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Efficient synthesis of substituted imidazo[4,5-b]pyridines

  • Yuan-Yuan Xing EMAIL logo , Chuanxiang Liu and Fanhong Wu EMAIL logo
Published/Copyright: October 2, 2013
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 19 Issue 5

Abstract

An efficient approach to the synthesis of 1-methylimidazo[4,5-b]pyridine derivatives 5–10 of biological interest has been developed. The key intermediate product 4 is obtained by cyclization of 2-amino-3-methylaminopyridine (3) with phenylacetic acid.

Keywords: cyclization; imidazo[4,5-b]pyridine; synthesis

Among heterocyclic compounds, imidazo[4,5-b]pyridines represent a class of useful precursors for preparation of a variety of drugs [1, 2]. Previous studies have shown that substituted imidazo[4,5-b]pyridines are, for example, anticancer [3], inotropic [4], antimitotic [5], and selective antihistamine agents [6]. A survey of previous reports indicates that introduction of a methyl group at the N1-position increases bioactivity of imidazo[4,5-b]pyridines [7, 8]. Hence, it is of interest to prepare new 1-methyl-substituted imidazo[4,5-b]pyridine derivatives for the development of bioactive heterocyclic compounds.

It is difficult to prepare N1-substituted imidazo[4,5-b] pyridines in a regioselective manner by direct alkylation of unsubstituted imidazo[4,5-b]pyridines because this reaction is not selective [9]. Successful attempts to circumvent this problem include a low-yield synthesis of methyl-substituted azabenzimidazoles [8] and Pd-catalyzed coupling of amides and 3-amino-2-chloropyridines to prepare 1-substituted imidazo[4,5-b]pyridines [9]. Although good to excellent yields have been obtained for the latter reaction, expensive Pd catalyst and phosphine ligand are required. Herein, we report a novel approach to the desired 1-methylimidazo[4,5-b]pyridines, in which a pyridine moiety with a pre-introduced N-methyl group undergoes cyclization with phenylacetic acid.

The synthetic route is shown in Scheme 1, where the key step is the use of pyridine 3 with a pre-introduced N-methyl group in the ring closure reaction to the desired intermediate product 4. Synthesis of 3 was achieved in two simple steps starting with commercially available 3-methoxy-2-nitropyridine (1) [8]. Cyclization reaction of 3 with phenylacetic acid was conducted in the presence of N,N′-carbonyldiimidazole (CDI) in 51% yield. Oxidation of 4 with H2O2 gave 5 [10], which was then treated with POCl3 to produce the chloro-substituted product 6 in 54% yield [11]. The targeted 1-methyl-imidazo[4,5-b]pyridines 7–10 functionalized at the 7 position were then prepared by a nucleophilic displacement of chloride in 6. Removal of the benzyl group in 7 with CAN gave the free amine 8 [12].

Scheme 1
Scheme 1

A concise and highly efficient approach to the preparation of substituted imidazo[4,5-b]pyridines has been successfully developed.

Experimental

Melting points are uncorrected. Commercial reagents were used directly without further purification. Solvents were treated according to standard methods prior to use. 1H NMR and 13C NMR spectra were recorded on a Bruker spectrometer. Mass spectra were obtained on a Shimadzu LCMS instrument. High resolution mass spectra (HRMS) were recorded on a KE465 LCT Premier/XE spectrometer. Elemental analyses were performed on an Elementar Vario EL III instrument. Prep-HPLC was performed on a Shimadzu instrument with a Fuji C18 (300 × 25) column; wavelength: 220 nm; mobile phase A, CH3CN (0.1% trifluoroacetic acid); B, water (0.1% trifluoroacetic acid).

3-Methylamino-2-nitropyridine (2)

To a stirred solution of 30% MeNH2 in EtOH (550 mL) was added 3-methoxy-2-nitropyridine (1, 50.0 g, 0.32 mol). The mixture was heated under reflux overnight, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether/ethyl acetate (19:1) as eluent to give 29.6 g (59%) of 2 as yellow solid, mp 108–110°C [lit. mp 109–110°C] [13]; 1H NMR (400 MHz, DMSO-d6): δ 2.95 (d, J = 5 Hz, 3H), 7.53–7.81 (m, 3H), 7.90 (br, 1H).

