The synthesis of a novel imidazo[4,5-b]pyridine and its partially saturated derivative relied on Michael addition of 1-methyl-1H-imidazol-4-amine to fumaric/maleic or acetylene dicarboxylates, followed by intramolecular cyclization into target compounds. The common transformations of the resulting pyridine carboxylate were performed to obtain a series of building blocks, i.e. carboxylic acids, amides, and amines. The pyridone fragment was transformed into the fused bromopyridine moiety which was used for Buchwald–Hartwig and Suzuki cross-coupling reactions providing a versatile access to an extended scope of imidazopyridines. All synthesized building blocks could be considered as promising purine bioisosteres for the synthetic and medicinal chemistry.
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The design and synthesis of bioisosteres is an important part of medicinal chemistry and drug discovery.1,2,3,4,5 Their application improves selectivity, pharmacokinetics, metabolic stability and reduces different side effects, including toxicity.1 In recent years, special attention has been paid to the synthesis of fused pyridines6,7,8 due to their biochemical activity and considering them as promising bioisosteres. Imidazopyridines are among the most promising purine bioisosteres for potential medical applications.9,10,11 Special attention has been paid in recent years to imidazo[4,5-b]pyridine derivatives, which allowed for the design of compounds with valuable medicinal properties. The most successful examples are rimegepant (approved agent for the treatment of migraines),12,13,14 telcagepant (investigational drug for the treatment of migraines),15,16,17,18 ralimetinib (investigational agent for the treatment of cancer and Proteus syndrome),19,20,21 and miransertib (investigational drug for the treatment of Proteus syndrome)22,23,24 (Fig. 1).
Biologically active imidazo[4,5-b]pyridines.
Similarly to purines, many of the imidazo[4,5-b]pyridine derivatives were synthesized by the construction of imidazole fragments starting from readily available 2,3-diaminopyridines (Scheme 1).25,26 In the case of formaldehyde as the carbonyl component for this transformation, an unsubstituted imidazole ring could be obtained, while iodine atom could be introduced in this ring via the metalation–halogenation sequence. Further, the obtained iodide can be used for the Suzuki reaction to introduce various aryl substituents.27 Another common approach is based on the construction of pyridine ring starting from 4-aminoimidazole and 1,3-dicarbonyl compounds, which was used to obtain substituted imidazopyridines (Scheme 1).28,29,30
Approaches to the synthesis of imidazo[4,5-b]pyridine building blocks
In this work, we have aimed at the synthesis of novel derivatives of (partially saturated) imidazopyridines. In particular, the preparation of various building blocks as purine bioisosteres for drug discovery was envisaged. In addition, we have aimed at the introduction of one or more halogen atoms into the pyridine ring for further cross-coupling reactions.
Imidazopyridine core and its saturated derivatives were constructed using Michael addition31 followed by the intramolecular cyclization as the key step (Scheme 2). First, compound 3 was obtained according to the reported reaction sequence.32 Alkylation of nitroimidazole 1 was accomplished using MeI and K2CO3 in MeCN followed by reduction of obtained product 2 with H2 in the presence of 5% Pd/C in MeOH. Then, compound 3 was introduced into the Michael reactions with a mixture of fumarate/maleate 4 (reflux in EtOH for 16 h) and with acetylene dicarboxylate 5 (in 1,4-dioxane at room temperature for 16 h). The resulting Michael adducts were not isolated in pure form, but used in the intramolecular cyclization; the reaction was carried out in m-xylene at 110°C for 3 h (28% yield of compound 6a, and 56% yield of compound 6b over two steps).
Synthesis of imidazopyridine-derived carboxylic acids 7a–b
For the hydrolysis of compounds 6a,b, it was found that 5 M aq HCl at 60°C was optimal to obtain carboxylic acid 7a (80% yield), while the preparation of acid 7b required refluxing in 6 M aq HCl (90% yield). Carboxylic acid 7b was used for the synthesis of various amides using chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) as a coupling agent and 1-methyl-1H-imidazole (NMI) as a base in MeCN (Scheme 3). To our delight, all model amines (i.e., morpholine, piperidine, n-butylamine, and aniline) were suitable for the preparation of amides 8a–d (45–64% yields).
Synthesis of amides 8a–d from carboxylic acid 7b
Another valuable building block, amine 10, was obtained from carboxylic acid 7b using the modified Curtius rearrangement. The reaction was carried out in the presence of Et3N and diphenylphosphoryl azide (DPPA) in refluxing t-BuOH. While monitoring the reaction progress, we observed the formation of a mixture of N-Boc-amine 9 and N-Boc-deprotected amine 10 (likely through the thermal decomposition of amine 9). Therefore, the reaction mixture was heated for 48 h until the complete conversion of intermediate 9 was achieved, and solely the target amine 10 was obtained (Scheme 4).
