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1-Hydroxyethyl-2-Substituted Phenoxymethyl Benzimidazoles: Synthesis and Crystal Structures.

Byline: Jiacheng Wu, Li Zhao, Changqing Zhao, Zhiyuan Wang, Haibin Gu and Wuyong Chen

Summary: Five novel 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles c1-c5 were successfully synthesized by a three-step route. Firstly, five substituted phenoxymethyl acids a1-a5 were prepared by the O-carboxymethylation reaction of the starting substituted phenols under microwave irradiation. Then, these compounds reacted with o-phenylendiamine to get the key intermediates 2-substituted phenoxymethyl benzimidazoles b1-b5. At last, the target compounds were synthesized by the N-hydroxyethylation reaction of b1-b5 with 2-chloroethyl alcohol through the solid-liquid phase transfer catalysis method, where tetrabutyl ammonium bromide (TBAB) was used as the catalyst. The structures of the target compounds were well characterized and verified by elemental analysis, MS, IR, 1H NMR, 13C NMR and single crystal X-ray diffraction analysis.

Keywords: Benzimidazole, O-carboxymethylation, N-hydroxyethylation, Synthesis, Crystal structures.

Introduction

Within the vast range of heterocycles, benzimidazole and its derivatives are found to be trendy structures employed for drug discovery in the field of pharmaceutical and medicinal chemistry.[1-3] In past a few decades, many organic and medicinal chemists paid huge attention on the synthesis of benzimidazole derivatives because of their diverse biological and clinical applications including anticancer, antiviral, anti-HIV, anthelmintic, antihypertensive, anxiolytic, anti-inflammatory, hormone antagonist, antioxidant and antidiabetic activities.[4-8] In this field, substitution of benzimidazole nucleus, which can happen at the phenyl ring or/and the imidazole ring, is an important and effective synthetic strategy in the drug discovery process. So, in this study, the substituted phenoxymethyl structures were introduced to the 1(C)-position of the imidazole ring.

This incorporation was carried out by reaction of o- phenylendiamine with the corresponding substituted phenoxymethyl acid which have attracted much attention in biochemistry, agriculture and pharmacology due to their antiviral, antimicrobial activities and phytohormone activities.[9-11] Subsequently, using the N-hydroxyethylation reaction with 2-chloroethyl alcohol, the hydrogen atom of 1(N)-position of the imidazole ring was replaced by the hydroxyethyl group that can be used as an active site to introduce other bioactive structures. The prepared five target compounds, 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles, were characterized by elementary analysis, MS, IR, 1H and 13C NMR. Single crystal X-ray technique was also used to obtain information about the stereochemistry of these molecules and verify the assigned structures.

Experimental

2-Substituted phenoxymethyl benzimidazoles (b1-b5) were synthesized under microwave irradiation condition according to the procedure reported in the literature.[12,13] All the other compounds used were research grade, commercially purchased and used as received. All the solvents used were dried and freshly distilled. Melting points were performed on a Shanghai Zhongguang WRS-2 melting point apparatus and uncorrected. Elemental analysis (C, H, N) were determined on a Carlo-Erba 1106 analyser. FT-IR spectra obtained on a Magna. IR506 (Nicolet Ltd, USA) FT-IR spectrophotometer using KBr disk in the range 4000-400 cm-1. 1H and 13C NMR spectra were recorded at 25 C with a Bruker AV II-400 or 600 MHz spectrometer. All the chemical shifts are reported in parts per million (d, ppm) with reference to tetramethylsilane (TMS). Mass spectra were measured on a GCMS-QP2010 Plus Model GC-MS spectrometer.

Measurements of the crystals were carried out on a CCD X-ray single crystal diffractometer (Xcalibur, Eos, UK) with a graphite-monochromated MoKa radiation. A single crystal of a compound was mounted on a glass fiber, X-ray diffraction intensity data were collected using the -2th scan technique. The Multi-scan/CrysAlisPro, Oxford Diffraction Ltd., was applied for the data reduction and absorption correction. All the structures were solved by direct method and refined by full matrix least squares method using SHELX-2012 program.[14]

The hydrogen atoms located in a difference Fourier map were limitedly refined with isotropic temperature factors and other hydrogen atoms that were added in their calculated positions were refined using a riding model.[15].

