An Efficient Synthesis of Tri- and Tetrasubstituted Imidazoles from

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An efficient synthesis of tri and tetrasubstituted imidazoles from benzils using functionalised chitosan as biodegradable solid acid catalyst Kulsum Khan, and Zeba N. Siddiqui Ind. Eng. Chem. Res., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2015 Downloaded from http://pubs.acs.org on June 9, 2015

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Industrial & Engineering Chemistry Research

An efficient synthesis of tri and tetrasubstituted imidazoles from benzils using functionalised chitosan as biodegradable solid acid catalyst Kulsum Khan and Zeba N. Siddiqui* Department of Chemistry, Aligarh Muslim University, Aligarh, 202002, India. *Corresponding author. Phone No. +91 9412653054 Email: [email protected]

1 ACS Paragon Plus Environment


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Abstract An environmentally benign, highly efficient one pot four component synthesis of highly functionalised imidazole derivatives using different aldehydes, substituted amines, benzil and ammonium acetate in the presence of biodegradable and highly efficient catalyst chitosanSO3H were described. Chitosan-SO3H was found to be heterogeneous acidic catalyst which allowed easy recovery of the catalyst. Use of microwave irradiation along with chitosanSO3H for the synthesis of imidazole derivatives make this protocol green. Moreover, excellent yields, shorter reaction time, chromatography-free purification, and elimination of environmentally hazardous solvents are other advantages of this protocol which leads to sustainability. Key words: Imidazole, chitosan-SO3H, heterogeneous catalysis, microwave irradiation.


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1. Introduction Green chemistry directs synthetic chemists to redesign the synthetic methodologies taking environment into concern for sustainable development of the society. Multicomponent reactions (MCRs) based organic synthesis contributes to sustainability by shortening the synthetic route. It combines at least three reactants at a time in the same pot to generate a product incorporating all the atoms of the reactants in a single step in contrast to a divergent multistep synthesis.1 Their efficiency, mild reaction conditions, atom economy and high convergence make it an important tool for implementing green chemistry. Microwaveassisted organic synthesis (MAOS) has an impressive impact on organic synthesis. Lesser reaction time, high yields of the products, and better selectivity are the advantages of microwave conditions relative to conventional thermal heating.2 The utilization of polymer bound catalysts is well recognized these days because of their ease of workup, separation of products and catalysts and from the economical point of view.3 In this context, chitosan is a good candidate as it is a natural, biocompatible, and biodegradable.4 As an ideal support material, it has unique properties including availability, safety, nontoxicity, and insolubility in the vast majority of solvents.5,6 Owing to these properties, it has been used as a support for a large number of catalysts.7 The amine and hydroxyl groups in chitosan provide active sites for numerous attractive chemical modifications. One such modification is sulfonation which leads to the formation of chitosan-SO3H. Chitosan-SO3H has been utilized as biodegradable solid acid catalysts for a few organic transformations.8, 9 Imidazoles are a class of heterocyclic compounds that contain nitrogen and are present in compounds possessing various pharmaceutical properties such as anti-inflammatory,10 antibacterial,11 CSBP kinase inhibitor,12 glucagon receptor antagonists,13 p38 MAP kinase inhibitors,14 modulators of Pgp-mediated multidrug resistance,15 ligands of the Src SH2 protein,16 antitumor agents,17 inhibitors of mammalian 15-LOX,18 CB1 cannabinoid receptor 3 ACS Paragon Plus Environment


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antagonists,19 and inhibitors of B-Raf kinase.20 It is the core structural skeleton in many important biological molecules like biotin, histamine and histidine.21-23 Some drugs which have

trisubstituted and tetrasubstituted imidazole moeity in their structure are losartan,

trifenagrel, and omlesartan (Figure 1). Recent development of sustainability and organometallic chemistry further adds to the application of imidazoles as ionic liquids and Nheterocyclic carbenes.24,

25

Encouraged by the wide applications of imidazoles, we have

synthesised some new trisubstituted and tetrasubstituted imidazoles bearing heterocyclic substituents at 2-position with expected pharmaceutical properties.