Synthesis of amine 10 from carboxylic acid 7b
Next, we have aimed at the synthesis of 5-haloimidazopyridine carboxylate 11 for its further study in the cross-coupling reactions. To this end, pyrimidone 6b was subjected to the reaction with POBr3 in MeCN to give target bromide 11 (39% yield, Scheme 5). Product 11 was then subjected to Suzuki reaction with phenylboronic acid in the presence of Pd(dppf)Cl2 and K2CO3 in aqueous 1,4-dioxane at 100°C. The cross-coupling reaction proceeded successfully and was followed by K2CO3-mediated hydrolysis of the ester group to give carboxylic acid 12 in 47% yield (Scheme 6). The amination reaction at the C-5 position was carried out in morpholine at 130°C, which provided the expected SNAr product 13 (48% yield), amide byproduct 14 (17% yield), as well as other unidentified products.
Synthesis of bromide 11 as starting material for cross-coupling reactions
Suzuki and SNAr reactions of bromide 11
In turn, selective preparation of amide 16 (Scheme 7) without additional arylation reaction could be achieved by hydrolysis of ester 11 with 40% aqueous HBr at 100°C. Carboxylic acid 15 thus obtained (98% yield) was treated with morpholine, TCFH, and NMI in MeCN at room temperature to give the target product 16 in 65% yield.
Chemoselective synthesis of amide 16
Next, aniline, benzylamine, and acetophenone imine (an NH3 equivalent, see below) were chosen as model reagents for the study of the Buchwald–Hartwig reaction with amide 16 (Scheme 8). Aniline derivative 17 was easily synthesized in 61% yield. However, benzylamine derivative 18 was obtained in only 37% yield. Diphenylmethylimine derivative 19 could be isolated in 58% yield. In all cases, the amide group remained intact.
Buchwald–Hartwig reactions of amide 16
Finally, amides 17 and 19 were hydrolyzed by refluxing in 10 M aqueous HCl to give target carboxylic acids 20 and 21 in 80 and 99% yields, respectively (Scheme 9). Therefore, Buchwald–Hartwig amination of bifunctional imidazo[4,5-b]pyridine derivatives could be performed selectively at the bromopyridine fragment using amides of type 16 instead of esters 11. The amide fragment could be easily cleaved for the preparation of carboxylic acids after the Buchwald–Hartwig amination.
Hydrolysis of amides 17 and 19
In conclusion, a series of novel imidazopyridine building blocks – promising purine bioisosteres for medicinal chemistry – were synthesized and introduced into common C–C and C–N couplings, i.e., amide synthesis, Suzuki cross coupling, and Buchwald–Hartwig reaction. The target 5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridine-7-carboxylate framework or its partially hydrogenated derivative was constructed by Michael reaction of 1-methyl-1H-imidazol-4-amine with acetylene or fumarate/maleate dicarboxylates, respectively, followed by thermal intramolecular hetero-cyclization. The synthesized intermediate was successfully used for further functionalization at the pyridine ring.
In particular, synthesis of the corresponding carboxylic acids, amides, and amines at the C-7 position was performed through hydrolysis, amide coupling, and modified Curtius reaction, respectively. In addition to that, functionalization of the C-5 position was achieved through cross-coupling reactions. Thus, pyridone moiety of 5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridine-7-carboxylate could be easily transformed into the corresponding fused bromopyridine, which in turn was successfully used in Suzuki reaction. It was also found that the selective C(5)-amination of fused 2-bromo-pyridine-4-carboxylic acid derivatives could be achieved by the initial transformation into morpholinamides (the direct use of esters was not possible due to the formation of amide byproducts). After the Buchwald–Hartwig reactions and further hydrolysis, 5-oxo-4,5-dihydro-1H-imidazo[4,5-b]-pyridine-7-carboxylic acids could be obtained.
