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Synlett 2013; 24(5): 595-602
DOI: 10.1055/s-0032-1318221
DOI: 10.1055/s-0032-1318221
letter
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
Weitere Informationen
Publikationsverlauf
Received: 29. Dezember 2012
Accepted after revision: 24. Januar 2013
Publikationsdatum:
28. Februar 2013 (online)
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 reactionsSupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. Included are experimental details, 1H NMR, 13C NMR, FT-IR and elemental analysis of new compounds.
- Supporting Information
-
References and Notes
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- 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.