Figure 1. Bioactive compounds with imidazole skeleton. There are several methods reported in the literature for the synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles and include heteropolyacid,26 zeolites HY/silica gel,27 sulphanilic acid,28 iodine,29 ionic liquids,30 NaHSO4-SiO2,31 HClO4.SiO2,32 FeCl3.6H2O,

33

BF3.SiO2,34 alumina,35 InCl3.3H2O,36 copper acetate,37 trifluroacetic acid,38 L-proline,39 nano4 ACS Paragon Plus Environment

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crystalline sulfated zirconia,40 Fe3O4@chitosan41 and also by microwave irradiation using acetic acid.42 Owing to the wide range of pharmacological and biological activities, the development of economical, efficient, neat, high-yielding and environmentally benign protocols are still desirable. Moreover, biodegradable and reusable catalysts are important for both economical and environmental points of view. As our continuous efforts in developing environmentally benign protocols for the synthesis of bioactive heterocyclic scaffolds,43-45 we wish to report herein, chitosan sulphuric acid (CTSA) catalysed microwave assisted multicomponent reaction for the synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazole derivatives. 2. Results and Discussion 2.1. Synthesis of catalyst The catalyst chitosan-SO3H (CTSA) was synthesized according to the Scheme 1. CTSA was characterized well with different techniques and are discussed below.

Scheme 1. Synthesis of catalyst chitosan sulphuric acid 2.2. FT-IR spectral analysis of the catalyst In order to show the functionalization of chitosan by chlorosulfonic acid, FT-IR spectra of chitosan and functionalized chitosan have been analysed (Figure 2). The FT-IR spectrum of chitosan (Figure 2 a) shows a broad band at 3419 cm−1 which is due to the stretching vibrations of N-H and O-H groups. Weak absorption band at 2920 cm−1 is characteristic of C-H stretching vibrations. The absorption band at 1648 cm−1 is attributed to N-H bending vibration. Absorption band of C-O stretching vibration of primary alcoholic groups in chitosan appeared at 1418 cm−1. The absorption bands at 1076 and 1017 cm−1 are due to the 5 ACS Paragon Plus Environment


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stretching vibrations of the C-O bonds8 present in the chitosan skeleton. The FT-IR spectrum of sulphuric acid modified chitosan (Figure 2 b) shows a slightly different absorption behaviour. The stretching vibration8 of acidic O-H groups appear as broad band at 2800–3500 and out-of-plane bending vibration8 of acidic O-H groups at 813 cm−1.-S= O stretching bands of -SO3H in –O-SO3H and NH-SO3H groups8 appear at 1226 cm−1 and 1064 cm−1, respectively. The stretching vibration of S—N bond46 in the -HN-SO3H is observed at 680 cm-1.

Figure 2. FT-IR spectra of a) chitosan b) Chitosan-SO3H 2.3. Elemental analyses In addition to structural confirmation by FT-IR, quantitative determination of sulfonic acid group onto chitosan was done by elemental analysis. The elemental analysis of CTSA showed the carbon and nitrogen content to be 27.10% and 6.07% respectively. The C/N ratio was calculated to be 4.46 which is fairly in good agreement with theoretical C/N ratio of


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chitosan.47 The S content of the catalyst was 5.35%. From this loading of sulfonic acid on chitosan was calculated to be 1.67 mmol/g of support. 2.4. Back titration analysis The number of acidic sites (H+) of the chitosan-SO3H was determined by acid–base titration and it was found to be 1.75 meq/g. This further confirms the amount of loading of sulfonic acid group on chitosan. The amount of H+ ion determined by acid base titration is from both alcoholic OH group of chitosan as well as SO3H group. As the H+ ion only from SO3H group would be approximately 1.67 meq/g (as determined by loading of S from elemental analysis). But due to the presence of alcoholic H+ ion of chitosan it is found to be 1.75 meq/g. 2.4.5. SEM and EDX analysis The SEM micrographs (Figures 3, 4) were used to study surface morphology of CTSA and it was revealed that a homogeneous fibrous surface remained intact after modification.

Figure 3. SEM image Chitosan



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Figure 4. SEM images CTSA at different magnifications.

EDX analysis (Figure 5) confirmed the presence of C, N, O and S elements in the modified chitosan CTSA.