Experimental
1H and 13C NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (500 and 126 MHz, respectively), a Varian Unity Plus 400 spectrometer (400 and 101 MHz, respectively), or an Agilent ProPulse 600 spectrometer (13C NMR spectra only, 151 MHz). NMR chemical shifts were referenced using residual NMR solvent peaks at 7.26 and 77.2 ppm for 1H and 13C nuclei, respectively, in CDCl3 and 2.50 and 39.5 ppm for 1H and 13C nuclei, respectively, in DMSO-d6, 4.79 ppm for 1H nuclei in D2O. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (electrospray atmospheric pressure ionization with quadrupole analyzer). High-resolution mass spectra were recorded on an Agilent 6224 Accurate-Mass TOF LC/MS instrument (electrospray ionization with time-of-flight analyzer). Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, National Taras Shevchenko University of Kyiv (Elementar vario MICRO cube CHNS/O analyzer). Melting points were determined on an MPA100 OptiMelt automated melting point system.
The solvents were purified according to the standard procedures.33 Compounds 1, 4, and 5 were available from Enamine Ltd.
1-Methyl-4-nitro-1H-imidazole (2) was obtained according to the slightly modified literature procedure.34 Imidazole 1 (50.0 g, 0.442 mol) was added to K2CO3 (122 g, 0.884 mol) and MeI (41.3 ml, 0.663 mol) in MeCN (500 ml), and the resulting mixture was refluxed for 16 h. Then, the reaction mixture was cooled to room temperature. The inorganic precipitate was filtered off, and then washed with MeCN (200 ml). The filtrate was evaporated under reduced pressure and the residue was dissolved in EtOAc (500 ml), washed with H2O (100 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure. Yield 50.5 g (90%). The spectral and physical data correspond to those reported in the literature.
1-Methyl-1H-imidazol-4-amine (3) was obtained according to the slightly modified literature procedure.32 5% Pd/C (4 g) was added to imidazole 2 (20.0 g, 0.157 mol) in MeOH (200 ml). The resulting mixture was stirred under H2 atmosphere (1 atm) at room temperature for 16 h. The conversion was controlled by 1H NMR. Afterward, Pd/C was filtered off, the filtrate was evaporated under reduced pressure, and the resulting crude compound 3 was used immediately in the next step due to its low stability. Yield 12.2 g (80%), brownish oil. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 7.15–6.95 (1H, m, CH); 6.08 (1H, d, J = 1.4, CH); 4.07 (2H, br. s, NH2); 3.46 (3H, s, CH3).
Ethyl 1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-imidazo-[4,5-b]pyridine-7-carboxylate (6a). Diester 4 (33.3 ml, 0.206 mol) was added to imidazole derivative 3 (20.0 g, 0.206 mol) in EtOH (100 ml), and the resulting mixture was refluxed for 16 h. Then, the reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was suspended in m-xylene (100 ml), and the resulting mixture was stirred at 110°C for 3 h. Then, the reaction mixture was cooled to room temperature and evaporated in vacuo. The resulting solid product was purified by crystallization from minimal amount of MeCN. Yield 12.9 g (28% over two steps), brownish solid, mp 182– 183°C. 1H NMR spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 8.86 (1H, s, NH); 7.22 (1H, s, H-2); 4.15 (2H, q, J = 7.1, CH2CH3); 3.85 (1H, dd, J = 8.3, J = 2.2, 6-CH); 3.65 (3H, s, NCH3); 3.06 (1H, dd, J = 16.5, J = 2.2) and 2.88 (1H, dd, J = 16.5, J = 8.3, 5-CH2); 1.24 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, CDCl3), δ, ppm: 170.6; 167.8; 139.6; 135.3; 106.2; 62.0; 35.5; 34.2; 32.3; 14.2. Mass spectrum, m/z (Irel, %): 224 [M+H]+ (100). Found, %: C 54.20; H 6.16; N 18.74. C10H13N3O3. Calculated, %: C 53.81; H 5.87; N 18.82.
Methyl 1-methyl-5-oxo-4,5-dihydro-1H-imidazo[4,5-b]-pyridine-7-carboxylate (6b). Diester 5 (15.7 ml, 0.128 mol) was added to imidazole derivative 3 (12.4 g, 0.128 mol) in 1,4-dioxane (100 ml), and the resulting mixture was stirred at room temperature for 16 h. The precipitate was filtered off and washed with 1,4-dioxane (50 ml). The resulting product was suspended in m-xylene (100 ml), and the mixture was stirred at 110°C for 3 h. Then, the reaction mixture was cooled to room temperature. The resulting solid product was filtered off and washed with n-hexane (2×100 ml). Yield 14.8 g (56% over two steps), brownish solid, mp 205–207°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 11.66 (1H, br. s, NH); 8.15 (1H, s, CH); 6.68 (1H, s, CH); 3.92 (3H, s, CH3); 3.84 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 164.6; 160.4; 151.8; 146.0; 128.9; 114.9; 110.1; 52.8; 34.8. Mass spectrum, m/z (Irel, %): 208 [M+H]+ (100). Found, %: C 51.89; H 4.62; N 20.42. C9H9N3O3. Calculated, %: C 52.17; H 4.38; N 20.28.
