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Eco-Friendly and Facile Synthesis of Substituted Imidazoles via Nano Zirconia Catalyzed One-Pot Multicomponent Reaction of Isatin Derivatives with Ammonium Acetate and Substituted Aromatic Aldehydes under Solvent Free Conditions

Written By

Sundaram Singh and Shivam Bajpai

Submitted: May 14th, 2018 Reviewed: November 26th, 2018 Published: March 4th, 2019

DOI: 10.5772/intechopen.82720

From the Edited Volume

Nanocatalysts

Edited by Indrajit Sinha and Madhulata Shukla

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Abstract

An eco-friendly and highly efficient approach for the synthesis of substituted imidazoles via nano zirconia catalyzed multicomponent reaction of isatin derivatives with ammonium acetate and aromatic aldehydes under solvent-free conditions has been developed. This approach can be mostly applied to medicinal chemistry due of the simple and readily available starting materials, effortless methodology, and biologically active nature of imidazoles. An additional gain of the suggested technique is the reusability of the nano ZrO2 catalyst.

Keywords

  • nano ZrO2 catalyst
  • multicomponent reaction
  • imidazole
  • solvent-free
  • Isatin

1. Introduction

Imidazole is a “1, 3-diazole” and is classified as an alkaloid. Imidazole (1) refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents. This ring system is present in important biological building blocks, such as histidine (2), and the related hormone histamine (3). Imidazole can serve as a base and as a weak acid. Many drugs contain an imidazole ring, such as antifungal drugs and Nitroimidazole (4) [1, 2, 3, 4, 5].

Imidazole derivatives are mostly used as organic resources [6, 7] and it also plays important roles in various types of biological activities [8, 9]. This multitalented applicability of Imidazole draws attention towards the importance of access to efficient synthetic routes to well-designed and highly substituted imidazole derivatives.

Due to their impressive significance, various synthetic routes have been designed. Substituted imidazoles are generally prepared by microwave irradiated one pot three-component cyclocondensation of a 1, 2-diketone, α-hydroxy ketone or α-ketomonoxime with an aldehyde and ammonium acetate [10, 11, 12, 13], ionic liquids [14, 15], refluxing in acetic acid [16], silica sulfuric acid [17, 18], Yb(OTf)3 [19], Yb(OPf)3 [20], iodine [21], Zr(acac)4 [22], InCl3·3H2O [23], heteropolyacid [24], sodium bisulfate [25], potassium aluminum sulfate (alum) [26], ceric ammonium nitrate (CAN) [27], (NH4)6 Mo7O24·4H2O [28], zeolite HY/silica gel [29], ZrCl4 [30], polymer-supported ZnCl2 [31] and L-proline [32]. Moreover, they have also been prepared by the addition of substituted amino alcohol to a thioamide and subsequent oxidation with PDC or by the reaction of aryl nitriles and α,α-dilithioarylnitromethanes or by multistep syntheses. p-TSA catalyzed synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketone or α-hydroxyketone, aldehyde and ammonium heptamolybdate tetrahydrate in tetrabutylammonium iodide was given by Khodaei and co-workers [33].

Due to their potential utility, majority of these synthetic routes experience one or more severe disadvantages, such as difficult and intricate work-up and purification, huge amounts of waste materials, strongly acidic conditions, occurrence of side reactions, low yields, high temperature, long reaction time and the use of expensive reagents. Hence, there is a great demand of a highly efficient protocol with mild reaction conditions to synthesize substituted imidazoles.

In recent times, metal nanoparticles are used as heterogeneous catalysts in organic synthesis mainly because they achieve the objectives of green and sustainable chemistry. Recently Scientists have done a lot of work to synthesize precise metal nanoparticles. The new path is the coherent design and synthesis of very active and selective nanocatalysts by controlling the structure and composition of the active nanoparticles among all of them. The easiness of separation, recovery, and reuse of these NPs further enhance their attractiveness as green and sustainable catalysts [3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45].