2-Amino-3-methylaminopyridine (3)

To a stirred solution of compound 2 (28.0 g, 0.18 mol) in anhydrous methanol (450 mL) was added 10% Pd/C (5.8 g) and the mixture was hydrogenated under 1 atm at 5°C while stirring overnight. The catalyst was filtered off through celite and the filtrate was concentrated under reduced pressure to afford 22.0 g (98%) of 3 as a brown solid, mp 124–125°C [lit. mp 124–125°C] [13]; 1H NMR (400 MHz, DMSO-d6): δ 2.69 (d, J = 5 Hz, 3H), 4.88 (d, J = 4 Hz, 1H), 5.41 (s, 2H), 6.46–6.53 (m, 2H), 7.28 (dd, J = 5 Hz, 2 Hz, 1H).

2-Benzyl-1-methyl-1H-imidazo[4,5-b]pyridine (4)

To a suspension of phenylacetic acid (32.0 g, 0.24 mol) in tetrahydrofuran (THF) (300 mL) was added CDI (39.0 g, 0.24 mmol) at 0°C, and the mixture was stirred at 60°C for 1 h. Then compound 3 (20.0 g, 0.16 mmol) was added, and the mixture was stirred at 60°C overnight. After cooling, the mixture was concentrated and the residue dissolved in ethyl acetate (400 mL). The solution was washed successively with saturated aqueous NaHCO3 (150 mL × 5), brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/methanol (50:1) as eluent to afford a crude product with impurity of imidazole, identified by 1H NMR. The crude product was washed with saturated aqueous NaHCO3 (150 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 18.2 g (51%) of compound 4 as a brown solid, mp 124–126°C [lit. mp 123–125°C] [14]; 1H NMR (400 MHz, DMSO-d6): δ 3.73 (s, 3H), 4.36 (s, 2H), 7.20–7.35 (m, 6H), 7.93 (m, 1H), 8.35 (m, 1H).

2-Benzyl-1-methyl-1H-imidazo[4,5-b] pyridine-4-oxide (5)

To a stirred solution of compound 4 (18.0 g, 0.08 mol) in acetic acid (200 mL) was added dropwise 30% aqueous H2O2 (20 mL, 0.17 mol), and the mixture was stirred at 70°C overnight. After cooling, the mixture was treated with Na2SO3 (11.3 g, 0.09 mmol) and stirred for an additional 10 min. Solid material was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (800 mL) and the solution washed with 10% NaOH (200 mL × 2) and then brine (200 mL × 2). The ethyl acetate phase was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as eluent to afford 9.2 g (48%) of compound 5 as a yellow solid, mp 143–145°C; 1H NMR (300 MHz, DMSO-d6): δ 3.77 (s, 3H), 4.35 (s, 2H), 7.16–7.37 (m, 6H), 7.58 (d, J = 8 Hz, 1H), 8.13 (d, J = 6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 146.3, 144.7, 136.7, 135.2, 130.6, 129.3, 126.3, 122.8, 121.7, 119.9, 31.2, 29.3; HRMS (ESI) m/z calcd for C14H14N3O (M+H)+: 240.1137, found: 240.1139.

2-Benzyl-7-chloro-1-methyl-1H-imidazo [4,5-b]pyridine (6)

Compound 5 (9.0 g, 37.6 mmol) was dissolved in POCl3 (160 mL) and the solution stirred under reflux overnight. After cooling, the mixture was concentrated and the residue dissolved in ethyl acetate (600 mL). The solution was washed with saturated aqueous NaHCO3 (200 mL × 2) and brine (200 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with petroleum ether/ethyl acetate (1:2) as eluent to afford 5.2 g (54%) of compound 6 as a yellow solid, mp 168–170°C; 1H NMR (300 MHz, DMSO-d6): δ 3.96 (s, 3H), 4.37 (s, 2H), 7.24–7.36 (m, 6H), 8.27 (d, J = 5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 154.1, 149.8, 144.7, 139.5, 133.6, 129.3, 128.8, 126.2, 124.7, 120.3, 32.2, 31.5; HRMS (ESI) m/z calcd for C14H13ClN3 (M+H)+: 258.0798, found: 258.0793.