1-Methyl-5-oxo-4,5,6,7-tetrahydro-1H-imidazo[4,5-b]-pyridine-7-carboxylic acid (7a). Ester 6a (10.0 g, 44.8 mmol) was dissolved in 5 M aqueous HCl (50 ml), and the resulting mixture was heated at 60°C for 2 h. After that, the reaction mixture was evaporated in vacuo. The resulting solid product was purified by crystallization from minimal amount of MeOH. Yield 6.99 g (80%), brownish powder, mp >300°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm (J, Hz): 7.40 (1H, s, H-2); 3.81 (1H, dd, J = 8.7, J = 3.4, 6-CH); 3.63 (3H, s, CH3); 3.06 (1H, dd, J = 16.9, J = 8.7) and 2.89 (1H, dd, J = 16.9, J = 3.4, 5-CH2). 13C NMR spectrum (151 MHz, D2O), δ, ppm: 178.9; 172.4; 136.0; 135.0; 111.1; 37.4; 35.1; 31.6. Mass spectrum, m/z (Irel, %): 196 [M+H]+ (100). Found, m/z: 196.0719 [M+H]+. C8H10N3O3. Calculated, m/z: 196.0717.
1-Methyl-5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridine-7-carboxylic acid hydrochloride (7b). Ester 6b (6.51 g, 31.4 mmol) was dissolved in 6 M aqueous HCl (50 ml), and the resulting mixture was refluxed for 16 h. After that, the reaction mixture was evaporated in vacuo. Yield 6.49 g (90%), brownish solid, mp 286–288°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 9.16 (1H, s, CH); 7.05 (1H, s, CH); 4.98 (3H, br. s, OH, NH, NH+); 4.02 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 164.5; 162.8; 144.9; 142.7; 131.8; 115.9; 110.0; 37.3. Mass spectrum, m/z (Irel, %): 194 [M–Cl]+. Found, m/z: 194.0561 [M–Cl]+. C8H8N3O3. Calculated, m/z: 194.0560.
Synthesis of amides 8a–d (General method). TCFH (871 mg, 3.11 mmol) was added to carboxylic acid 7b (500 mg, 2.59 mmol) in MeCN (10 ml) at 0°C, followed by adding of NMI (618 μl, 7.77 mmol). The resulting mixture was stirred at 0°C for 5 min, and then the respective amine (2.59 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 16 h. After that, reaction mixture was evaporated under reduced pressure. The obtained crude product was triturated with EtOAc–i-PrOH (1:1 v/v, 10 ml).
1-Methyl-7-(morpholine-4-carbonyl)-1,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one (8a). Yield 433 mg (64%), greenish solid, mp 261–263°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 11.73 (1H, br. s, NH); 8.04 (1H, s, CH); 6.19 (1H, s, CH); 3.75–3.62 (7H, m), 3.59–3.49 (2H, m), and 3.39–3.33 (2H, m, 4CH2, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 163.8; 160.9; 149.3; 143.9; 133.4; 113.1; 107.7; 66.0; 65.8; 47.1; 41.5; 32.4. Mass spectrum, m/z (Irel, %): 263 [M+H]+ (100). Found, m/z: 263.1141 [M+H]+. C12H15N4O3. Calculated, m/z: 263.1139.
1-Methyl-7-(piperidine-1-carbonyl)-1,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one (8b). Yield 323 mg (48%), colorless solid, mp 260–261°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 11.67 (1H, br. s, NH); 8.03 (1H, s, CH); 6.12 (1H, s, CH); 3.75–3.55 (5H, m) and 3.32–3.28 (2H, m, 2CH2, CH3); 1.67–1.52 (4H, m) and 1.52–1.37 (2H, m, 3CH2). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 163.4; 161.0; 149.1; 143.8; 134.2; 113.0; 107.3; 47.6; 41.7; 32.3; 25.8; 25.1; 23.8. Mass spectrum, m/z: (Irel, %) 261 [M+H]+ (100). Found, m/z: 261.1351 [M+H]+. C13H17N4O2. Calculated, m/z: 261.1346.
