Synthesis of imidazo[1,2-a]-pyridine derivatives

Journal of Chemistry, Vol. 45 (6), P. 781 - 784, 2007<br /> <br /> <br /> Synthesis of imidazo[1,2-a]-pyridine derivatives<br /> Received 2 April 2007<br /> Tran Van Chien, Dao Duc Thien, Tran Van Loc, Tran Van Sung<br /> Department of organic synthesis, Institute of Chemistry<br /> Vietnamese Academy of Science and Technology<br /> <br /> <br /> Summary<br /> The synthesis of imidazo[1,2-a]-pyridine derivatives was carried out by subsequential<br /> reactions: condensation, substitution and reduction, using the commercially available 2-<br /> aminopyridine as starting material.<br /> Keywords: 2-aminopyridine, 2-chloroimidazo[1,2-a]-pyridine, 1,1'-carbonyldiimidazole.<br /> <br /> <br /> I - Introduction in 60 ml H2O. 2-aminopyridine (100 mmol) was<br /> added slowly into the mixture. The mixture was<br /> Alkaloids, one of the most naturally then refluxed for 5 hours. The white solid was<br /> abundant organic compound classes, are well precipitated, filtered and dissolved again in 25%<br /> known for their bioactivities. The total or semi- aqueous NaOH (50 ml). The solution was<br /> synthesis of alkaloids has been focused due to refluxed for further 5 min, cooled in an ice bath.<br /> the pharmacological interest. Imidazo[1,2-a]- The salt was then filtered, washed with<br /> pyridine and its derivatives are interesting isopropanol and dried at 50oC in vacuo.<br /> compounds because of their gastric The salt obtained above was refluxed in<br /> antisecretory [1, 2], local anesthetic [3], POCl3 (20 ml) for 1.5 h. The mixture was<br /> antiviral, antibacterial [4], hypnotic and extracted with CH2Cl2 (3x 250 ml). The solvent<br /> antianxiety [5], antimicrobial, antiulcer [6], was evaporated and the residue was purified to<br /> cytoprotective activity and against respiratory of give product 3 in 47% overall yield. 1H-NMR<br /> syncytial virus [7]. The nature and position of (CDCl3): (ppm): 6.82 (dt, J = 0.6 Hz, 6.8 Hz,<br /> the substituents on the imidazole or pyridine H-6); 7.19 (dt, J = 1.2 Hz, 7.6 Hz, H-7); 7.48 (s,<br /> moiety also affect much to their activities [4]. H-3); 7.52 (d, J = 9 Hz, H-8); 8.03 (d, J = 6.8<br /> In this paper, we present the preparation of Hz, H-5).<br /> some new imidazo[1,2-a]-pyridine derivatives.<br /> The structures of synthesized compounds were 2. Preparation of 3-nitro-2-<br /> determined by IR, 1H-, 13C-NMR, and mass chloroimidazo[1,2-a]-pyridine (4)<br /> spectra analysis. To a solution of 2-chloroimidazo[1,2-a]-<br /> pyridine 3 (10 mmol) in water at 0oC was added<br /> II - Experimental 15 mmol of a mixture of concentrated<br /> HNO3/H2SO4 (mole ratio: 1.3/1). The mixture<br /> 1. Preparation of 2-chloroimidazo[1,2-a]- was stirred for 30 min. at this temparature, and<br /> pyridine (3) then poured into ice-water to form a yellow<br /> A mixture of monochloroacetic acid (106 solid. The solid was filtered and dried in vacuo<br /> mmol) and Na2CO3 (128 mmol) was dissolved to give 4 in 85% yield. 1H-NMR (CDCl3):<br /> 781<br /> (ppm): 7.34 (t, J= 7 Hz, H-6); 7.7 (t, J = 7 Hz, 7 Hz, H-6); 7.1 (s, H-4'); 7.2 (dt, J = 1.3 Hz, 7<br /> H-7); 7.78 (d, J = 9 Hz, H-8); 9.44 (d, J = 7 Hz, Hz, H-7); 7.48 (dd, J = 1Hz, 9 Hz, H-8); 7.65 (t,<br /> H-5). J = 1 Hz, H-5'); 8.09 (dt, J = 1 Hz, 7 Hz, H-5);<br /> 8.25 (s, H-2'). 