Recently, nano zirconia (ZrO2) has attracted considerable attention due to their wide applicability as a heterogeneous catalyst [46, 47, 48, 49, 50, 51]. The catalytic activities and selectivities of nano zirconia are highly affected by their crystal phase (monoclinic and tetragonal) [52, 53, 54]. ZrO2 nanoparticle catalyst is a cheap, moisture stable, safe, reusable, and commercially available white powder is of big curiosity to many researchers. It has been revealed from the literature that numerous parallel applications of nano zirconia, as an effective catalyst in green/sustainable synthetic chemistry, have already been reported [55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67].

In view of the above and as a part of our research group to synthesize the biologically active compounds [68, 69, 70, 71, 72], it was thought worthwhile to synthesize some novel imidazoles fused with indole nucleus of biocidal interest because the combination of two or more different heterocyclic compounds in a single molecule frequently increases the biocidal profile amazingly. With the aim of getting targeted products, i.e., substituted imidazole a greener “NOSE” (nanoparticles-catalyzed organic synthesis enhancement) approach has been designed under solvent-free conditions.

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2. Results and discussion

Imidazole derivatives 4a–s was synthesized by one pot multicomponent reaction of isatin derivatives 1a–g with ammonium acetate 2 and substituted benzaldehydes 3a–f in the presence of catalytic amount of ZrO2 NPs under solvent-free conditions at 110°C, in good to excellent yields (Scheme 1).

Scheme 1.

Nano ZrO2 catalyzed synthesis of imidazole derivatives.

To optimize the reaction conditions, several parameters were tested. The catalytic efficiency of the ZrO2 NPs was highly influenced by their amount (mol%). Therefore, a model reaction of isatin with ammonium acetate and benzaldehyde using different amounts of ZrO2 NPs was carried out (Table 1). It has been observed that there is a notable impact of the catalyst on the yield of product and in the absence of catalyst only poor yield was obtained after 120 min (Entry 1, Table 1). It was found that product yield is increased with increasing catalyst concentration. Only 5 mol% of catalyst was required to provide 60% yield in 60 min (Entry 2, Table 1). The best yield of 88% was obtained with 15 mol% of ZrO2 NPs (Entry 5, Table 1). However, the reaction rate and product yield were not improved by further increase of catalyst concentration (>15 mol%) (Entry 6, Table 1).

Entry ZrO2 mol% Time (min.) %Yield
1 0 120 23
2 5 60 60
3 10 45 75
4 12 35 82
5 15 30 88
6 20 30 88

Table 1.

Effect of catalyst amount (mol%) on yield of the product 4a.

Note: Bold values represent optimized reaction condition.

To optimize the molar proportion of the reactant, the model reaction was carried out using different molar proportions of reactants (Table 2). A scrutiny of the table clearly shows that the best result was obtained using isatin, ammonium acetate, benzaldehyde in the molar proportion 1.0:5.0:1.0 at 110°C under solvent free conditions (Entry 5, Table 2).

Entry Molar ratio of reactants %Yield
Isatin:ammoniumacetate:benzaldehyde
1 1.0:1.0:1.0 Trace amount
2 1.0:2.0:1.0 35
3 1.0:3.0:1.0 52
4 1.0:4.0:1.0 78
5 1.0:5.0:1.0 88
6 1.0:6.0:1.0 87
7 1.0:5.0:1.2 87
8 1.2:5.0:1.0 86

Table 2.

Effect of molar ratio of substrates on the yield of the product 4a.

Note: Bold values represent optimized reaction condition.

To see the effect of temperature, the model reaction was examined under different temperatures. Obviously, reaction rate and product yield both were increased with enhancing temperature from 50 to 110°C. This study shows that the 110°C was favorable temperature for the multicomponent reaction of isatin with ammonium acetate and benzaldehyde (Table 3).

Entry Temp. °C Time % Yield
1 rt - No reaction
2 50 10 h Trace amount
3 60 6 h 65
4 70 4 h 70
5 80 1.5 h 78
6 90 55 min 84
7 100 45 min 86
8 110 30 min 88
9 120 30 min 88

Table 3.

Effect of temperature on the yield of the product 4a.

Note: Bold values represent optimized reaction condition.