N-Butyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazo[4,5-b]-pyridine-7-carboxamide (8c). Yield 379 mg (59%), greenish solid, mp 244–246°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 11.71 (1H, br. s, NH); 8.77–8.70 (1H, m, NH); 8.02 (1H, s, CH); 6.25 (1H, s, CH); 3.72 (3H, s, CH3); 3.27–3.23 (2H, m, CH2); 1.52 (2H, quint, J = 7.2, CH2); 1.35 (2H, sext, J = 7.2, CH2); 0.91 (3H, t, J = 7.2, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 164.6; 160.9; 149.3; 144.0; 135.5; 113.5; 109.2; 38.7; 33.4; 30.8; 19.6; 13.6. Mass spectrum, m/z (Irel, %): 249 [M+H]+ (100). Found, m/z: 249.1347 [M+H]+. C12H17N4O2. Calculated, m/z: 249.1346.
1-Methyl-5-oxo-N-phenyl-4,5-dihydro-1H-imidazo-[4,5-b]pyridine-7-carboxamide (8d) was synthesized according to the general method except that the obtained crude product was triturated with MeOH (8 ml). Yield 312 mg (45%), colorless solid, mp 280–282°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 11.80 (1H, br. s, NH); 10.74 (1H, s, NH); 8.08 (1H, s, CH); 7.75 (2H, d, J = 7.8, H Ph); 7.38 (2H, t, J = 7.8, H Ph); 7.15 (1H, t, J = 7.8, H Ph); 6.47 (1H, s, CH); 3.74 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 163.2; 160.9; 149.7; 144.4; 138.4; 134.8; 128.8; 124.3; 120.1; 113.6; 109.3; 33.5. Mass spectrum, m/z (Irel, %): 269 [M+H]+ (100). Found, m/z: 269.1035 [M+H]+. C14H13N4O2. Calculated, m/z: 269.1033.
7-Amino-1-methyl-1,4-dihydro-5H-imidazo[4,5-b]-pyridin-5-one (10). Et3N (19.4 ml, 140 mmol) was added to the suspension of compound 7b (10.0 g, 43.6 mmol) in t-BuOH (200 ml) followed by DPPA (10.3 ml, 48.0 mmol) being added dropwise at room temperature. The resulting mixture was refluxed for 48 h (control by 1H NMR). After that, the formed precipitate was filtered off and washed with t-BuOMe (2×70 ml). Yield 3.86 g (54%), brownish solid, mp 293–295°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 11.13 (1H, br. s, NH); 7.69 (1H, s, H-2); 6.01 (2H, s, NH2); 5.19 (1H, s, 6-CH); 3.89 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 163.2; 147.0; 146.2; 140.9; 107.6; 91.0; 33.5. Mass spectrum, m/z (Irel, %): 165 [M+H]+ (100). Found, m/z: 165.0773 [M+H]+. C7H9N4O. Calculated, m/z: 165.0771.
Methyl 5-bromo-1-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylate (11). POBr3 (4.90 ml, 48.2 mmol) was added in one portion to compound 6b (5.00 g, 24.1 mmol) in MeCN (30 ml) at room temperature, and the resulting mixture was stirred at 80°C for 14 h. Then, MeCN was evaporated under reduced pressure, and ice water (80 ml) was added to the residue. After that, saturated aqueous NaHCO3 was added until the basic pH was reached (control using indicator paper), and then product 11 was extracted with CH2Cl2 (3×50 ml). Yield 2.54 g (39%), yellowish solid, mp 174–176°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 8.61 (1H, s, H-2); 7.73 (1H, s, H-6); 3.95 (6H, s, 2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 163.5; 157.9; 150.8; 133.5; 126.3; 122.9; 121.0; 53.1; 35.3. Mass spectrum, m/z (Irel, %): 272 [M(81Br)+H]+ (100), 270 [M(79Br)+H]+ (100). Found, m/z: 271.9853 [M+H]+. C9H981BrN3O2. Calculated, m/z: 271.9852. Found, m/z: 269.9873 [M+H]+. C9H979BrN3O2. Calculated, m/z: 269.9873.
