Three Novel Sequential Reactions for the Facile Synthesis of a Library of Bisheterocycles Possessing the 3-Aminoimidazo[1,2-a]pyridine Core Cata­lyzed by Bismuth(III) Chloride

Abstract

Novel, one-pot, two-step, sequential protocols for the synthesis of 1,4-phenylene bisheterocyclic compounds have been developed. Successive sequencing of the Groebke–Blackburn–­Bienaymé reaction with Ugi-azide, Hantzsch and Biginelli reactions results in rapid and efficient formation of bisheterocyclic compounds. A simple, fast and high yielding method for the synthesis of 3-aminoimidazo[1,2-a]pyridines catalyzed by bismuth(III) chloride under solvent-free conditions is reported. Bismuth(III) chloride is also an efficient catalyst for the Ugi-azide reaction under solvent free conditions.

Keywords

sequential reactions - Groebke–Blackburn–Bienaymé reaction - 1,4-phenylene bisheterocyclic compounds - Ugi-azide reaction - bismuth(III) chloride - solvent-free reactions

• References and Notes

• 1 Orru RV. A, Ruijter E. Synthesis of Heterocycles via Multicomponent Reactions. Springer Verlag; Berlin: 2010
• 2a Lygin AV, de Meijere A. Angew. Chem. Int. Ed. 2010; 49: 9094
• 2b Sadjadi S, Heravi MM. Tetrahedron 2011; 67: 2707
• 2c Eckert H. Molecules 2012; 17: 1074
• 2d Zou Y, Hu Y, Liu H, Shi D. ACS Comb. Sci. 2011; 14: 38
• 2e Pellegatti L, Vedrenne E, Hiebel MA, Buron F, Massip S, Leger JM, Jarry C, Routier S. Tetrahedron Lett. 2011; 52: 5224
• 2f Akritopoulou-Zanze I, Wakefield BD, Gasiecki A, Kalvin D, Johnson EF, Kovar P, Djuric SW. Bioorg. Med. Chem. Lett. 2011; 21: 1480
• 2g Guntreddi T, Allam BK, Singh KN. Synlett 2012; 23: 2635
• 3 Sanger DJ, Depoortere H. CNS Drug Rev. 1998; 4: 323
• 4 Warner GT, Jarvis B. Drugs 2002; 62: 1345
• 5 Wellington K, Scott LJ. Drugs 2003; 63: 2613
• 6a Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hedberg A, O’Reilly BC. J. Med. Chem. 1991; 34: 806
• 6b Rovnyak GC, Atwal KS, Hedberg A, Kimball SD, Moreland S, Gougoutas JZ, O’Reilly BC, Schwartz J, Malley MF. J. Med. Chem. 1992; 35: 3254
• 7a Groebke K, Weber L, Mehlin F. Synlett 1998; 661
• 7b Blackburn CA. Tetrahedron Lett. 1998; 39: 5469
• 7c Bienayme H, Bouzid K. Angew. Chem. Int. Ed. 1998; 37: 2234
• 8 Rival Y, Grassy G, Michel G. Chem. Pharm. Bull. 1992; 40: 1170
• 9 Rival Y, Grassy G, Taudou A, Ecalle R. Eur. J. Med. Chem. 1991; 26: 13
• 10 Fisher MH, Lusi A. J. Med. Chem. 1972; 15: 982