6b: 6.34 (t, J = 2 Hz, 2H: H-3',<br /> 3. Preparation of 3-nitro-2-imidazolyl-<br /> H-4'); 6.84 (dt, J = 1Hz, 6.8 Hz, H-6 ); 7.15 (dt,<br /> imidazo[1,2-a]-pyridine (5a)<br /> J = 1 Hz, 7 Hz, H-7); 7.44 - 7.46 (m, 3H: H-8,<br /> To a mixture of 3-nitro-2- H-2’, H-5’); 8.04 (dt, J = 1 Hz, 6.8 Hz, H-5).<br /> chloroimidazo[1,2-a]-pyridine (4, 10 mmol) and 6. Preparation of 7a-b<br /> K2CO3 (20 mmol) in 10 ml DMF were added<br /> imidazole (15 mmol) in DMF (5 ml). The A mixture of 6a or 6b (0.4 mmol) and 1,1'-<br /> mixture was stirred and refluxed for 4 hours. carbonyldiimidazole (0.6 mmol), in toluene (10<br /> The solvent was evaporated in vacuo and the ml) was refluxed for 2 hours. The solvent was<br /> product was purified by flash column then evaporated and the residue was<br /> chromatography on silica gel. 5a was obtained chromatographed on silica gel to afford a white-<br /> as a light yellow solid (74% yield). 1H-NMR yellow solid 7a-b in 38 - 42% yield. 7a : 1H-<br /> (CDCl3): (ppm): 7.2 (s, H-4'); 7.34 (dt, J = 1.3 NMR (DMSO): (ppm): 7.1 (t, J = 6.8 Hz, H-<br /> Hz, 7 Hz, H-6 ); 7.76 (dt, J = 1Hz, 7 Hz, H-7 ); 6); 7.2 (s, H-4’); 7.3 (t, J= 6.8 Hz, H-7); 7.61-<br /> 7.80-7.82 (m, 2H: H-8, H-5'); 8.49 (s, H-2'); 7.63 (m, 2H: H-8, H-5’); 8.2 (s, H-5); 9.03 (s,<br /> 9.53 (d, J = 7 Hz, H-5). CONH).<br /> 13<br /> 4. Preparation of 3-nitro-2-pyrrolyl C-NMR (DMSO): (ppm): 106.8 (C-2);<br /> imidazo[1,2-a]-pyridine (5b) 112.8 (C-8); 117.3 (C-6); 120.3 (C-3) 123.4 (C-<br /> 5’); 125.9 (C-5); 129.2 (C-7); 134.6 (C-2’);<br /> To a solution of pyrrole (8 mmol) in THF 135.2 (C-4’); 139.7 (C-9); 154.6 (NHCO-). IR:<br /> (10 ml) was added t-BuOK (10 mmol) in THF (cm-1) 3275.5 (NHCO); 3117.73 (-CH=),<br /> (10 ml) at 00C. After that 3-nitro-2- 1646.2 (NHCO).<br /> chloroimidazo[1,2-a]-pyridine (4, 7 mmol) in<br /> THF (3 ml) was dropped into the mixture and 7b: 1H-NMR (DMSO): (ppm):: 6.7 (t, J =<br /> the mixture was stirred overnight at room 2.7, H-3'); 7.08 (dt, J = 1Hz, 7 Hz, H-6); 7.11<br /> temperature. The solvent was evaporated and the (dd, J = 1.3 Hz, 4Hz, H-4'); 7.3 (dt, J = 1.3 Hz, 7<br /> product was purified by column Hz, H-7); 7.63 (d, J = 9 Hz, H-8); 7.85 (d, J =<br /> chromatography on silica gel. 5b was obtained 1.3 Hz, 2 Hz, H-5'); 8.54 (d, J = 7 Hz, H-5);<br /> in 78% yield. 1H-NMR (CDCl3): (ppm): 6.4 (t, 12.3 (s, NH).<br /> 13<br /> J = 2.3 Hz, 2H: H-3', H-4');7.26 (dt, J = 2 Hz, 7 C-NMR (DMSO): (ppm): 111.9 (C-4’);<br /> Hz, H-6); 7.64 (t, J = 2.3 Hz, 2H: H-2', H-5'); 112.3 (C-8); 112.6 (C-8); 112.6 (C-3); 116.5 (C-<br /> 7.66 - 7.73 (m, H-7, H-8); 9.51 (d, J = 7 Hz, H- 3’); 116.6 (C-5); 122.6 (C-7); 123.1 (C-5’);<br /> 5). 123.3 (C-2); 125 (C-2’); 137 (C-9); 154 (-<br /> 5. Preparation of 3-amino-2-imidazolyl- NHCO-). IR: (cm-1) 3276 (NHCO), 3091.3 (-<br /> CH=), 1632.2 (NHCO). Positive ESI-MS: m/z =<br /> imidazo[1,2-a]-pyridine (6a) or 3-amino-2-<br /> 225 [M+H]+.<br /> pyrrolylimidazo[1,2-a]-pyridine (6b)<br /> A solution of 5a or 5b (0.6 mmol) in III - Results and discussion<br /> methanol (10 ml) and Pd/C 10% was stirred<br /> under hydrogen atmosphere. The mixture was The synthesis of imidazo[1,2-a]-pyridine<br /> warmed outside and stirred at 50oC for 48 - 54 derivatives has been started from preparation of<br /> hours. The Pd/C was removed by filtration and 2-chloroimidazo[1,2-a]-pyridine as a main<br /> the filtrate was evaporated to obtain the residue. intermediate for the following conversions.