Screening of solvent showed that solvent had a remarkable impact on the yield of product. It was observed that polar solvent provided better yield than nonpolar solvent, but excellent yield was obtained without solvent in smaller time. This may be due to the competitive adsorption of the solvent with the substrate molecule on the catalyst surface; hence reaction under solvent-free conditions gives excellent yield in short reaction time (Entry 5, Table 4). Another reason is that the eutectic mixture having uniform distribution of the reactants brings the reacting species in close proximity to react in solvent free condition than in the presence of solvent (Entry 1–4, Table 4).

Entry Solvents Time %Yield
1 Ethanol 10 h 68
2 Acetonitrile 10 h 59
3 Xylene 13 h 55
4 Tolune 18 h 52
5 Solvent free 30 min 88

Table 4.

Effect of solvents on the yield of the product 4a.

Note: Bold values represent optimized reaction condition.

Under the optimized set of reaction conditions, the effect of type of ZrO2 (nano or bulk) was also examined using model reaction(Table 5). This important parameter was studied by using four concentrations 5, 10, 12 and 15 mol% of ZrO2. These data proved that particle size and surface area would be an important factor for the catalytic efficiency of the ZrO2 NPs.

Type of ZrO2 Mol% % Yield
ZrO2 (Bulk) 5 42
Surface area: 6.95m2/g 10 51
Average particle size: 2 μm 12 56
15 66
ZrO2 (Nano) 5 59
Surface area: 44.70 m2/g 10 72
Average particle size: 20 nm 12 84
15 88

Table 5.

Effect of type of ZrO2 (bulk & nano) on the yield of the product 4a.

Reaction condition: Isatin, ammonium acetate & benzaldehyde (1.0, 5.0, 1.0) were stirred at 110°C to produce solid product.


The efficiency of the catalytic activity of the ZrO2 NPs with several other catalysts was compared and is summarized in Table 6. The result indicates that ZrO2 NPs was the best catalyst in terms of mol%, reaction time and percentage yield (Table 6).

Type of catalyst Mol% Time (min.) % Yield
Bentonite clay 20 60 55
K-10 clay 20 60 58
PTSA 40 75 45
NH4Cl 30 75 44
EDTA 40 75 40
Iodine 30 60 53
Yb(OTf)3 25 60 51
TiO2 (Nano) 20 30 80
ZrO2(Nano) 15 30 88

Table 6.

Effect of different catalysts on the yield of the product 4a.

Note: Bold values represent optimized reaction condition.

Under the optimized reaction condition, the scope of this methodology was extended to the reaction of different isatin with a wide range of aromatic aldehydes. The findings reveal that the proposed methodology is equally applicable for the presence of both electron donating as well as electron withdrawing groups at the 5-position of isatin moiety (Table 7).

Table 7.

Synthesis of substituted imidazoles (4a–s).

The model reaction was carried out to examine the reusability of the catalyst, After each reaction, catalyst was recovered by filtration, washed, air-dried and reused directly for the next time up to run no. 10.The results showed that there is no obvious loss in product yield in subsequent reuse which proves the reusability and recyclability of ZrO2 NPs (Table 8).

Entry Number of cycle %Yield
1 - 88
2 1 88b
3 2 87b
4 3 86b
5 4 83b
6 5 80b
7 6 80b,c
8 7 80b
9 8 78b
10 9 75b
11 10 76b,c

Table 8.

Reusability and recyclability of ZrO2 NPs catalysta.

Reaction condition: Isatin, ammonium acetate, benzaldehydes (1.0:5.0:1.0) and ZrO2 NPs (15 mol%) were stirred at 110°C to produce solid product.


The catalyst was washed and dried at 80–90°C for 12 h.


ZrO2 NPs were calcinated at 600°C for 3 h.


The following mechanism was proposed for the formation of substituted imidazoles catalyzed by the ZrO2 NPs is given in Scheme 2. The reaction proceeds via the diamine intermediate [X]. Condensation of diamine with isatin derivatives followed by dehydration, and then rearrangement through the imino intermediate [Y] yielded the desired product.

Scheme 2.