Figure 5. EDX spectra of CTSA


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Figure 6. TG analysis of Chitosan-SO3H catalyst. Chitosan is highly stable both in acidic and basic solutions. There is extensive intramolecular and/or intermolecular hydrogen bonding due to presence of OH and NH groups which lead to the formation of a helical structure of chitosan and makes it rigid and stable towards various chemical modifications including sulfonation and salt formation by acid treatment.48 Further thermal stability of the catalyst (chitosan-SO3H) is evaluated with the help of TGA by heating chitosan-SO3H up to 600 °C (Figure 6). The TG curve of catalyst shows two stage weight losses at 91 °C and another at 270 °C. The first weight loss of 22.2 % is attributed to removal of adsorbed solvent molecules from polymer matrix and the second weight loss of 55.7 % is due to the decomposition of the polysaccharide chain along with SO3H group. Thus the catalyst is stable up to 270 °C. 2.6. Optimization of reaction conditions To find the best solvent for the synthesis of titled compounds, one-pot four component reaction between aldehyde (1a, 1 mmol), benzil (2a, 1 mmol), ammonium acetate (3, 3 9 ACS Paragon Plus Environment


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mmol), and aniline (5a,1 mmol), in the presence of chitosan-SO3H (100 mg) to form the product 6a (Scheme 2) was selected as a model reaction. Keeping environment into concern, the yield of the product and reaction time were analysed in different environmentally benign solvents at 100 °C under microwave irradiation and the obtained results are summarized in Table 1. In polyethylene gylcols (Table 1, entries 1-3) poor yield of products were obtained in longer time period. In protic solvents such as MeOH and iPrOH (Table 1, entries 4-5) yield of the products were good. Water was also equally good in terms of yield of the product and reaction time (Table 1, entry 6). However, maximum yield of the product was obtained in EtOH (Table 1, entry 7). Table 1. Effect of different solvents on the model reactiona

Entry

a

Solvent

Microwave irradiation Time(min)b

Yield (%)c

1.

MeOH

7

80

2.

iPrOH

10

76

3.

PEG-200

25

45

4.

PEG-400

25

36

5.

PEG-600

32

34

6.

H2O

7

89

7.

EtOH

7

91

Experimental condition: Aldehyde (1a, 1 mmol), benzil (2, 1 mmol), ammonium acetate (3,

3 mmol), aniline (5a, 1 mmol) in 5 mL of EtOH and 100 mg of catalyst at 100 °C (microwave irradiation). b

c

Reaction progress monitored by TLC

isolated yield 10 ACS Paragon Plus Environment

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Reaction temperature and amount of catalyst has also pronounced effect on yield of the products. In order to show the effect of temperature on product yield, the model reaction was conducted under MI at different temperatures (Table 1). At 40 °C poor yield of the product was obtained (Table 1, entry 1). Raising the temperature to 60, 80 and 100 °C the yield of the product increased subsequently while reaction time period decreased (Table 1, entries 2, 3, 4). At 120 °C the yield of the product and time period for completion of the reaction remained the same (Table 1 entry 5). Therefore 100 °C was chosen as the optimized temperature for the synthesis of tri and tetra substituted imidazole derivatives. On further increasing the temperature to 130, 140, 150 °C (Table 1 entries 6, 7, 8), the reaction completed in relatively shorter time period but lead to the formation of side products affecting the yield of the products. Amount of catalyst is also crucial for the reaction. It was found that when the catalyst amount was increased from 20 mg to 100 mg (Table 2 entries 10, 11, 12, 13 , 14) the yield of the product increased significantly from 56% to 91%. With further increase to 120 mg the time taken and yield obtained did not change (Table 2 entry 14). Thus Optimum amount of the catalyst signifies the minimum amount of catalyst required to activate the substrate for the formation of products. Using more than optimized amount of the catalyst then does not have any effect on the yield of product.

Table 2. Optimization for the synthesis of Imidazole under microwave irradiationa

Entry

1.

Temperature

Amount of CTSA

Microwave irradiation

( °C)

(mg)

Time (min)b

Yield (%)c

40

100

25

55



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a

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2.

60

100

22

67

3.

80

100

15

72

4.

100

100

7

91

5.

120

100

7

91

6.

130

100

6

90

7.

140

100

6

90

8.

150

100

5

88

9

100

-

35

48

10.

100

20

30

56

11.

100

40

26

64

12.

100

60

15

76

13.

100

80

10

82

14.

100

100

7

91

15.