Synthesis of C1: 2-(o-methyl)-phenoxymethyl benzimidazole b1 (2.38 g, 0.01 mol) and 2-chloroethyl alcohol (1.61 g, 0.02 mol) were dissolved in 100 mL of acetone, and then tetrabutylammonium bromide (64.5 mg, 0.2 mmol) and NaOH (0.8 g, 0.02 mol) were added. The mixture was refluxed at 65 C for 5h, added into 1000 mL cold distilled water, and cooled to room temperature. The obtained precipitate was filtered, washed with water (3 x 15 mL), recrystallized from 65% (v/v) ethanol, and dried to get c1 as a white solid. The synthesis of c2-c5 also followed the similar procedure.

Yield: 93.8%. m. p. 171C. Anal. calcd. (%) for C17H18O2N2: C, 72.34; H, 6.38; N, 9.93. Found (%): C,72.23; H, 6.32; N, 9.87. MS (ESI, m/z), calcd. for C17H18O2N2: 282.34; found: 283.13 (M+H+). Selected IR (KBr, cm-1): 3242.26 (OH), 1603.65 (C=N), 1592.11, 1495.28 (C=C, Ar), 1337.80 (C-N), 1239.82 (Ar-O-C). 1H NMR (400 MHz, DMSO-d6), dppm: 7.673-6.859 (m, 8H, Ar-H), 5.440 (s, 2H, CH2-O-Ar), 5.067 (t, 1H, OH), 4.419 (t, 2H, N-CH2), 3.776-3.737 (q, 2H, CH2OH), 2.172 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6), dppm: 155.95, 150.04 (NCN), 141.91, 135.55, 130.57, 126.96, 125.84, 122.57, 121.68, 120.87, 119.26, 111.34, 110.85, 62.81 (CH2O-Ar), 59.83 (CH2OH), 46.11 (NCH2), 16.01 (CH3).

C2: white solid. Yield: 89.1%. m. p. 173. Anal. calcd. (%) for C17H18O2N2: C, 72.34; H, 6.38; N, 9.93. Found (%): C, 72.36; H, 6.29; N, 9.97. MS (ESI, m/z), calcd. for C17H18O2N2: 283.34; found: 283.15 (M+). Selected IR (KBr, cm-1): 3231.32 (OH), 1601.76 (C=N), 1583.94, 1493.08 (C=C, Ar), 1358.71 (C-N), 1257.43 cm-1 (Ar-O-C). 1H NMR (600 MHz, DMSO-d6), appm: 7.657-6.788 (m, 8H, Ar-H), 5.399 (s, 2H, CH2-O-Ar), 5.046 (t, 1H, O-H), 4.378 (t, 2H, N-CH2), 3.764-3.737 (q, 2H, CH2OH), 2.282 (s, 3H, CH3). 13C NMR (150 MHz, DMSO-d6), appm: 158.37, 150.04 (NCN), 142.41, 139.58, 136.05, 129.76, 123.04, 122.46, 122.14, 119.72, 115.93, 112.18, 111.31, 63.10 (CH2O-Ar), 60.32 (CH2OH), 46.63 (NCH2), 21.57 (Ar-CH3).

C3: white solid. Yield: 93.7%. m. p. 198. Anal. calcd. (%) for C H O N Cl: C, 63.47; H 4.96; N, 9.26. Found (%): C, 63.44; H, 4.94; N, 9.22. MS (ESI, m/z), calcd. for C16H15O2N2Cl: 302.78; found: 303.09 (M ). Selected IR (KBr, cm): 3198.48 (OH), 1597.05 (C=N), 1583.57, 1492.45 (C=C, Ar), 1364.45 (C-N), 1239.03 (Ar-O-C).