Proposed mechanism for the formation of substituted imidazoles 4a–s.

ZrO2 NPs were prepared and characterized by FTIR, XRD, SEM and TEM analysis. The BET surface area analyzer was used to calculate the specific surface area of synthesized ZrO2 NPs.

The molecular nature of the synthesized material was identified by the FT-IR spectrum of the ZrO2 sample. The FT-IR spectrum of ZrO2 NPs depends on the nature of the material, preparative procedures used, solid-state structure, and so forth. In FT-IR, a strong absorption peak at about 500 cm−1 region is due to the Zr–O vibration, which confirm the formation of ZrO2 structure while the peak at 751 cm−1 is due to stretching vibrations of Zr–O–Zr, prominent peak at 1340 cm−1 represents O–H bonding, peak at 1622 cm−1 perhaps owing to the adsorbed moisture and peaks at about 2855–2922 cm−1 region is due to stretching of O–H groups.

The broad peaks with high intensity in XRD pattern of ZrO2 NPs indicates that the sample was highly crystalline. The peaks observed at 2θ = 24.2 (011), 28.2 (−111), 31.4 (111), 35.0 (020), 40.5 (−112), 45.0 (211), and 55.4 (−311) are characteristics peaks of monoclinic zirconia (JCPDS card no. 37–1484) while diffraction peak observed at 2θ = 30.3 (101), 50.3 (212) and 60.2 (211) are due to tetragonal zirconia (JCPDS card no. 79-1769). The broadening of peaks shows the smaller particle size of ZrO2 NPs (Figure 1).

Figure 1.

XRD spectra of ZrO2 NPs.

Morphological studies were done with the help of SEM and TEM analysis of 600°C calcinated ZrO2 NPs sample that are shown in Figures 2 and 3, respectively. SEM analysis shows that NPs are non-homogenous and agglomerated and it also indicates the spherical nature and nano size (nm regime) of the ZrO2 nanoparticles but size could be finely decided from TEM. For the purpose, TEM of sample has been shown in Figure 3.

Figure 2.

SEM image of ZrO2 NPs.

Figure 3.

TEM image of ZrO2 NPs.

As it is clear from TEM micrograph of sample, some agglomeration of the NPs, has been seen due to presence of different m- and t-phases in the sample. It was also observed that the sizes of the particles are of the order 20 nm along with agglomeration.

BET surface area analyzer was used to calculate the surface area of synthesized ZrO2 NPs by nitrogen absorption which was found to be 44. 70 m2/g.

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3. Experimental

3.1. Typical procedure for the synthesis of ZrO2 NPs

0.075 M solution of ZrOCl2.8H2O was prepared and then precipitated with NH4OH (25%) with continuous stirring on a magnetic stirrer till the PH raises in the range of 10–10.5.This resulted in the formation of precipitate of zirconium hydroxide. The precipitate was filtered and washed with double distilled water until traces of chloride ion were completely removed from the filtrate. Complete removal of chloride ion from filtrate was checked by titrating it with AgNO3 solution using potassium chromate as indicator. Now, the precipitate was dried in oven at 80–90°C for 24 h and calcinated at 600°C for 3 h in order to formation of white nano zirconia powder.

3.2. General procedure for the synthesis of substituted imidazoles 4a-s

To a mixture of isatin derivatives 1a–g (1 mmol), ammonium acetate 2 (5 mmol), substituted aromatic aldehydes 3a–f (1 mmol), 15 mol% of ZrO2 NPs was added (Scheme 1). The mixture was heated and stirred at 110°C for 30 min. The progress of the reaction was monitored by thin layered chromatography (n-hexane:ethyl acetate, 1:1). After completion, 20 ml acetone was added to the reaction mixture; the catalyst was removed by filtration and washed with xylene and acetone. Then, 50 ml of double distilled water is added to the liquid portion. This resulted in the formation of precipitate of products 4a–s. The precipitate was filtered, dried and recrystallized with ethanol.