100

120

7

91

Experimental condition: Aldehyde (1a, 1 mmol), benzil (2, 1 mmol), ammonium acetate (3,

3 mmol), aniline (5a, 1 mmol) in 5 mL of EtOH and 100 mg of catalyst at 100 °C (microwave irradiation). b

c


isolated yield

To show the merit of chitosan-SO3H as a catalyst in organic synthesis, we compared model reaction with other acidic catalysts with same amount of H+ under reflux condition by conventional heating. With polymer supported sulfonic acid catalysts such as PEG-SO3H, Xanthan-SO3H, Camphor-SO3H, Cellulose-SO3H, (Table 3, entries 1, 2, 3, 4) moderate yield of the products were obtained. With sulfamic acid and PTS (Table 3, entries 5, 6), the yield 12 ACS Paragon Plus Environment

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of the products further reduced. Again the yields of products were not satisfactory with Lewis acids such as Zn(L-proline)2 and L-proline (Table 3, entries 7, 8). Thus chitosan-SO3H was found to be best catalyst in terms of yield of the product and reaction time (Table 3, entry 9). Table 3. Effect of different catalyst on the model reaction under conventional heatinga

a

Entry

Catalyst

H+ ion conc.

Time (h)b

Yield (%)c

1.

PEG-SO3H

1.21 meq/g

4.5

69

2.

Xanthan-SO3H

1.09 meq/g

6

65

3.

Camphor-SO3H

20 mol%

10

63

4.

Cellulose-SO3H

1.11 meq/g

3.5

73

5.

Sulfamic acid

20 mol%

18

56

6.

PTS

20 mol%

20

54

7.

Zn(L-proline)2

20 mol%

3.5

76

8.

L-proline

20 mol%

4.5

79

9.

Chitosan-SO3H

1.67 meq/g

1.5

91

Experimental condition: Aldehyde (1a, 1mmol), benzil (2, 1mmol), ammonium acetate (3, 3

mmol), aniline (5a, 1 mmol) in 5mL of EtOH under reflux condition in the presence of different catalyst b

c


isolated yield



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Scheme 2. Synthesis of 2,4,5-trisubstituted imidazole derivatives catalysed chitosan sulphuric acid under microwave irradiation.

With these optimized reaction conditions in hand, we explored the generality of this protocol. Initially we synthesized 2,4,5-trisubstituted imidazole (Scheme 2 ) with different aldehydes (1a-f), benzil (2) and ammonium acetate (3). The obtained results are summarized in Table 4. Table 4 One-pot synthesis of trisubstituted imidazoles in the presence of chitosan-SO3H Entry

Product

Conventional

Microwave

heating

irradiation

Time

Yield

Time

M.P(°C)

Yield


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1.

(h)

(%)

(min)

(%)

2

88

5

93

105

1.5

89

7

96

305

2.5

88

10

91

297

2

86

6

91

135

4

85

15

90

232

3.5

86

12

89

234

4a

2. 4b

3. 49

4c H N N

N Cl

4.49 4d

6.50 4e

7.51



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4f

8.

2

89

11

90

93

4a’

We then further extended this protocol for the synthesis of tetrasubstituted imidazole with 1phenyl-3-methyl-5-pyrazole 3-carbaldehyde (1a)/ 3-formylindole (1c), benzil (2), ammonium acetate (3) different substituted aniline (5a-i) (Scheme 3). The reaction proceeded smoothly with different electron donating and electron withdrawing substituents on aniline (Table 5). All the synthesized products are characterized well with spectral analyses. The IR spectrum of the novel compound 6b showed sharp strong bands at 1596 cm-1 and 1501 cm-1 for C=C and C=N group of imidazole moiety respectively. The 1H NMR spectra exhibited multiplets in the range of δ 6.79–7.42 for all the aromatic protons. A singlet integrating for three protons at δ 3.31 was assigned to the methoxy proton. The three methyl protons of pyrazolyl moiety were discernible as singlet at δ 2.12. Four aromatic protons of substituted amine appeared as a singlet at δ 7.16. The 13C NMR spectrum showed signals at δ 12.87 and 55.09 for CH3 and OCH3 groups respectively, whereas C-4 and C-5 carbons of imidazole moiety appeared at δ 137.36 and 137.34 respectively. C-2 carbon of imidazole appeared at δ 138.20. Pyrazoly C-3 and C-4 carbon are discernible at δ 149.32 and 110.34 respectively whereas its C-5 carbon appeared at δ 130.74. The aromatic carbons appeared at their appropriate chemical shift values and are given in spectral data.


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Scheme 3. Synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives catalysed chitosan sulphuric acid under microwave irradiation. Table 5 Multicomponent synthesis of tetrasubstituted imidazoles in the presence of chitosanSO3H Entry

Product

Conventional

Microwave

heating

Irradiation

M.P(°C)

( 5-10watt)

1.

Time

Yield

Time

Yield

(h)

(%)

(h)

(%)

7

91

1.5

87

305

6a



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2.