H NMR (600 MHz, DMSO-d6), appm: 7.672-6.984 (m, 8H, Ar-H), 5.552 (s, 2H, CH2-O-Ar), 5.056 (t, 1H, OH), 4.439 (t, 2H, N- CH2), 3.792-3.766 (q, 2H, CH2OH). 13C NMR (150 MHz, DMSO-d6), appm: 153.61, 149.78 (NCN), 142.36, 136.08, 130.53, 128.78, 123.19, 122.69, 122.25, 121.89, 119.81, 114.98, 111.43, 64.03 (CH O-Ar), 60.39 (CH OH), 46.63 (NCH).

C4 : white solid. Yield: 75.7%. m. p. 182. Anal. calcd. (%) for C16H15O2N2Cl: C, 63.47; H, 4.96; N, 9.26. Found (%): C, 63.26; H, 4.77; N, 9.34. MS (ESI, m/z), calcd. for C16H15O2N2Cl: 302.78; found: 303.09 (M+). Selected IR (KBr, cm-1): 3233.74 (OH), 1598.21 (C=N), 1580.95, 1520.92 (C=C, Ar), 1370.14 (C-N), 1243.70 (Ar-O-C). 1H NMR (600 MHz, DMSO- d6), appm: 7.668-7.040 (m, 8H, Ar-H), 5.482 (s, 2H, CH2-O-Ar), 5.064(s, 1H, OH), 4.386 (t, 2H, N-CH2), 3.747 (t, 2H, CH2OH). 13C NMR (150 MHz, DMSO-d6), appm: 159.25, 149.96 (NCH2), 142.24, 135.96, 134.23, 131.40, 123.17, 122.28, 121.70, 119.70, 115.44, 114.43, 111.39, 63.44 (CH2O-Ar), 60.31 (CH2OH), 46.65 (NCH2).

C5: white solid. Yield: 88.2%. m. p. 173C. Anal. calcd. (%) for C16H14O2N2Cl2: C, 56.97; H, 4.15; N, 8.31. Found (%): C, 56.90; H, 4.11; N, 8.21. MS (ESI, m/z), calcd. for C16H14O2N2Cl2: 337.23; found: 337.04 (M+). Selected IR (KBr, cm-1): 3167.44 (OH), 1599.86 (C=N), 1589.63, 1496.78 (C=C, Ar), 1362.63 (C-N), 1237.07 (Ar-O-C). 1H NMR (400 MHz, DMSO-d6), appm: 7.662-7.210 (m, 8H, Ar-H), 5.581 (s, 2H, CH2-O-Ar), 5.081 (t, 1H, OH), 4.435 (t, 2H, N- CH2), 3.799-3.759 (q, 2H, CH2OH). 13C NMR (100 MHz, DMSO-d6), appm: 152.25, 149.00 (NCN), 141.85, 135.55, 129.37, 128.05, 125.21, 122.74, 122.47, 121.79, 119.34, 115.70, 110.95, 63.83 (CH O-Ar), 59.89 (CH OH), 46.14 (NCH ).

Results and Discussion

Synthesis

As shown in Scheme 1, to prepare the target compounds, the substituted phenols were used as the starting materials. Firstly, under microwave irradiation and phase-transfer catalysis conditions, these phenols reacted with methyl chloroacetate to synthesize substituted phenoxyacetates that were then hydrolyzed to get the corresponding phenoxyacetic acid compounds (a1-a5) according to the reported procedure.[12] Secondly, the key intermediates - 2- substituted phenoxymethyl benzimidazoles (b1-b5) was achieved by the reaction of the obtained compounds a1-a5 with o-phenylendiamine. Finally, as a consequence of the solid-liquid phase transfer catalysis method, these intermediates reacted with 2- chloroethyl alcohol to prepare the final new products 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles (c1-c5) in high yield.

Prominently, all these compounds, which are white solid, were purified by the simple recrystallization technique, and no complex purification process such as column chromatography was used. Thus, the synthetic methodology adopted in the present work is green and economic.