2-Benzyl-7-benzylamino-1-methyl-1H-imidazo[4,5-b]pyridine (7)

To a solution of 6 (1.0 g, 3.9 mmol), benzylamine (0.46 g, 4.3 mmol) and Pd2(dba)3 (0.36 g, 0.39 mmol) in 1,4-dioxane (25 mL) was added Cs2CO3 (1.9 g, 0.59 mmol) and xantphos (0.67 g, 1.16 mmol) under nitrogen atmosphere. The mixture was stirred at 90–100°C for 16 h. After cooling, the mixture was concentrated and the residue was purified by flash column chromatography with dichloromethane/methanol (10:1) as eluent to afford 1.2 g (94%) of compound 7 as a yellow solid, mp 203–205°C; 1H NMR (400 MHz, DMSO-d6): δ 3.98 (s, 3H), 4.27 (s, 2H), 4.44 (d, J = 6 Hz, 2H), 6.17 (d, J = 6 Hz, 1H), 6.75 (t, J = 5 Hz, 1H), 7.20–7.42 (m, 10H), 7.83 (d, J = 6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 158.3, 152.2, 146.4, 140.2, 137.2, 128.6, 127.6, 127.3, 127.1, 126.8, 126.1, 125.8, 118.9, 116.2, 58.2, 33.0, 31.8; LC-MS: m/z 329.2 (M+1)+; HRMS (ESI) m/z calcd for C21H21N4 (M+H)+: 329.1766, found: 329.1762.

2-Benzyl-1-methyl-1H-imidazo[4,5-b] pyridine-7-amine, a salt with trifluoroacetic acid (8)

To a solution of 7 (0.6 g, 1.8 mmol) in a mixture of MeCN (10 mL) and H2O (2 mL) was added CAN (3.0 g, 5.5 mmol), and the mixture was stirred at 8–14°C overnight. The mixture was concentrated and the residue was treated with water (10 mL) and dichloromethane (10 mL). The resultant solid was filtered, suspended in methanol (30 mL), and the mixture was stirred for 10 min. After filtration the filtrate was collected and then concentrated. The residue was purified by preparative HPLC with 0.1% trifluoroacetic acid as additive to afford 0.19 g (44%) of 8 as a yellow salt with trifluoroacetic acid, mp 186–188°C (dec); 1H NMR (400 MHz, DMSO-d6); δ 4.01 (s, 3H), 4.35 (s, 2H), 6.61 (d, J = 7 Hz, 1H), 7.25–7.36 (m, 5H), 7.95–8.01 (m, 3H), 14.03 (br, 1H); 13C NMR (100 MHz, DMSO-d6): δ 151.1, 149.4, 146.2, 137.3, 127.6, 127.3, 127.1, 126.2, 118.6, 115.3, 33.2, 31.4; LC-MS: m/z 239.2 (M+1)+; HRMS (ESI) m/z calcd for C14H15N4 (M+H)+: 239.1297. Found: 239.1299. Anal. Calcd for C14H14N4‧2C2HF3O2: C, 46.36; H, 3.46; N, 12.01. Found: C, 46.23; H, 3.50; N, 12.18.

N-(2-Benzyl-1-methyl-1H-imidazo[4,5-b]pyridine-7-yl)-3,3-dimethylbutanamide, a salt with trifluoroacetic acid (9)