1-Methyl-5-phenyl-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (12). PhB(OH)2 (49.3 mg, 0.407 mmol) and K2CO3 (128 mg, 0.925 mmol) were added to ester 11 (100 mg, 0.370 mmol) in 1,4-dioxane–H2O, 4:1 (5 ml). Then, Ar was bubbled through the resulting mixture for 5 min, and Pd(dppf)Cl2 (13.5 mg, 18.5 μmol) was added. The reaction mixture was stirred at 100°C for 16 h and then evaporated under reduced pressure. The obtained product was purified by HPLC using a gradient mixture H2O–MeCN as an eluent (column Chromatorex 18 SMB, flow rate 30 ml/min). Yield 44.3 mg (47%), yellowish solid, mp >300°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.31 (1H, s, H-2); 8.06 (2H, d, J = 7.4, H Ph); 7.71 (1H, s, H-6); 7.48 (2H, t, J = 7.4, H Ph); 7.37 (1H, t, J = 7.4, H Ph); 4.01 (3H, s); 3.40 (1H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 167.3; 157.1; 150.2; 147.8; 139.9; 138.4; 128.6; 127.9; 126.4; 122.3; 113.4; 33.7. Mass spectrum, m/z (Irel, %): 254 [M+H]+ (100). Found, m/z: 254.0926 [M+H]+. C14H12N3O2. Calculated, m/z: 254.0924.
1-Methyl-5-(morpholin-4-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (13). Ester 11 (100 mg, 0.370 mmol) was dissolved in morpholine (2 ml), and the resulting mixture was stirred at 130°C for 16 h, then evaporated under reduced pressure. The obtained mixture of products 13 and 14 was separated by HPLC using a gradient mixture H2O–MeCN (with 0.1% HCO2H) as an eluent (column Kinetex PFP, flow rate 30 ml/min). Yield 46.7 mg (48%), beige solid, mp 243–245°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 13.77 (1H, br. s, OH); 8.24 (1H, s, H-2); 7.09 (1H, s, H-6); 3.89 (3H, s, CH3); 3.73 (4H, t, J = 4.7, 2CH2), 3.45 (4H, t, J = 4.7, 2CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 166.5; 156.6; 156.1; 147.6; 127.5; 117.1; 103.7; 66.0; 46.1; 34.8. Mass spectrum, m/z (Irel, %): 263 [M+H]+ (100). Found, m/z: 263.1141 [M+H]+. C12H15N4O3. Calculated, m/z: 263.1139.
[1-Methyl-5-(morpholin-4-yl)-1H-imidazo[4,5-b]pyridin-7-yl](morpholin-4-yl)methanone (14). Yield 21.4 mg (17%), brownish glass. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 8.20 (1H, s, H-2); 6.77 (1H, s, H-6); 3.82–3.63 (11H, m) and 3.61–3.34 (8H, m, 8CH2, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 164.7; 156.3; 155.7; 146.3; 129.5; 116.0; 100.7; 66.0; 65.8; 47.3; 46.2; 41.6; 32.3. Mass spectrum, m/z (Irel, %): 332 [M+H]+ (100). Found, m/z: 332.1719 [M+H]+. C16H22N5O3. Calculated, m/z: 332.1717.
5-Bromo-1-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylic acid hydrobromide (15). Ester 11 (3.00 g, 11.1 mmol) was suspended in 40% aqueous HBr, and the resulting mixture was stirred at 100°C for 4 h. After that, the reaction mixture was evaporated under reduced pressure. Yield 3.67 g (98%), brownish solid, mp 225–227°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 8.86 (1H, s, H-2); 9.64–8.11 (2H, m, NH, OH); 7.77 (1H, s, H-6); 4.01 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 164.5; 155.7; 149.9; 134.5; 128.6; 122.8; 121.7; 35.8. Mass spectrum, m/z (Irel, %): 258 [M(81Br)–Br]+ (100), 256 [M(79Br)–Br]+ (100). Found, m/z: 257.9798 [M–Br]+. C8H781BrN3O2. Calculated, m/z: 257.9696. Found, m/z: 255.9718 [M–Br]+. C8H779BrN3O2. Calculated, m/z: 255.9716.
(5-Bromo-1-methyl-1H-imidazo[4,5-b]pyridin-7-yl)-(morpholin-4-yl)methanone (16). NMI (2.27 ml, 28.5 mmol) and morpholine (736 μl, 8.54 mmol) were added to a suspension of compound 15 (2.40 g, 7.12 mmol) in MeCN (50 ml) upon cooling in water bath. After that, TCFH (3.00 g, 10.7 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. Then, the reaction mixture was evaporated under reduced pressure. The obtained product was purified by column chromatography on silica gel using n-hexane–THF (gradient from 1:0 to 0:1) as an eluent. Yield 1.51 г (65%), colorless solid, mp 251– 253°C. 1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.09 (1H, s, H-2); 7.25–7.22 (1H, m, H-6); 3.96–3.75 (7H, m), 3.73–3.54 (2H, m), and 3.49–3.30 (2H, m, 4CH2, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 162.7; 156.9; 149.1; 133.9; 130.4; 121.9; 118.0; 65.9; 65.7; 47.2; 41.7; 32.6. Mass spectrum, m/z (Irel, %): 327 [M(81Br)+H]+ (100), 325 [M(79Br)+H]+ (100). Found, m/z: 327.0275 [M+H]+. C12H1481BrN4O2. Calculated, m/z: 327.0274. Found, m/z: 325.0294 [M+H]+. C12H1479BrN4O2. Calculated, m/z: 325.0295.
