10 °C. Conversions obtained by microwave heating were higher than conventional heating in furnace or oil bath. In Conventional method, operating the reaction was difficult and non-homogeneous heating with variations in temperatures. In comparison, The MW method is very efficient with homogeneous heating which saves the energy and time.

The plausible mechanism for the formation of compounds 6a and 8a from 4a was proposed as follows when they individually reacted with phthalic and maleic anhydrides. The nucleophilic addition of amino group of 4a towards one of the carbonyl groups of phthalic/maleic anhydride results the formation of intermediates 9ad. The resulted 9d subsequently undergo dehydration by losing a molecule of H2O to form the final product 6a (Scheme 4).
Scheme 4

Plausible mechanism for the formation of 6a and 8a

The structures of all newly synthesised compounds were elucidated by 1H-NMR, 13C-NMR and LC–MS methods.

4 Conclusion

We have developed an efficient and simple microwave-assisted method for the synthesis of novel indole-pyrimidine-cyclic imide derivatives. Though we also explored conventional method where we dealt with solvent free conditions for the synthesis of target compounds, microwave irradiation method has advantages in terms of shorter reaction times i.e. within 5–6 min, clean reaction profiles and higher yields (90–92%) of the products compare with the conventional method. Another important advantage of microwave irradiation method over conventional method is that there is no further purifications needed and this procedure has been identified to be a green synthetic protocol.

Notes

Acknowledgements

The authors are thankful to the authorities of Jawaharlal Nehru Technological University, Hyderabad, for providing laboratory facilities.

Supplementary material

42250_2019_83_MOESM1_ESM.docx (3.5 mb)
Supplementary material 1 (DOCX 3552 kb)

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Copyright information

© The Tunisian Chemical Society and Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mahesh Goud Bakkolla
    • 1
    Email author
  • Ashok Kumar Taduri
    • 1
  • Rama Devi Bhoomireddy
    • 1
  1. 1.Department of Chemistry, College of EngineeringJawaharlal Nehru Technological University HyderabadKukatpally, HyderabadIndia

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