3.2.1. 2-Phenyl-3,4-dihydroimidazo[4,5-b]indole (4a)

Brownsolid, IR (KBr) υ: 3400, 3209, 3019, 2964, 1660, 1614, 1567, 1484, 1316, 1210, 1171, 1010, 877, 742, 653, 580 cm−1. 1H NMR (300 MHz, DMSO) δ: 7.80–8.86 (m, 9H, aromatic protons), 9.15 (s, 1H, NH), 9.66 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 124.0, 126.7, 127.5, 130.2, 130.7, 132.0, 133.7, 135.5, 139.1, 148.2, 160.9 ppm. Anal. Calcd for C15H11N3: C, 77.24; H, 4.74; N, 18.01 Found C, 77.20; H, 4.76; N, 18.03.

3.2.2. 7-Chloro-2-phenyl-3,4-dihydroimidazo[4,5-b]indole (4b)

Brownsolid, IR (KBr) υ: 3364, 3190, 2981, 2964, 1648, 1609, 1559, 1447, 1311, 1199, 1143, 1019, 872, 744, 651, 566 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.51–8.59 (m, 8H, aromatic protons), 9.14 (s, 1H, NH), 9.45 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 123.9, 125.7, 128.5, 128.6, 130.3, 130.8, 132.7, 135.0, 137.5, 149.2, 159.4 ppm. Anal. Calcd for C15H10ClN3: C, 67.28; H, 3.78; N, 15.72. Found C, 67.32; H, 3.76; N, 15.70.

3.2.3. 2-(2-Nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4c)

Brownsolid, IR (KBr) υ: 3332, 3201, 2995, 2917, 1658, 1623, 1549, 1485, 1348, 1280, 1176, 1068, 864, 708, 667, 544 cm−1. 1H NMR (300 MHz, DMSO) δ: 7.61–8.69 (m, 8H, aromatic protons), 9.67 (s, 1H, NH), 9.94 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 123.8, 126.7, 128.8, 129.8, 130.1, 131.8, 135.4, 135.8, 135.9, 148.3, 160.7 ppm. Anal. Calcd for C15H10N4O2: C, 64.74; H, 3.62; N, 20.13 Found C, 64.69; H, 3.65; N, 20.14.

3.2.4. 7-Chloro-2-(2-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4d)

Brownsolid, IR (KBr) υ: 3399, 3229, 2916, 2885, 1645, 1600, 1539, 1457, 1329, 1253, 1162, 1027, 885, 703, 647, 553 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.66–8.36 (m, 7H, aromatic protons), 8.96 (s, 1H, NH), 9.50 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 123.4, 123.8, 124.8, 127.1, 128.0, 128.6, 129.4, 133.9, 134.1, 134.4, 139.7, 148.7, 150.4, 160.6 ppm. Anal. Calcd for C15H9ClN4O2: C, 57.60; H, 2.91; N, 17.91 Found C, 57.51; H, 3.0; N, 17.94.

3.2.5. 2-(3-Nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4e)

Brownsolid, IR (KBr) υ: 3315, 3194, 3066, 2978, 1662, 1623, 1572, 1482, 1353, 1286, 1135, 1025, 832, 797, 661, 542 cm−1. 1H NMR (300 MHz, DMSO) δ: 7.58–8.55 (m, 8H, aromatic protons), 8.97 (s, 1H, NH), 9.67 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 122.3, 123.6, 125.2, 127.9, 128.4, 129.7, 130.4, 134.4, 134.5, 135.2, 139.0, 147.6, 161.7 ppm. Anal. Calcd for C15H10N4O2: C, 64.70; H, 3.63; N, 20.16 Found C, 64.51; H, 3.72; N, 20.23.

3.2.6. 7-Chloro-2-(3-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4f)

Brownsolid, IR (KBr) υ: 3385, 3211, 3003, 2959, 1646, 1603, 1538, 1458, 1367, 1248, 1122, 1022, 831, 741, 635, 564 cm−1. 1H NMR (300 MHz, DMSO) δ: 7.77–8.83 (m, 7H, aromatic protons), 9.13 (s, 1H, NH), 9.62 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 124.0, 126.6, 127.5, 127.6, 130.2, 130.7, 132.0, 133.6, 135.4, 139.1, 148.2, 160.8, 160.9 ppm. Anal. Calcd for C15H9ClN4O2: C, 57.61; H, 2.90; N, 17.92 Found C, 57.67; H, 2.90; N, 17.90.