NMR Spectra

1H NMR spectra of all the obtained compounds c1-c5 were recorded in DMDO-d6. No speak at 12.2-12.9 ppm or so, which arises from the N-H proton of benzimidazole structure, is observed. Instead, peaks assigned to the protons of hydroxyethyl group appeared. For example, in the 1H NMR spectrum of compound c1, the triple peak, corresponding to the methylene protons close to the nitrogen atom of imidazole ring, appeared at 4.419 ppm, and the multiple peaks at 3.776-3.737 ppm were assigned to the methylene protons adjacent to hydroxy group, while the triple peak at 5.067 ppm originated from the active proton of hydroxy group.

These results demonstrated definitely the successful formation of the target compound c1 by the N- hydroxyethylation reaction of b1. For other 1- hydroxyethyl-2-substituted phenoxymethyl benzimidazoles (c2-c5), similar peaks can also be observed in their 1H NMR spectra. It should be noted that the positions of these peaks were hardly affected by nucleophilic or electrophilic properties of the substituent groups on the phenoxymethyl structures. Moreover, the peaks at 5.399-5.581 ppm appeared as singlet due to the presence of the methylene protons of the phenoxymethyl unit, and these peaks varied their location with the properties of substituent groups. All the other peaks were obviously assigned and matched well with the structures of target compounds.

13C NMR spectra can further confirm their structures. For example, the two carbons corresponding to hydroxyethyl group appeared at 46 and 60 ppm or so, respectively. The peaks at approximately 63 ppm were assigned to the methylene carbons of phenoxymethyl moieties, while the peaks at about 150 ppm originated from the carbons of imidazole rings. Other peaks arose from the carbons of benzene rings.

FT-IR Spectra

Similar FT-IR spectra were observed for all the target compounds. The broad absorption bands at about 3200 cm-1 corresponded to the stretching vibration of OH group, which further confirmed the successful N-hydroxyethylation of the intermediates b1-b5. The peaks observed at approximately 1600 cm-1 were attributed to the stretching vibration of C=N groups of imidazole rings, while the absorption bands found in the range of 1337-1370 cm-1 were assigned to the C-N bond. The peaks due to the presence of ether bond (Ar-O-C) were observed at 1237-1239 cm-1, except for 1257.43 cm-1 for c2 and 1243.7 cm-1 for c4 whose substituted groups are located at the meta-position of the benzene ring. Moreover, the several absorption peaks at 1600-1450 cm-1 were the characteristic skeletal vibration of benzene rings.

Single Crystal X-Ray Analysis

For the target compounds c1, c2, c4 and c5, except for c3, single crystals suitable for the X-ray diffraction study were obtained by slow evaporation of the hydrous ethanol solution of the corresponding compounds. Their crystal molecular structures and structure refinements details are shown in Fig. 1 and Table-1, respectively. Selected bond lengths and angles, and hydrogen bond lengths and angles were gathered in the supplementary material.

Table-1: Crystal data and structure refinement details for c1, c2, c4 and c5.

###Compounds###c1###c2###c4###c5

###Formula###C17H18N2O2###C17H18N2O2###C16H15ClN2O2###C16H14Cl2N2O2

###Molecular weight###282.33###282.33###302.75###337.19

###Temperature/K###293.15###296.15###296.15###293.15

###Crystal system###monoclinic###monoclinic###monoclinic###monoclinic

###Space group###P21/c###P21/c###P21/c###P21/c

###a/A###11.3505(5)###11.3301(15)###11.374(4)###4.7133(2)

###b/A###8.63499(19)###8.6024(12)###8.503(3)###13.1105(6)

###c/A###15.9695(5)###15.774(2)###15.816(6)###24.8860(8)

###/, /, /###90, 108.257(4),90###90, 103.202(2),90###90, 105.845(6),90###90, 92.780(4),90

###Volume/A 3###1486.40(9)###1496.8(4)###1471.6(10)###1536.00(11)

###Z, calc(mg/mm3)###4, 1.262###4, 1.253###4, 1.366###4, 1.458

###/mm-1, F(000)###0.084, 600.0###0.083, 600.0###0.265, 632.0###0.430, 696.0

###Crystal size/mm3###0.3 A- 0.2 A- 0.2###0.4 A- 0.2 A- 0.13###0.35 A- 0.25 A- 0.2###0.3 A- 0.25 A- 0.25