• 11 Gueiffier A, Mavel S, Lhassani M, Elhakmaoui A, Snoeck R, Andrei G, Chavignon O, Teulade JC, Witvrouw M, Balzarini J. J. Med. Chem. 1998; 41: 5108
• 12 Ismail MA, Brun R, Wenzler T, Tanious FA, Wilson WD, Boykin DW. J. Med. Chem. 2004; 47: 3658
• 13 Almirante L, Polo L, Mugnaini A, Provinciali E, Rugarli P, Biancotti A, Gamba A, Murmann W. J. Med. Chem. 1965; 8: 305
• 14 Langer SZ, Arbilla S, Benavides J, Scatton B. Adv. Biochem. Psychopharmacol. 1990; 46: 61
• 15 Bode ML, Gravestock D, Moleele SS, van der Westhuyzen CW, Pelly SC, Steenkamp PA, Hoppe HC, Khan T, Nkabinde LA. Bioorg. Med. Chem. 2011; 19: 4227
• 16 Dahan-Farkas N, Langley C, Rousseau AL, Yadav DB, Davids H, de Koning CB. Eur. J. Med. Chem. 2011; 46: 4573
• 17a Chen JJ, Golebiowski A, McClenaghan J, Klopfenstein SR, West L. Tetrahedron Lett. 2001; 42: 2269
• 17b Shaabani A, Soleimani E, Maleki A, Moghimi-Rad J. Synth. Commun. 2008; 38: 1090
• 18 Shaabani A, Maleki A, Moghimi Rad J, Soleimani E. Chem. Pharm. Bull. 2007; 55: 957
• 19 Shaabani A, Soleimani E, Maleki A. Monatsh. Chem. 2007; 138: 73
• 20 Katritzky AR, Xu YJ, Tu H. J. Org. Chem. 2003; 68: 4935
• 21a Rousseau AL, Matlaba P, Parkinson CJ. Tetrahedron Lett. 2007; 48: 4079
• 21b Guchhait SK, Madaan C. Synlett 2009; 628
• 22 Varma RS, Kumar D. Tetrahedron Lett. 1999; 40: 7665
• 23 Parchinsky VZ, Shuvalova O, Ushakova O, Kravchenko DV, Krasavin M. Tetrahedron Lett. 2006; 47: 947
• 24 Shaabani A, Soleimani E, Sarvary A, Rezayan AH, Maleki A. Chin. J. Chem. 2009; 27: 369
• 25 Thompson MJ, Hurst JM, Chen B. Synlett 2008; 3183
• 26 Shaabani A, Soleimani E, Malek A. Tetrahedron Lett. 2006; 47: 3031
• 27a Ugi I, Meyr R, Fetzer U, Steinbrückner C. Angew. Chem. 1959; 71: 386
• 27b Ugi I, Steinbrückner C. Angew. Chem. 1960; 72: 267
• 28a Bienaymé H, Bouzid K. Tetrahedron Lett. 1998; 39: 2735
• 28b Nixey T, Kelly M, Semin D, Hulme C. Tetrahedron Lett. 2002; 43: 3681
• 29 Hantzsch A. Justus Liebigs Ann. Chem. 1882; 215: 1
• 30 Biginelli P. Gazz. Chim. Ital. 1893; 23: 360
• 31a Gunawan S, Nichol G, Hulme C. Tetrahedron Lett. 2012; 53: 1664
• 31b Schaffert ES, Höfner G, Wanner KT. Bioorg. Med. Chem. 2011; 19: 6492
• 31c Gunawan S, Keck K, Laetsch A, Hulme C. Mol. Divers. 2012; 16: 601
• 31d Marcos CF, Marcaccini S, Menchi G, Pepino R, Torroba T. Tetrahedron Lett. 2008; 49: 149
• 31e Evans CG, Gestwicki JE. Org. Lett. 2009; 11: 2957
• 31f Wang R, Liu ZQ. J. Org. Chem. 2012; 77: 3952