3.2.7. 2-(3-Chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4g)

Brownsolid, IR (KBr) υ: 3405, 3217, 2948, 2909, 1671, 1617, 1568, 1454, 1371, 1283, 1134, 1018, 892, 754, 641, 577 cm−1. 1H NMR (300 MHz, DMSO) δ: 7.60–8.56 (m, 9H, aromatic protons and 1H, NH), 9.69 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 123.8, 126.6, 128.8, 128.7, 130.1, 131.0, 131.6, 135.2, 137.0, 148.4, 160.6 ppm. Anal. Calcd for C15H10ClN3: C, 67.30; H, 3.77; N, 15.70 Found C, 67.29; H, 3.75; N, 15.70.

3.2.8. 7-Chloro-2-(3-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4h)

Brownsolid, IR (KBr) υ: 3398, 3227, 2977, 2893, 1664, 1605, 1551, 1477, 1358, 1242, 1163, 1011, 844, 743, 650, 567 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.62–8.31 (m, 7H, aromatic protons), 8.90 (s, 1H, NH), 9.42 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 124.1, 125.8, 126.6, 128.6, 129.8, 130.3, 130.7, 133.2, 134.8, 135.2, 139.3, 149.0, 160.5 ppm. Anal. Calcd for C15H9Cl2N3: C, 59.62; H, 3.00; N, 13.91 Found C, 59.52; H, 3.05; N, 13.89.

3.2.9. 2-(4-Chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4i)

Brownsolid, IR (KBr) υ: 3362, 3255, 3015, 2882, 1669, 1620, 1565, 1482, 1375, 1235, 1140, 1026, 890, 777, 663, 526 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.48–8.58 (m, 8H, aromatic protons), 9.45 (s, 1H, NH), 10.16 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 123.3, 127.8, 127.9, 128.7, 129.7, 134.9, 135.6, 136.2, 149.7, 161.3 ppm. Anal. Calcd for C15H10ClN3: C, 67.30; H, 3.77; N, 15.70 Found C, 67.31; H, 3.75; N, 15.73.

3.2.10. 7-Chloro-2-(4-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4j)

Brownsolid, IR (KBr) υ: 3386, 3233, 3047, 2960, 1657, 1612, 1558, 1435, 1348, 1282, 1153, 1019, 871, 742, 654, 552 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.46–8.54 (m, 7H, aromatic protons), 8.99 (s, 1H, NH), 9.35 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 123.9, 125.8, 128.8, 129.8, 130.3, 133.0, 135.2, 136.0, 137.1, 149.1, 159.5 ppm. Anal. Calcd for C15H9Cl2N3: C, 59.62; H, 3.00; N, 13.91 Found C, 59.55; H, 3.10; N, 13.90.

3.2.11. 2-(4-Methoxyphenyl)-3,4-dihydroimidazo[4,5-b]indole (4k)

Brownsolid, IR (KBr) υ: 3351, 3138, 3001, 2944, 2881, 1667, 1619, 1575, 1450, 1371, 1284, 1157, 1021, 863, 743, 654, 534 cm−1. 1H NMR (300 MHz, DMSO) δ: 4.00 (s, 3H, CH3), 7.26–8.69 (m, 9H, aromatic protons and 1H, NH), 9.72 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 56.9, 122.2, 123.2, 125.9, 127.7, 127.4, 127.9, 128.7, 129.0, 129.6, 130.7, 131.2, 131.4, 131.5, 138.5, 139.7, 140.1, 143.9, 145.8, 154.6 ppm. Anal. Calcd for C16H13N3O: C, 72.99; H, 4.98; N, 15.96 Found C, 72.91; H, 5.04; N, 15.95.