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1.2

87

6

89

345

2

86

8

87

306

1.2

89

5

90

337

2

89

10

91

329

6b

3.

6c

4.

6d OH

Cl

5.

N N

N N CH3

6e


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Cl

8.

N N

N

1.5

88

6

90

330

2

90

9

90

314

1.5

88

7

89

332

2

82

10

88

315

N CH3

6f

10.

7a

11.

7b

12.

7c



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13.

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2.5

86

12

89

308

1.2

87

8

88

332

2

91

10

90

310

7d

14.

6g

15.

6h


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Scheme 4. Suggested mechanism for the synthesis of 2,4,5-trisubstituted imidazole derivatives catalysed chitosan sulphuric acid under microwave irradiation. A plausible mechanism for the synthesis of tetrasubstituted imidazole has been depicted in scheme 4. Based on this mechanism, this reaction is facilitated by activation of the carbonyl group of aldehyde 1a due its protonation by acidic catalyst CTSA. This facilitates the nucleophilic attack from aniline 5a to form schiffs base I.52 Further addition of ammonia to schiffs base forms diamine intermediate II. This step is followed by the nucleophilic attack of the diamine intermediate II to activated carbonyl group of benzil to give the intermediate III which after intramolecular cyclization leads to the formation of IV. This intermediate liberates a water molecule to produce tetrasubstituted imidazole 6a. Recycling study



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The recyclability of the catalyst is an important aspect to satisfy the green chemistry principle. The recyclability of the catalyst was examined using the model reaction in the presence of CTSA as a catalyst in ethanol under microwave irradiation (Figure 7). After completion of the reaction, the catalyst was recovered by filtration, washed ethanol, acetone and air dried. The recovered catalyst was reused in subsequent runs. There was slight decrease in catalytic activity after five runs. The SEM images (Figure 8) of the catalyst after five runs showed that the catalyst morphology was preserved during its reuse.

Figure 7. Reusability of the catalyst for the model reaction.

Figure 8. SEM images of recovered catalyst at different magnification

Conclusion 22 ACS Paragon Plus Environment

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In summary, we have developed an eco-compatible, efficient and simple procedure for the multicomponent reaction to the synthesis of a library of tri and tetrasubstituted heterocyclic imidazoles employing chitosan-SO3H as an environmentally benign and heterogeneous biopolymer supported solid acid catalyst under microwave irradiation. This protocol is efficiently applicable to a wide variety of aldehydes as well as amines affording the corresponding tri and tetrasubtituted imidazole derivatives in excellent yields. The catalyst is easily recoverable and recyclable up to five cycles. Moreover, microwave assisted synthesis makes this protocol more environmentally benign and a significant contribution towards sustainability. Acknowledgments The authors are thankful to the University Sophisticated Instrument Facility (USIF), AMU, Aligarh for providing powder SEM and EDX facilities. The authors would also like to thank SAIF Punjab University, Chandigarh for providing NMR and Mass spectra. One of the authors, K.K., is thankful to UGC for providing financial assistance in the form of MANF[No. F.40- 3(M/S)/2009(SA-III/MANF)]. Supporting Information Text describing the general experimental procedure and details of characterization data of the products. This material is available free of charge via the Internet at http://pubs.acs.org."



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References. (1) D’Souza, D. M.; Mueller, T. J. J. Multi-component syntheses of heterocycles by transition metal catalysis. Chem. Soc. Rev. 2007, 36, 1095. (2) Kappe, C. O.; Controlled Microwave Heating in Modern Organic Synthesis. Angew.

Chem., Int. Ed. 2004, 43, 6250. (3) Bailey, D. C.; Langer, S. H. Immobilized transition-metal carbonyls and related catalysts. Chem. Rev. 1981, 81, 109. (4) (a) Rinaudo, M. Chitin and chitosan: Properties and applications, Prog. Polym. Sci. 2006, 31, 603–632; (b) Dash, M.; Chiellini, F.; Ottenbrite R. M.; Chiellini, E. Chitosan-A versatile semi-synthetic polymer in biomedical applications.

Prog.