• 31g Mistry SR, Joshi RS, Sahoo SK, Maheria KC. Catal. Lett. 2011; 141: 1541
• 31h Reddy MV, Jeong YT. Synlett 2012; 23: 2985
• 32a Bothwell JM, Krabbe SW, Mohan RS. Chem. Soc. Rev. 2011; 40: 4649
• 32b Leonard NM, Wieland LC, Mohan RS. Tetrahedron 2002; 58: 8373
• 32c Kouznetsov VV, Gómez CM. M, Parada LK. L, Bermudez JH, Méndez LY. V, Acevedo AM. Mol. Divers. 2011; 15: 1007
• 33 Suzuki H, Matano Y. Organobismuth Chemistry. Elsevier; Amsterdam: 2001
• 34a Attanasi OA, Bartoccini S, Favi G, Giorgi G, Perrulli FR, Santeusanio S. J. Org. Chem. 2012; 77: 1161
• 34b Alizadeh A, Rezvanian A, Zhu LG. J. Org. Chem. 2012; 77: 4385
• 34c Balalaie S, Bararjanian M, Hosseinzadeh S, Rominger F, Bijanzadeh HR, Wolf E. Tetrahedron 2011; 67: 7294
• 34d Sreejalekshmi KG, Rajasekharan KN. Tetrahedron Lett. 2012; 53: 3627
• 34e Al-Tel TH, Al-Qawasmeh RA, Voelter W. Eur. J. Org. Chem. 2010; 29: 5586
• 34f Kalinski C, Umkehrer M, Gonnard S, Jäger N, Ross G, Hiller W. Tetrahedron Lett. 2006; 47: 2041
• 35a Shahrisa A, Miri R, Esmati S, Saraei M, Mehdipour AR, Sharifi M. Med. Chem. Res. 2012; 21: 284
• 35b Shahrisa A, Esmati S, Gholamhosseini Nazari M. J. Chem. Sci. 2012; 124: 927
• 36 General Procedure for the Synthesis of 3-Amino-imidazo[1,2-a]pyridines 5a–h: To a mixture of aldehyde (0.5 mmol), 2-aminopyridine or 2-amino-6-methylpyridine (0.5 mmol) and isocyanide (0.5 mmol) was added BiCl₃ (5 mol%) and the reaction mixture was stirred on a preheated oil bath at 110 °C. After completion of the reaction (monitored by TLC, within 2–5 min), the crude residue was either treated with EtOAc–n-hexane to afford the product as a precipitate, or was subjected to silica gel preparative layer chromatography (EtOAc–n-hexane, 1:3) to give the desired product. Compound 5a: cream solid; mp 168–170 °C. FT-IR (KBr): 3276, 3078, 2924, 2848, 1630, 1577 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.11–1.36 (m, 5 H, CH₂ of cyclohexyl), 1.61–1.88 (m, 5 H, CH₂ of cyclohexyl), 3.04–3.07 (m, 2 H, CHN of cyclohexyl and NH), 6.74 (t, J = 6.6 Hz, 1 H, ArH), 7.08–7.13 (m, 2 H, ArH), 7.31 (d, J = 4.8 Hz, 1 H, ArH), 7.50 (d, J = 8.9 Hz, 1 H, ArH), 7.59 (d, J = 2.9 Hz, 1 H, ArH), 8.06 (d, J = 6.6 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.8, 24.7, 33.2, 55.9, 110.5, 116.1, 121.6, 122.7, 122.9, 123.0, 123.5, 126.5, 131.8, 136.3, 140.7. Anal. Calcd for C₁₇H₁₉N₃S: C, 68.65; H, 6.44; N, 14.13. Found: C, 68.37; H, 6.46; N, 14.02.