###2 range for data collection###6.046 to 52.742###3.692 to 50.696###3.722 to 50.7###5.816 to 52.742

###-14 h 14,###-13 h 13,###-13 h 13,###-5 h 5,

###Index ranges###-10 k 10,###-10 k 10,###-10 k 10,###-14 k 16,

###-17 l 19###-19 l 19###-19 l 19###-31 l 31

###Reflections collected###8027###15298###14959###6947

###Independent reflections (Rint)###3026(0.0148)###2743 (0.0260)###2691(0.0796)###3125(0.0222)

###Data/restraints/parameters###3026/0/192###2743/0/192###2691/0/191###3125/0/208

###Goodness-of-fit on F2###1.063###1057###1.047###1.055

###R1 = 0.0512,###R1 = 0.0438,###R1 = 0.0524,###R1 = 0.0484,

###Final R indexes [I2 (I)]

###wR2 = 0.1330###wR2 = 0.1136###wR2 = 0.1441###wR2 = 0.1107

###R1 = 0.0583###R1 = 0.0496###R1 = 0.0611###R1 = 0.0648,

###Final R indexes (all data)

###wR2 = 0.1388###wR2 = 0.1204###wR2 = 0.1543###wR2 = 0.1201

###Largestdiff.peak/hole/eA -3###0.48/-0.26###0.39/-0.27###0.64/-0.43###0.25/-0.30

All the crystal molecular structures of c1, c2, c4 and c5 belong to monoclinic system and only one molecular unit were observed, although these compounds have different types and positions of substituents in the phenoxymethyl unit. In these four crystals, the planes between imidazole ring and the substituted benzene ring are not co-plane and the intersection angles are 74.43(c1), 68.89(c2), 74.87(c4), 81.36(c5), respectively. Obviously, the electron-withdrawing group (for example, m-Cl in c4) can result in bigger intersection angle than electron- donating group (for example, m-CH3 in c2), and the greater the number of electron-withdrawing group is, the bigger the angle becomes (for example, c5). Furthermore, the position of substituents has also significant effect on the intersection angle, which can be verified by comparing the angle values of c1 and c2.

As shown in Fig. 1, in the molecules of c1, c2, c4 and c5, all the hydroxyethyl groups were observed to be connected to the N atoms of imidazole rings, which further confirmed the success of the N- hydroxyethylation synthesis route for the target compounds. The bond lengths between the C and N atoms are 1.457 (2), 1.4604 (17), 1.463 (3) and 1.456 (3) A for c1, c2, c4 and c5, respectively. The bond angles of C1-N1-C15 (c1), C1-N1-C8 (c2), C1-N1-C8 (c4) and C1-N1-C15 (c5) are 124.86(14), 124.89(11), 124.84(17) and 125.11(19), respectively. Furthermore, the bond angles of C7-N1- C15 (c1), C7-N1-C8 (c2), C7-N1-C8 (c4) and C7-N1- C15 (c5) are 128.52(14), 128.53(12), 128.39(18) and 128.1(2), respectively. The similar values of these bond lengths and angles in the four compounds indicate that the substituents have little effect on them due to the far distance between the phenoxymethyl and imidazole structures.

A lot of hydrogen bonds were found in the four crystal molecular structures, and types and positions of substituents in the phenoxymethyl moiety significantly influence the number, kind and site of these hydrogen bonds. In the crystal molecular structure of c1, the intermolecular hydrogen bonds exist not only between the H2 atom of hydroxyl group and the N2 atom of another c1 molecule (O2- H2...N21, 2.070 A), but also between the H6 atom connected to the C6 of benzimidazole ring and the O2 atom of hydroxyl group from another molecule (C6-H6...O22, 2.573 A), and no intramolecular hydrogen bond was observed. In the crystal molecular structure of c2, however, there are intramolecular and intermolecular hydrogen bonds, which is obviously due to its different substituent site of methyl group compared to that of c1.