<br /> The product was purified by column Condensation of 2-aminopyridine (1) and<br /> chromatography to give 6a-b in 38 - 45% yield. monochloroacetic acid, followed by C-<br /> 1<br /> H-NMR (CDCl3): (ppm): 6a: 6.9 (dt, J = 1 Hz, alkalylation in the presence of Na2CO3 and<br /> 782<br /> NaOH gave the salt 2.<br /> <br /> <br /> N i N ii N<br /> ONa Cl<br /> NH2 N N<br /> 1 2 3<br /> Scheme 1: i) monochloroacetic acid, Na2CO3, NaOH; ii) POCl3, reflux, 1.5 h<br /> <br /> The product 3 was formed by refluxing of conditions for obtaining compound 5a and 5b.<br /> the salt 2 with POCl3 for 1.5 hours [7]. The Compound 5a was prepared by refluxing a<br /> overall yield was 47% (scheme 1). mixture of imidazole and 4 in DMF and K2CO3<br /> Further transformation of 3 to desired as catalyst for 4 hours [9] with 74% yield. The<br /> products were carried out under milk conditions. preparation of 3-nitro-2-pyrrolyl imidazo[1,2-a]-<br /> Compound 3 was first nitrated at the position pyridine (5b) was performed by the reaction of<br /> three of imidazole moiety [8] to afford 4 in 86% pyrrole and compound 4 in the presence of t-<br /> yield. In this reaction, we found that the use of BuOK [10] and THF as the solvent at room<br /> fume nitric acid/concentrated sulfuric acid in temperature for 24h.<br /> mole ratio 1.3:1 provided product in better yield. The nitro products 5a-b was reduced to the<br /> The product was formed in very low yield if we corresponding amines using hydrogen and Pd/C<br /> used only concentrated nitric acid as the reagent as catalyst. The reaction proceeded at 500C for<br /> (scheme 2). 48-54 hours affording 6a-b in 48-56%.<br /> The products 5a-b were formed by Finally, the amidation of 6a-b to 7a-b were<br /> nucleophile substitution reactions of 3-nitro-2- performed by refluxing of a mixture of 6a-b and<br /> chloroimidazo[1,2-a]-pyridine with imidazole 1,1'-carbonyldiimidazole in toluene for 2 hours.<br /> and pyrrole in the presence of a base. The The products were formed in 38-43% yield<br /> reactions have been carried out in different (scheme 3).<br /> <br /> NO2<br /> 4N<br /> 5 2'<br /> 6 3<br /> 2 Cl 6<br /> 5 N<br /> 4 3 1' 3'<br /> 7 9 1 2 N<br /> 8<br /> N 7 9 1<br /> 4'<br /> 8<br /> N<br /> 3 5b<br /> 5'<br /> <br /> <br /> i iii<br /> NO2<br /> NO2<br /> 2' 3'<br /> 5 4 N ii 6<br /> 5<br /> 4 N 3 1' N<br /> 6 3<br /> 2 Cl 7 9 1<br /> 2 N<br /> 7<br /> 8<br /> 9 1<br /> N<br /> 8<br /> N 5'<br /> 4'<br /> <br /> <br /> 4 5a<br /> <br /> Scheme 2: i) HNO3 /H2SO4 = 1.3/1, 0oC, 30 min; ii) K2CO3, imidazole, DMF, refluxing, 4h;<br /> iii) t-BuOK, pyrrole, THF, rt., overnight<br /> <br /> <br /> <br /> 783<br />  O<br /> NO2 NH2<br /> 3'<br /> HN<br /> 2'<br /> N X i X<br /> 4N ii N X<br /> 5 3<br /> 6 1'<br /> N 7 9 1<br /> 2 N N<br /> N 8<br /> N 5'<br /> 4'<br /> N<br /> 5a-b 6a-b 7a-b<br /> a: X= N<br /> b: X=C<br /> <br /> Scheme 3: i) H2/ Pd/C, MeOH, 48h, 50oC; ii) 1,1'-carbonyldiimidazole, toluene, reflux, 1.5h.<br /> <br /> References novel Experimental and Therapeutic<br /> Approach. 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