• 37 General Procedure for the Synthesis of Imidazo[1,2-a]pyridin-2-yl Benzaldehydes 7a–d: To a mixture of terephthalaldehyde (0.55 mmol), 2-aminopyridine or 2-amino-6-methylpyridine (0.5 mmol) and isocyanide (0.5 mmol) was added BiCl₃ (5 mol%) and the reaction mixture was stirred on a preheated oil bath at 110 °C. After completion of the reaction (monitored by TLC, within 5 min), the crude residue was subjected to silica gel preparative layer chromatography (EtOAc–n-hexane, 1:3) to give the desired product. Compound 7a: yellow solid; mp 126–128 °C. FT-IR (KBr): 3298, 3050, 2926, 2849, 2721, 1695, 1598 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.99–1.06 (m, 5 H, CH₂ of cyclohexyl), 1.53–1.68 (m, 5 H, CH₂ of cyclohexyl), 2.77 (m, 1 H, CHN of cyclohexyl), 2.93 (s, 3 H, CH₃), 3.13 (br s, 1 H, NH), 6.46 (d, J = 6.6 Hz, 1 H, ArH), 7.04 (dd, J = 8.9, 6.6 Hz, 1 H, ArH), 7.42 (d, J = 8.9 Hz, 1 H, ArH), 7.94 (d, J = 8.0 Hz, 2 H, ArH), 8.21 (d, J = 8.0 Hz, 2 H, ArH), 10.04 (s, 1 H, aldehyde). ¹³C NMR (100 MHz, CDCl₃): δ = 19.1, 23.8, 24.7, 32.2, 58.1, 112.9, 115.1, 123.8, 126.9, 128.8, 133.9, 135.2, 136.5, 140.3, 142.6, 191.1. Anal. Calcd for C₂₁H₂₃N₃O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.42; H, 6.89; N, 12.37.
• 38 General Procedure for the Synthesis of GBB/Ugi Azide Products 8a–i: A mixture of terephthalaldehyde (0.55 mmol), 2-aminopyridine or 2-amino-6-methylpyridine (0.5 mmol) and isocyanide (0.5 mmol) containing BiCl₃ (5 mol%) was stirred on a preheated oil bath at 110 °C for 5 min. Without workup, to the resulting mixture containing imidazo[1,2-a]pyridin-2-yl benzaldehyde 7 (after being cooled to r.t.) were added the desired amine (0.5 mmol), TMSN₃ (0.5 mmol), isocyanide (0.5 mmol) and BiCl₃ (5 mol%) and the reaction mixture was stirred at r.t. for 10 min (completion of the reaction monitored by TLC). The crude product was purified by silica gel preparative layer chromatography (EtOAc–CHCl₃–n-hexane, 1:1:3) to give the desired product. Compound 8h: yellow solid; mp 204–206 °C. FT-IR (KBr): 3320, 2924, 2852, 1616, 1517 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.06–1.73 (m, 19 H, 5 × CH₂ of cyclohexyl, t-Bu), 2.14 (s, 3 H, CH₃), 2.85–2.89 (m, 2 H, CHN of cyclohexyl and NH), 4.66 (d, J = 6.7 Hz, 1 H, NH), 6.06 (d, J = 6.7 Hz, 1 H, benzylic), 6.56 (d, J = 8.2 Hz, 2 H, ArH), 6.72 (t, J = 6.7 Hz, 1 H, ArH), 6.90 (d, J = 8.2 Hz, 2 H, ArH), 7.05–7.08 (m, 1 H, ArH), 7.31 (d, J = 8.3 Hz, 2 H, ArH), 7.46 (d, J = 8.9 Hz, 1 H, ArH), 7.97 (d, J = 8.3 Hz, 2 H, ArH), 8.02 (d, J = 6.7 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 19.4, 23.8, 24.7, 29.1, 33.2, 54.2, 55.9, 60.5, 110.7, 113.9, 116.4, 121.7, 123.2, 124.2, 126.6, 127.1, 127.7, 128.9, 133.8, 134.5, 135.9, 142.6, 154.3. Anal. Calcd for C₃₂H₃₈N₈: C, 71.88; H, 7.16; N, 20.96. Found: C, 71.56; H, 7.22; N, 20.64.