The former was found between the H8A atom connected to the C8 of hydroxyethyl group and the O2 atom of phenoxymethyl structure (C8-H8A...O2, 2.645 A). The latter was observed between the H1 atom of hydroxyl and the N2 atom of another c2 molecule (O1-H1...N21, 2.063 A), between the H6 atom connected to the C6 of benzimidazole ring and the O1 atom of hydroxyl from another molecule (C6- H6...O12, 2.646 A) as well. In the crystal molecular structure of c4, whose electron-withdrawing chloride group is located at meta-position like the electron- donating methyl group of c2, only intermolecular hydrogen bonds were found. They exist between the H2 atom in hydroxyl and the N2 atom of another c4 molecule (O2-H21...N2, 2.041 A), between the H6 atom connected to the C6 of benzimidazole ring and the O2 atom of hydroxyl from another molecular unit (C6-H6...O22, 2.620 A), and between the H8A atom of hydroxyethyl group and the Cl1 atom of another c4 molecule (C8-H8A...Cl13, 2.958 A), respectively.

Apparently, the charge properties of substituent groups in c2 and c3 lead to their difference in the type of hydrogen bonds. As expected, many intramolecular and intermolecular hydrogen bonds were found in the crystal molecular structure of c5 that contains two chlorine substituents. There are two intramolecular hydrogen bonds between the O atom of hydroxyl group and the H8A atom connected to the C8 of phenoxymethyl structure (C8-H8A...O, 2.641 A), and the H14 atom connected to the C14 of benzene ring (C14-H14...O, 2.351 A), respectively. The intermolecular hydrogen bond was observed between the H atom in hydroxyl group and the N2 atom of another c5 molecule (O-H...N21, 2.010 A).

Furthermore, there are also intermolecular hydrogen bonds between the H8B atom connected to the C8 of phenoxymethyl structure and the N2 atom of imidazole rings in another unit (C8-H8B...N22, 2.624 A), between the H16A atom of hydroxyethyl group and the Cl1 atom of another c5 molecule (C16- H16A...Cl13, 2.688 A), and between the H16B atom and the O1 atom of another c5 molecule (C16- H16B...O14, 2.502 A). Therefore, these results show clearly that the properties of substituent groups can influence the type and number of hydrogen bonds in the crystal structures of the obtained target compounds.

Conclusion

Five new 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles c1-c5 were successfully synthesized using a reliable route in reasonable yields. In this route, five substituted phenoxyacetates a1-a5 was firstly prepared from corresponding substituted phenols under microwave irradiation, and then, the obtained a1-a5 reacted with o-phenylendiamine to get the key intermediates - 2- substituted phenoxymethyl benzimidazoles (b1-b5) which were N-hydroxyethylated with 2-chloroethyl alcohol to get the final target products c1-c5 through a solid-liquid phase transfer catalysis method. The structures of the five new compounds were well characterized and proved by various techniques including the single crystal X-ray diffraction analysis.

It was found that the type and position of substituents in the phenoxymethyl unit can significantly influence the crystal structures of these compounds such as the intersection angle between the substituted benzene and imidazole rings, number, kind and site of hydrogen bonds. These new benzimidazole derivatives with hydroxy group will probably have wide potential in the development of bioactive medicines.

Supplementary Material

The NMR, FT-IR and mass spectra of compounds c1-c5, selected bond lengths and angles for compounds c1, c2, c4, and c5, and hydrogen bond lengths and angles for compounds c1, c2, c4, and c5 are included in the supplementary material. Crystallographic data for the compounds c1, c2, c4, and c5 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication. The deposition numbers are CCDC 1059992, CCDC 1060135, CCDC 1059993, CCDC 1059994, for the structure of c1, c2, c4, and c5, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data request/cif, by e-mailing data request@ccdc.cam.ac.uk or by contacting the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

Acknowledgements

The project is financially supported by the National Science Foundation of China (No. 21106088) and the Ph. D. Programs Foundation of Ministry of Education of China (No. 20110181120079) and Science and Technology Department of Sichuan Province (No. 2014JY0011).

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Author:Wu, Jiacheng; Zhao, Li; Zhao, Changqing; Wang, Zhiyuan; Gu, Haibin; Chen, Wuyong
Publication:Journal of the Chemical Society of Pakistan
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Date:Apr 30, 2016
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