Polym. Sci. 2011, 36, 981. (5) Macquarrie, D. J.; Hardy, J. J. E. Applications of Functionalized Chitosan in Catalysis. Ind. Eng. Chem. Res, 2005, 44, 8499. (6) a) Xiao, L. F.; Li, F. W.; Xia, C. G. An easily recoverable and efficient natural biopolymer-supported zinc chloride catalyst system for the chemical fixation of carbon dioxide to cyclic carbonate. Appl. Catal. A, 2005, 279, 125. b) Huai-min, G.; Xian-su, C.; Study of cobalt(II)-chitosan coordination polymer and its catalytic activity and selectivity for vinyl monomer polymerization. Polym. Adv. Technol, 2004, 15, 89. c) Quignard, F.; Choplin, A.; Domard, A. Chitosan: A Natural Polymeric Support of Catalysts for the Synthesis of Fine Chemicals. Langmuir, 2000,

16, 9106. d) Hardy, J. J. E.; Hubert, S.; Macquarrie, D. J.; Wilson, A. J. Chitosanbased heterogeneous catalysts for Suzuki and Heck reactions. Green Chem, 2004, 6, 53.


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(7) Guibal, E. Heterogeneous catalysis on chitosan-based materials: a review, Prog.

Polym. Sci. 2005, 30, 71. (8) Mohammadi, R.; Kassaee, M. Z. Sulfochitosan encapsulated nano-Fe3O4 as an efficient and reusable magnetic catalyst for green synthesis of 2-amino-4H-chromen4-yl phosphonates. J. Mol. Catal. A: Chem. 2013, 380, 152. (9) Reddy, B. V. S.; Venkateswarlu, A.; Reddy, G. N.; Reddy, Y. V. R.; Chitosan-SO3H: an efficient, biodegradable, and recyclable solid acid for the synthesis of quinoline derivatives via Friedländer annulation. Tetrahedron Lett. 2013, 54, 5767. (10) Gallagher, T. F.; Fier-Thompson, S. M.; Garigipati, R. S.; Sorenson, M. E.; Smietana, J. M.; Lee, D.; Bender, P. E.; Lee, J. C.; Laydon, J. T. ; Griswold, D. E.; Chabot-Fletcher, M. C.; Breton J. J.; Adams, J. L. 2,4,5- triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg. Med. Chem. Lett. 1995, 5, 1171. (11) Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G. Rossi T.; Ursini, A. Analogues of

4,5-bis(3,5-Dichlorophenyl)-2-Trifluoromethyl-1H-Imidazole

as

Potential

Antibacterial Agents. Bioorg. Med. Chem. Lett. 1999, 9, 1023. (12) Adams, J. L.; Boehm, J. C.; Kassis, S.; Gorycki, P. D.; Webb, E. F.; Hall, R.; Sorenson, M.; Lee,

J. C.; Ayrton, A.; Griswold, D. E.; Gallagher, T. F.;

Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome p450 enzymes. Bioorg. Med. Chem. Lett. 1998, 8, 3111. (13) de Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J. V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Potent, orally absorbed glucagon receptor antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 641.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 32

(14) Laufer, S.; Hauser, D.; Stegmiller, T.; Bracht, C.; Ruff, K.; Schattel, V.; Albrecht, W.; Koch, P. Tri- and tetrasubstituted imidazoles as p38α mitogen-activated protein kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 6671. (15) Sarshar, S.; Zhang, C.; Moran, E. J.; Krane, S.; Rodarte, J. C.; Benbatoul, K. D.; Dixon, R.; Mjallik, A. M. M. 2,4,5-Trisubstituted Imidazoles: Novel Nontoxic Modulators of P-glycoprotein Mediated Multidrug Resistance. Part 1, Bioorg. Med.

Chem. Lett. 2000, 10, 2599. (16) Deprez, P.; Mandine, E.; Vermond A.; Lesuisse, D. Imidazole-based Ligands of the Src SH2 Protein. Bioorg. Med. Chem. Lett. 2002, 12, 1287. (17) Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y. H.; Marsh, K.; Warner, R.; Lee, J. Y.; ZielinskyMozng, N.;

Frost, D.; Rosenberg S. H.; Sham, H. L. Potent, orally active

heterocycle-based combretastatin A-4 analogues: synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation. J. Med.

Chem. 2002, 45, 1697. (18) Weinstein, D. S.; Liu, W.; Ngu, K.; Langevine, C.; Combs, D. W.; Zhuang, S.; Chen, C.; Madsen, C. S.; Harper T. W.; Robl, J. A. Discovery of selective imidazole-based inhibitors of mammalian 15-lipoxygenase: Highly potent against human enzyme within a cellular environment. Bioorg. Med. Chem. Lett. 2007, 17, 5115. (19) Lange, J. H. M.; Stuivenberg, H. H. V.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; Looff, W. de; Verveer P. C.; Kruse, C. G. Bioisosteric replacements of the pyrazole moiety of

rimonabant:

synthesis,

biological

properties,

and

molecular

modeling

investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists. J. Med. Chem. 2005, 48, 1823.