[1-Methyl-5-(phenylamino)-1H-imidazo[4,5-b]pyridin-7-yl](morpholin-4-yl)methanone (17). Amide 16 (400 mg, 1.23 mmol) was added to a suspension of XPhos (176 mg, 369 μmol), Cs2CO3 (401 mg, 1.23 mmol), and PhNH2 (0.135 ml, 1.48 mmol) in PhMe (7 ml). Then, Ar was bubbled through the resulting suspension for 5 min, and Pd2(dba)3 (113 mg, 123 μmol) was added. The resulting mixture was stirred at 100°C for 16 h. After that, the reaction mixture was cooled to room temperature. The inorganic precipitate was filtered off and washed with 1,4-dioxane (2×4 ml). The filtrate was evaporated under reduced pressure. The obtained product 17 was purified by HPLC using gradient H2O–MeCN as an eluent (column Chromatorex 18 SMB, flow rate 30 ml/min). Yield 252 mg (61%), yellowish solid, mp 246–248°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 9.09 (1H, s, NH); 8.21 (1H, s, H-2); 7.78 (2H, d, J = 7.7, H Ph); 7.28 (2H, t, J = 7.7, H Ph); 6.88 (1H, t, J = 7.7, H Ph); 6.66 (1H, s, H-6); 3.76–3.69 (7H, m, 2CH2, CH3); 3.55 (2H, t, J = 4.8) and 3.36–3.33 (2H, m, 2CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 164.4; 155.3; 152.0; 145.8; 141.9; 129.4; 128.5; 120.1; 117.4; 116.1; 104.0; 66.2; 65.9; 47.3; 41.6; 32.4. Mass spectrum, m/z (Irel, %): 338 [M+H]+ (100). Found, m/z: 338.1612 [M+H]+. C18H20N5O2. Calculated, m/z: 338.1612.
[5-(Benzylamino)-1-methyl-1H-imidazo[4,5-b]pyridin-7-yl](morpholin-4-yl)methanone (18). Amide 16 (400 mg, 1.23 mmol) was added to a suspension of BINAP (92.0 mg, 148 μmol), Cs2CO3 (401 mg, 1.23 mmol), and BnNH2 (0.161 ml, 1.48 mmol) in 1,4-dioxane (7 ml). Then, Ar was bubbled through the resulting suspension for 5 min, and Pd(OAc)2 (16.6 mg, 73.8 μmol) was added. The resulting mixture was stirred at 100°C for 16 h. After that, the reaction mixture was cooled to room temperature. The inorganic precipitate was filtered off and washed with 1,4-dioxane (2×4 ml). The filtrate was evaporated under reduced pressure The obtained product 18 was purified by HPLC using a gradient mixture H2O–MeCN (with 0.1% NH3·H2O) as an eluent (column XBridge C18, flow rate 30 ml/min). Yield 158 mg (37%), yellowish glass. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.05 (1H, s, H-2); 7.36 (2H, d, J = 7.5, H Ph); 7.30 (2H, t, J = 7.5, H Ph); 7.21 (1H, t, J = 7.5, H Ph); 7.03 (1H, t, J = 5.9, NH); 6.38 (1H, s, H-6); 4.52 (2H, d, J = 5.9, NHCH2); 3.72–3.66 (4H, m, 2CH2); 3.65 (3H, s, CH3); 3.50 (2H, t, J = 4.7) and 3.27 (2H, t, J = 4.7, 2CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 164.8; 156.0; 155.4; 144.8; 140.6; 129.1; 128.1; 127.3; 126.4; 114.9; 101.8; 66.0; 65.9; 47.2; 41.5; 44.4; 32.3. Mass spectrum, m/z (Irel, %): 352 [M+H]+ (100). Found, m/z: 352.1768 [M+H]+. C19H22N5O2. Calculated, m/z: 352.1768.