To a solution of 6 (200 mg, 0.78 mmol), 3,3-dimethylbutanamide (104 mg, 0.9 mmol) and Pd2(dba)3 (13 mg, 0.01 mmol) in 1,4-dioxane (7 mL) was added Cs2CO3 (507 mg, 1.56 mmol) and xantphos (9 mg, 0.01 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 16 h. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate (150 mL), and the solution washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by preparative HPLC with 0.1% trifluoroacetic acid as additive to afford 61 mg (23%) of 9 as an off-white salt with trifluoroacetic acid, mp 192–194°C (dec); 1H NMR (300 MHz, CDCl3) δ 1.09 (s, 9H), 2.49 (s, 2H), 3.91 (s, 3H), 4.23 (s, 2H), 7.14–7.33 (m, 5H), 7.59–7.71 (m, 2H), 8.62 (br, 1H), 10.53 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 174.1, 149.7, 145.4, 138.6, 137.0, 127.5, 127.1, 126.7, 126.1, 117.9, 115.2, 52.5, 33.1, 31.8, 31.3, 29.2; LC-MS: m/z 336.5 (M)+; HRMS (ESI) m/z calcd for C20H25N4O (M+H)+: 337.2028, found: 337.2022. Anal. Calcd for C20H24N4O‧C2HF3O2: C, 58.66; H, 5.59; N, 12.44. Found: C, 58.78; H, 5.71; N, 12.52.

N-(2-Benzyl-1-methyl-1H-imidazo[4,5-b]pyridine-7-yl)-3-cyclohexylpropanamide, a salt with trifluoroacetic acid (10)

To a solution of 6 (200 mg, 0.76 mmol), 3-cyclohexylpropanamide (118 mg, 0.76 mmol) and Pd2(dba)3 (14 mg, 0.01 mmol) in 1,4-dioxane (5 mL) was added Cs2CO3 (493 mg, 1.52 mmol) and xantphos (9 mg, 0.01 mmol) under nitrogen atmosphere. The mixture was stirred at 110°C for 16 h. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate (150 mL). The solution was washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by preparative HPLC with 0.1% trifluoroacetic acid as additive to afford 81 mg (28%) of 10 as a yellow salt with trifluoroacetic acid, mp 197–199°C (dec); 1H NMR (400 MHz, CDCl3) δ 0.78–0.86 (m, 2H), 1.03–1.18 (m, 5H), 1.50–1.63 (m, 6H), 2.51 (m, 2H), 3.85 (s, 3H), 4.22 (s, 2H), 7.06–7.22 (m, 5H), 7.65 (s, 1H), 7.92 (s, 1H), 10.14 (br, 1H), 10.53 (br, 1H); 13C NMR (100 MHz, CDCl3): δ 176.3, 150.1, 146.3, 138.3, 137.2, 127.4, 127.1, 126.7, 125.9, 116.8, 115.4, 36.8, 34.6, 32.9, 32.7, 32.3, 31.6, 26.1. 25.7; LC-MS: m/z 376.9 (M+1)+; HRMS (ESI) m/z calcd for C23H29N4O (M+H)+: 377.2341, found: 377.2337. Anal. Calcd for C23H28N4O‧C2HF3O2: C, 61.21; H, 5.96; N, 11.42. Found: C, 61.35; H, 6.06; N, 11.53.

Corresponding authors: Yuan-Yuan Xing and Fanhong Wu, School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, P.R. China, e-mail: ;

We are grateful for the financial support from Shanghai Training Program Foundation for the Talents (yyy11026).

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Received: 2013-4-10
Accepted: 2013-5-24
Published Online: 2013-10-02
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2013-0059
Keywords for this article
cyclization; imidazo[4,5-b]pyridine; synthesis
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Reviews
  4. Methods for the synthesis of xanthine-derived polycyclic fused systems
  5. Heterocyclic synthesis via catalysis of N-heterocyclic carbenes: very classical and very modern chemical species
  6. Preliminary Communication
  7. Efficient synthesis of substituted imidazo[4,5-b]pyridines
  8. Research Articles
  9. Synthesis of N-(2-pyridyl)imidazolidin-2-ones and 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-ones with potential biological activities
  10. Design, synthesis, antibacterial, and antifungal studies of novel 3-substituted coumarinyl-triazine derivatives
  11. Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds
  12. Synthesis of 9-(Cn-1F2n-1)-substituted acridine by the reaction of 2-(CnF2n+1)-substituted aniline with ortho-methyl-substituted aromatic Grignard reagent
  13. Microwave-assisted synthesis of 2-(4,5-dihydro-5-(tetrazolo[1,5-a]quinoline-4-yl)-1H-pyrazol-3-yl)-substituted phenols
  14. A computational study on azaazulenes
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