Page 27 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(20) Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman J. G.; Wilson, D. M. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase, Bioorg. Med. Chem. Lett. 2006, 16, 378. (21) George T. DeTitta, James W. Edmonds, William Stallings, and Jerry Donohue, Molecular Structure of Biotin. Results of Two Independent Crystal Structure Investigations, J. Am. Chem. Soc., 1976, 98, 1920. (22) Bonnet, J. J.; Ibers, J. A.; Structure of histamine, J. Am. Chem. Soc. 1973, 95, 4829. (23) Li S.; Hong, M. Protonation, Tautomerization, and Rotameric Structure of Histidine: A Comprehensive Study by Magic-Angle-Spinning Solid-State NMR, J. Am. Chem.

Soc., 2011, 133, 1534. (24) Dupont,J.; de Souza, R. F.; Suarez, P. A. Z.; Ionic Liquid (Molten Salt) Phase Organometallic Catalysis, Chem. Rev. 2002,102, 3667. (25) Chowdhury, S.; Mohan, R. S.; Scott, J. L.; Reactivity of ionic liquids, Tetrahedron 2007, 63, 2363. (26) Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. Highly efficient, four-component one-pot synthesis of tetrasubstituted imidazoles using Keggin-type heteropolyacids as green and reusable catalysts, J. Mol. Catal. A: Chem. 2007, 263, 112. (27) Balalaie, S.; Arabanian, A. One-pot synthesis of tetrasubstituted imidazoles catalyzed by zeolite HY and silica gel under microwave irradiation, Green Chem. 2000, 2, 274. (28) Mohammed, A.; Kokare, N.; Sangshetti, J.; Shinde, D. Sulphanilic Acid Catalyzed Facile One-pot Synthesis of 2,4,5-Triarylimidazoles From Benzil/Benzoin and Aromatic Aldehydes. J. Korean Chem. Soc. 2007, 51, 418.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 32

(29) Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.; Ethayathulla, A. S.; Dey, S.; Singh, T. P. One-pot synthesis of highly substituted imidazoles using molecular iodine: A versatile catalyst, J. Mol. Catal. A: Chem. 2007, 265, 177. (30) Siddiqui, S.; Narkhede, U.; Palimkar, S.; Daniel, T.; Lahoti, R.; Srinivasan, K. Room temperature ionic liquid promoted improved and rapid synthesis of 2,4,5-triaryl imidazoles from aryl aldehydes and 1,2-diketones or a-hydroxyketone. Tetrahedron 2005, 61, 3539. (31) Karimi,

A.

R.;

Alimohammadi,

Z.;

Azizian,

J.;

Mohammadi,

A.

A.;

Mohammadizadeh, M. R. Solvent-free synthesis of tetrasubstituted imidazoles on silica gel/NaHSO4 support. Catal. Commun. 2006, 7, 728. (32) Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.; Nagarapu, L Highly efficient, one-pot, solvent-free synthesis of tetrasubstituted imidazoles using HClO4–SiO2 as novel heterogeneous catalyst, J. Mol. Catal. A: Chem. 2007, 266, 109. (33) Heravi, M. M.; Derikv, F.; Haghighi, M., Highly Efficient, Four Component, Onepot Synthesis of Tetrasubstituted Imidazoles Using a Catalytic Amount of FeCl3.6H2O, Monatsh. Chem. 2008, 139, 31. (34) Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M., BF3.SiO2: an efficient reagent system for the one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles, Tetrahedron

Lett. 2008, 49, 2575. (35) Usyatinsky, A. Y.; Khmelnitsky, Y. L. Microwave-assisted synthesis of substituted imidazoles on a solid support under solvent-free conditions, Tetrahedron Lett. 2000,

41, 5031. (36) Sharma, S. D.; Hazarika, P.; Konwar, D. An efficient and one-pot synthesis of 2,4,5trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed by InCl3.3H2O.

Tetrahedron Lett. 2008, 49, 2216.