3.2.12. 7-Chloro-2-(4-methoxyphenyl)-3,4-dihydroimidazo[4,5-b]indole (4l)

Brownsolid, IR (KBr) υ: 3370, 3259, 2991, 2911, 1675, 1614, 1558, 1480, 1436 1377, 1291, 1186, 1049, 869, 745, 651, 522 cm−1. 1H NMR (300 MHz, CDCl3) δ: 3.61 (s, 3H, CH3), 7.44–8.47 (m, 8H, aromatic protons), 8.58 (s, 1H, NH), 9.36 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 61.8, 122.16, 122.29, 124.0, 125.3, 126.6, 130.1, 130.4, 132.3, 133.9, 135.5, 138.5, 148.1, 148.2, 157.8 ppm. Anal. Calcd for C16H12ClN3O: C, 64.54; H, 4.06; N, 14.11 Found C, 64.70; H, 4.00; N, 14.10.

3.2.13. 1-(2-(3-Nitrophenyl)imidazo[4,5-b]indol-4(3H)-yl)ethanone (4m)

Brownsolid, IR (KBr) υ: 3389, 3266, 2978, 2935, 1694, 1645, 1616, 1571, 1467, 1346, 1224, 1133, 1021, 823, 744, 641, 572 cm−1. 1H NMR (300 MHz, CDCl3) δ: 1.91 (s, 3H, CH3), 7.22–8.51 (m, 8H, aromatic protons), 9.40 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 23.7, 122.1, 122.4, 123.2, 123.5, 124.8, 127.2, 127.4, 127.6, 128.2, 129.7, 130.1, 130.9, 133.0, 134.1, 134.4, 135.6, 138.0, 141.0, 148.7, 150.4, 160.3, 172.2 ppm. Anal. Calcd for C17H12N4O3: C, 63.75; H, 3.78; N, 17.49 Found C, 63.68; H, 3.88; N, 17.52.

3.2.14. 1-(2-(3-Chlorophenyl)imidazo[4,5-b]indol-4(3H)-yl)ethanone (4n)

Brownsolid, IR (KBr) υ: 3367, 3215, 2947, 2923, 1692, 1662 1607, 1580, 1477, 1359, 1272, 1144, 1042, 807, 735, 653, 546 cm−1. 1H NMR (300 MHz, CDCl3) δ: 1.25 (s, 3H, CH3), 7.34–8.11 (m, 8H, aromatic protons), 9.36 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 23.6, 122.5, 124.1, 125.3, 126.6, 130.1, 130.4, 130.7, 132.3, 133.9, 134.6, 135.5, 138.5, 148.1, 148.2, 157.8, 160.9, 166.2 ppm. Anal. Calcd for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57 Found C, 66.01; H, 3.95; N, 13.47.

3.2.15. 1-(2-(4-Chlorophenyl)imidazo[4,5-b]indol-4(3H)-yl)ethanone (4o)

Brownsolid, IR (KBr) υ: 3350, 3285, 3011, 2935, 1685, 1654 1611, 1572, 1485, 1455, 1343, 1284, 1132, 1062, 899, 783, 659, 531 cm−1. 1H NMR (300 MHz, CDCl3) δ: 1.66 (s, 3H, CH3), 7.35–8.12 (m, 8H, aromatic protons), 9.37 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 23.5, 123.3, 125.6, 127.2, 128.1, 128.4, 128.7, 129.0, 129.2, 129.5, 133.1, 134.3, 134.6, 134.7, 136.4, 137.0, 142.0, 150.5, 160.2, 160.9 ppm. Anal. Calcd for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57 Found C, 65.99; H, 3.93; N, 13.54.

3.2.16. 4-Ethyl-2-(2-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4p)

Brownsolid, IR (KBr) υ: 3416, 3199, 3012, 2999, 2942, 2872, 1654, 1607, 1561, 1441, 1453 1351, 1283, 1192, 1021, 861, 741, 657, 526 cm−1. 1H NMR (300 MHz, DMSO) δ: 1.41–1.45 (t, J = 6.6, 3H, CH3), 4.38–4.45 (q, J = 6.9, 2H, CH2), 7.53–8.63 (m, 8H, aromatic protons), 9.63 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 12.5, 24.9, 122.1, 122.8, 123.1, 124.6, 127.5, 127.8, 130.2, 130.4, 130.7, 133.5, 134.4, 137.7, 135.4, 136.4, 137.5, 140.7, 148.3, 149.7, 159.9 ppm. Anal. Calcd for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29 Found C, 66.74; H, 4.65; N, 18.20.