{5-[(Diphenylmethylidene)amino]-1-methyl-1H-imidazo-[4,5-b]pyridin-7-yl}(morpholin-4-yl)methanone (19). Amide 16 (400 mg, 1.23 mmol) was added to a suspension of XantPhos (42.7 mg, 73.8 μmol), Cs2CO3 (401 mg, 1.23 mmol), and Ph2C=NH (335 mg, 1.85 mmol) in 1,4-dioxane (7 ml). Then, Ar was bubbled through the resulting suspension for 5 min, and Pd2(dba)3 (33.8 mg, 36.9 μmol) was added. The resulting mixture was stirred at 100°C for 16 h. After that, the reaction mixture was cooled to room temperature. The inorganic precipitate was filtered off and washed with 1,4-dioxane (2×4 ml). The filtrate was evaporated under reduced pressure. Obtained product 19 was purified by HPLC using gradient H2O–MeCN as an eluent (column XBridge C18, flow rate 60 ml/min). Yield 304 mg (58%), greenish solid, mp 148–150°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 8.32 (1H, s, H-2); 7.71 (2H, d, J = 7.4, H Ph); 7.58 (1H, t, J = 7.4, H Ph); 7.51 (2H, t, J = 7.4, H Ph); 7.31–7.25 (3H, m, H Ph); 7.19–7.11 (2H, m, H Ph); 6.45 (1H, s, H-6); 3.67 (3H, s, CH3); 3.65–3.59 (4H, m, 2CH2); 3.42–3.33 (2H, m) and 2.81–2.69 (2H, m, 2CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 169.6; 163.8; 158.6; 156.0; 147.5; 138.2; 135.9; 131.4; 129.0; 128.7; 128.4; 128.0; 118.7; 107.2; 65.7; 46.8; 41.5; 32.5. Mass spectrum, m/z (Irel, %): 426 [M+H]+ (100). Found, m/z: 426.1921 [M+H]+. C25H24N5O2. Calculated, m/z: 426.1925.
1-Methyl-5-(phenylamino)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (20). Compound 17 (189 mg, 0.559 mmol) was dissolved in 10 M aqueous HCl (3 ml), and the resulting mixture was refluxed for 20 h. Then, the reaction mixture was cooled to room temperature. The formed solid product was filtered off and washed with H2O (2×3 ml). The obtained product was triturated in boiling i-PrOH (3 ml). Yield 120 mg (80%), greenish solid, mp 218–220°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 9.74 (1H, s, NH); 8.93 (1H, s, H-2); 7.81 (2H, d, J = 7.5, H Ph); 7.42 (1H, s, H-6); 7.32 (2H, t, J = 7.5, H Ph); 6.96 (1H, t, J = 7.5, H Ph); 4.02 (1H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 165.3; 153.4; 150.0; 143.7; 141.0; 128.7; 128.6; 121.2; 118.1; 115.8; 110.4; 36.5. Mass spectrum, m/z (Irel, %): 269 [M+H]+ (100). Found, m/z: 269.1034 [M+H]+. C14H13N4O2. Calculated, m/z: 269.1033.
5-Amino-1-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (21) was synthesized analogously to compound 20 from compound 19 (235 mg, 0.553 mmol). Yield 105 mg (99%), yellowish solid, mp 277–278°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 8.55 (1H, s, H-2); 6.94 (1H, s, H-6); 3.93 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 165.7; 156.8; 144.1; 135.7; 129.1; 115.2; 107.1; 35.9. Mass spectrum, m/z (Irel, %): 193 [M+H]+ (100). Found, m/z: 193.0721 [M+H]+. C8H9N4O2. Calculated, m/z: 193.0720.
Supplementary information file, containing NMR and mass spectra of the synthesized compounds, is available at the journal website http://springerlink.bibliotecabuap.elogim.com/journal/10593.
The work was funded by Enamine Ltd. An additional funding was received from Ministry of Education and Sciences of Ukraine, grants No. 0121U100387 (21BF037-01M) and 0122U001962 (22BF037-02). The authors thank Prof. Andrey A. Tolmachev for his encouragement and support and the people of Ukraine who made finalizing this publication possible.
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Published in Khimiya Geterotsiklicheskikh Soedinenii, 2024, 60(3/4), 175–182
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Dubina, T.F., Kosarevych, A.V., Kucher, O.V. et al. Synthesis and reactions of novel imidazo[4,5-b]pyridine building blocks. Chem Heterocycl Comp 60, 175–182 (2024). https://doi.org/10.1007/s10593-024-03315-1
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DOI: https://doi.org/10.1007/s10593-024-03315-1