• 39 General Procedure for the Synthesis of GBB/Hantzsch Products 9a,b: A mixture of terephthalaldehyde (0.55 mmol), 2-amino-6-methylpyridine (0.5 mmol) and isocyanide (0.5 mmol) containing BiCl₃ (5 mol%) was stirred on a preheated oil bath at 110 °C for 5 min. Without workup, to the resulting imidazo[1,2-a]pyridin-2-yl benzaldehyde 7 were added ethyl acetoacetate (1 mmol), NH₃ (0.5 mL) and CeCl₃·7H₂O (25 mol%) and the mixture was refluxed in EtOH for 5 h. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel preparative layer chromatography (EtOAc–CHCl₃–n-hexane, 1:1:2) to give the desired product. Compound 9b: yellow solid; mp 252 °C (dec.). FT-IR (KBr): 3275, 3174, 3053, 2924, 1686 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (s, 9 H, t-Bu), 1.19 (t, J = 7.1 Hz, 6 H, COOCH₂CH ₃), 2.28 (s, 6 H, CH₃), 2.96 (s, 3 H, CH₃), 3.09 (br s, 1 H, NH), 3.99–4.11 (m, 4 H, COOCH ₂CH₃), 4.97 (s, 1 H, DHP H-4), 6.47 (d, J = 6.7 Hz, 1 H, ArH), 7.03–7.07 (m, 1 H, ArH), 7.37–7.42 (m, 3 H, ArH), 7.63 (d, J = 7.9 Hz, 2 H, ArH), 8.15 (br s, 1 H, DHP NH). ¹³C NMR (100 MHz, CDCl₃): δ = 13.3, 17.8, 19.8, 28.5, 38.8, 55.4, 58.4, 102.5, 112.9, 113.9, 123.5, 124.7, 126.9, 127.4, 131.9, 136.2, 140.7, 141.9, 144.0, 147.2, 166.8. Anal. Calcd for C₃₁H₃₈N₄O₄: C, 70.16; H, 7.22; N, 10.56. Found: C, 69.92; H, 7.27; N, 10.32.
• 40 Bose DS, Fatima L, Mereyala HB. J. Org. Chem. 2003; 68: 587
• 41 General Procedure for the Synthesis of GBB/Biginelli Products 10a,b: As with the GBB/Hantzsch procedure, after formation of the carbaldehyde intermediate, ethyl acetoacetate (0.5 mmol), urea (1.5 mmol) and CeCl₃·7H₂O (25 mol%) were added and the reaction mixture was refluxed for 4 h. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel preparative layer chromatography (EtOAc–CHCl₃–n-hex-ane, 1:1:2) to give the desired product. 10a: yellow solid; mp 216–218 °C. FT-IR (KBr): 3205, 3086, 2926, 1689 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.98–1.05 (m, 5 H, CH₂ of cyclohexyl), 1.14 (t, J = 7.1 Hz, 3 H, COOCH₂CH ₃), 1.47–1.67 (m, 5 H, CH₂ of cyclohexyl), 2.38 (s, 3 H, CH₃), 2.74–2.76 (m, 1 H, CHN of cyclohexyl), 2.93 (s, 3 H, CH₃), 3.09 (br s, 1 H, NH), 4.02–4.10 (m, 2 H, COOCH ₂CH₃(, 5.44 (s, 1 H, pyrimidone H-4), 5.63 (br s, 1 H, NH), 6.43 (d, J = 6.7 Hz, 1 H, ArH), 6.99–7.03 (dd, J = 7.0, 8.8 Hz, 1 H, ArH), 7.37 (d, J = 8.1 Hz, 2 H, ArH), 7.41 (d, J = 8.8 Hz, 1 H, ArH), 7.66 (br s, 1 H, NH), 7.90 (d, J = 8.1 Hz, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 13.1, 17.8, 19.2, 23.8, 24.7, 32.1, 54.8, 57.8, 58.9, 100.0, 112.6, 114.7, 123.3, 125.8, 126.9, 128.1, 133.7, 135.3, 141.4, 142.1, 142.9, 144.4, 151.6, 164.7. Anal. Calcd for C₂₈H₃₃N₅O₃: C, 68.97; H, 6.82; N, 14.36. Found: C, 68.67; H, 6.75; N, 14.15.