3.2.17. 2-(3-Nitrophenyl)-4-propyl-3,4-dihydroimidazo[4,5-b]indole (4q)

Brownsolid, IR (KBr) υ: 3400, 3301, 3221, 3135, 3009, 2951, 2912, 2865, 1664, 1616, 1571, 1478, 1422, 1371, 1271, 1181, 1037, 873, 739, 649, 536 cm−1. 1H NMR (300 MHz, CDCl3) δ: 1.05–1.10 (t, J = 6.9, 3H, CH3), 1.70–1.82 (m, 2H, CH2), 3.19–3.24 (t, J = 6.6, 2H, CH2), 7.47–8.41 (m, 8H, aromatic protons), 8.94 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, CDCl3) δ: 10.1, 21.3, 44.0, 121.5, 124.2, 125.2, 125.5, 125.6, 129.3, 136.1, 136.7, 140.5, 150.9, 159.3 ppm. Anal. Calcd for C18H16N4O2 C, 67.49; H, 5.03; N, 17.49 Found C, 67.44; H, 5.10; N, 17.52.

3.2.18. Ethyl 2-(2-(2-nitrophenyl)imidazo[4,5-b]indol-4(3H)-yl)acetate (4r)

Brownsolid, IR (KBr) υ: 3389, 3255, 3129, 3116, 3027, 2969, 2913, 2847, 1735, 1657, 1618, 1569, 1435, 1353, 1264, 1158, 1049, 854, 751, 651, 546 cm−1. 1H NMR (300 MHz, DMSO) δ: 1.22–1.27 (t, J = 7.2, 3H, CH3), 4.19–4.26 (q, J = 6.9, 2H, CH2), 5.32 (s, 2H, CH2), 7.37–8.28 (m, 8H, aromatic protons), 9.63 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 15.0, 52.6, 65.1, 122.3, 123.6, 125.2, 127.9, 128.4, 130.5, 134.0, 135.2, 139.0, 148.3, 149.6, 161.7, 171.0 ppm. Anal. Calcd for C19H16N4O4: C, 62.63; H, 4.43; N, 15.38 Found C, 62.71; H, 4.51; N, 15.30.

3.2.19. 7-Methyl-2-phenyl-3,4-dihydroimidazo[4,5-b]indole (4 s)

Brownish whitesolid, IR (KBr) υ: 3398, 3242, 2963, 2931, 1648, 1607, 1559, 1451, 1311, 1232, 1142, 1027, 813, 741, 655, 534 cm−1. 1H NMR (300 MHz, DMSO) δ: 2.22 (s, 3H, CH3), 7.55–8.57 (m, 8H, aromatic protons), 9.69 (s, 1H, NH), 10.10 (s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO) δ: 23.9, 122.9, 123.1, 127.7, 128.5, 129.6, 130.2, 130.7, 131.3, 133.3, 136.8, 146.3, 154.1, 161.2 ppm. Anal. Calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99 Found C, 77.64; H, 5.34; N, 17.02.

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4. Conclusion

ZrO2 nanoparticles have been synthesized and a novel synthetic route has been developed for the multicomponent reaction of isatin derivatives with ammonium acetate and substituted aromatic aldehydes using ZrO2 nanoparticles under solvent-free conditions. The yields of the products obtained were up to 93% at 110°C. The advantage of the proposed method is its facile reaction conditions; the product can be isolated very easily without the use of column chromatography and the catalyst can be recycled. The simplicity of the presented protocol makes it an interesting alternative to other approaches. The obtained catalyst is expected to contribute to the development of environmentally benign methods and forms a part of nanomaterial chemistry.

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NMR spectra of compound 4a

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Written By

Sundaram Singh and Shivam Bajpai

Submitted: May 14th, 2018 Reviewed: November 26th, 2018 Published: March 4th, 2019