Page 29 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(37) Lipshutz, B. H.; Morey, M. C. An Approach to the Cyclopeptide Alkaloids (Phencyclopeptines) via Heterocyclic Diamide/Dipeptide Equivalents. Preparation and N-Alkylation Studies of 2,4(5)-Disubstituted Imidazoles, J. Org. Chem. 1983,

48, 3745. (38) Mohammadizadeh, M. R.; Hasaninejad, A.; Bahramzadeh, M. Trifluoroacetic Acid as an Efficient Catalyst for One-Pot, Four-Component Synthesis of 1,2,4,5Tetrasubstituted Imidazoles Under Microwave-Assisted, Solvent-Free Conditions,

Synth. Commun. 2009, 39, 3232. (39) Subhasis Samai, Ganesh Chandra Nandi, Pallavi Singh, M.S. Singh, L-Proline: an efficient catalyst for the one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5tetrasubstituted imidazoles, Tetrahedron, 2009, 65, 10155. (40) Teimouri, A.; Chermahini, A. N. An efficient and one-pot synthesis of 2,4,5trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed via solid acid nanocatalyst. J. Mol. Catal. A: Chem. 2011, 346, 39. (41) Zarnegar, Z.; Safari J.; Fe3O4@chitosan nanoparticles: a valuable heterogeneous nanocatalyst for the synthesis of 2,4,5-trisubstituted imidazoles RSC Adv., 2014, 4, 20932. (42) Zhou, J. F.; Song, Y. Z.; Zhu, Y. L.; Tu, S. J.; One-Step Synthesis of 2-Aryl-4,5diphenylimidazoles Under Microwave Irradiation. Synth. Commun. 2005, 35, 1369. (43) Siddiqui, Z. N.; Khan, K.; Ahmed, N. Nano Fibrous Silica Sulphuric Acid as an Efficient Catalyst for the Synthesis of β-Enaminone. Catal Lett. 2014, 144, 623. (44) Siddiqui, Z. N.; Khan, K. Friedlander synthesis of novel benzopyranopyridines in the presence of chitosan as heterogeneous, efficient and biodegradable catalyst under solvent-free conditions, New J. Chem., 2013, 37, 1595.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 32

(45) Siddiqui Z. N.; Khan, K. [Et3NH][HSO4]‑Catalyzed Efficient, Eco-Friendly, and Sustainable Synthesis of Quinoline Derivatives via Knoevenagel Condensation, ACS

Sustainable Chem. Eng. 2014, 2, 1187. (46) Ilczyszyn, M. M.; Ilczyszyn, M. Raman, infrared and

13

C NMR studies on betaine-

sulfamic acid (2 : 1) crystal and its hydrogen bonds. J. Raman Spectrosc. 2003, 34, 693. (47) Ghiaci, M.; Dorostkar, N.; Martínez-Huerta, M. V.; Fierro, J. L.G.; Moshiri. P.; Synthesis and characterization of gold nanoparticles supported on thiol functionalized chitosan for solvent-free oxidation of cyclohexene with molecular oxygen, J. Mol. Catal. A: Chem., 2013, 379, 340. (48) Sait, H.; Tabeta R.; High-Resolution Solid-state 13C NMR Study of Chitosan and Its Salts with Acids: Conformational Characterization of Polymorphs and Helical Structures as Viewed from the Conformation-Dependent

13

C Chemical Shifts,

Macromolecules 1987, 20, 2424. (49) Kidwai, M.; Saxena, S.; Ruby, Rastogi, S. An Efficient Synthesis of 2,4,5Trisubstituted and 1,2,4,5-Tetrasubstituted-1H-imidazoles, Bull. Korean Chem. Soc. 2005, 26, 2051. (50) Safari, J.; Khalili, S. D.; Rezaei, M.; Banitab S. H.; Meshkani, F. Nanocrystalline magnesium oxide: a novel and efficient catalyst for facile synthesis of 2,4,5trisubstituted imidazole derivatives, Monatsh. Chem., 2010, 141, 1339. (51) Siddiqui, S. A.; Narkhede, U. C.; Pallmkar, S. S.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Room temperature ionic liquid promoted improved and rapid synthesis of 2,4,5-triaryl imidazoles from aryl aldehydes and 1,2-diketones or αhydroxyketone Tetrahedron 2005, 61, 3539.


Page 31 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(52) Hasaninejad, A.; Zare, A., Shekouhy, M.; Rad, J. A.; Catalyst-Free One-Pot Four Component Synthesis of Polysubstituted Imidazoles in Neutral Ionic Liquid 1-Butyl3-methylimidazolium Bromide. J. Comb. Chem. 2010, 12, 844.



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