A Convenient Palladium-Catalyzed Azaindole Synthesis

Abstract

A one-pot protocol is described which allows direct access to azaindoles from amino-halopyridines and ketones.

Key words

microwave - palladium catalysis - ketone arylation - cyclization - azaindoles

• References and Notes


For examples of azaindoles exhibiting biological activity, see:
• 1a Prudhomme M. Eur. J. Med. Chem. 2003; 38: 123
• 1b Walker SR, Carter EJ, Huff BC, Morris JC. Chem. Rev. 2009; 109: 3080
• 1c Blaazer AR, Lange JH. M, van der Neut MA. W, Mulder A, den Boon FS, Werkman TR, Kruse CG, Wadman WJ. Eur. J. Med. Chem. 2011; 46: 5086
• 1d Sandham DA, Arnold N, Aschauer H, Bala K, Barker L, Brown L, Brown Z, Budd D, Cox B, Docx C, Dubois G, Duggan N, England K, Everett B, Furegati M, Hall E, Kalthoff F, King A, Leblanc CJ, Manini J, Meingassner J, Profit R, Schmidt A, Simmons J, Sohal B, Stringer R, Thomas M, Turner KL, Walker C, Watson SJ, Westwick J, Willis J, Williams G, Wilson C. Bioorg. Med. Chem. 2013; 21: 6582
• 1e Lee HY, Pan SL, Su MC, Liu YM, Kuo CC, Chang YT, Wu JS, Nien CY, Mehndiratta S, Chang CY, Wu SY, Lai MJ, Chang JY, Liou JP. J. Med. Chem. 2013; 56: 8008
• 1f Cheve G, Dayde-Cazals B, Fauvel B, Bories C, Yasri A. WO 2014102377 A1 20140703, 2014
• 1g Dodd R, Cariou K, Gourdain S, Delabar JM, Janel N, Rodrigues LF, Dairou J, Denhez C. WO 2014096093, A1 20140626, 2014

For selected reviews on the synthesis of azaindoles, see:
• 2a Popowycz F, Routier S, Mérour J.-Y, Joseph B. Tetrahedron 2007; 63: 1031
• 2b Song JJ, Reeves TJ, Gallou F, Tan Z, Yee NK, Senanayake CH. Chem. Soc. Rev. 2007; 36: 1120
• 2c Mérour J.-Y, Routier S, Suzenet F, Joseph B. Tetrahedron 2013; 69: 4767

For selected examples of azaindole synthesis, see:
• 3a Nazaré M, Schneider C, Lindenscmidt A, Will DW. Angew. Chem. Int. Ed. 2004; 43: 4526
• 3b Lachance N, April M, Jolzy MA. Synlett 2005; 2571
• 3c Fang YQ, Yuen J, Lautens M. J. Org. Chem. 2007; 72: 5152
• 3d de Mattos MC, Alatorre-Santamaria S, Gotor-Fernandez V, Gotor V. Synthesis 2007; 2149
• 3e Spergel SH, Okoro DR, Pitts W. J. Org. Chem. 2010; 75: 5316
• 3f Whelligan DK, Thomson DW, Taylor D, Hoelder S. J. Org. Chem. 2010; 75: 11
• 3g Majumdar KC, Ganai S, Chattopadhyay B, Ray K. Synlett 2011; 2369
• 3h Knapp JM, Zhu JS, Tantillo DJ, Kurth MJ. Angew. Chem. Int. Ed. 2012; 51: 10588
• 3i Frischmuth A, Knochel P. Angew. Chem. Int. Ed. 2013; 52: 10084
• 3j Leboho TC, van Vuuren SF, Michael JP, de Koning CB. Org. Biomol. Chem. 2014; 12: 307
• 4 See Supporting Information for details of the initial screening experiments performed.
• 5 When the 7-azaindole synthesis described in Scheme 1 was tested with acetone as solvent instead of methyl levulinate, the mass of the α-arylacetone could be detected by LC–MS (8%) along with 89% of the cyclized 7-azaindole product. Attempts to isolate this material via silica gel chromatography led to cyclization to the 7-azaindole.
• 6 In the following paper on α-arylation of ketones there is a preference for arylation at the less hindered site, see: Fox JM, Huang X, Chieffi A, Buchwald SL. J. Am. Chem. Soc. 2000; 122: 1360
• 7 General Procedure ATo a microwave vial equipped with a magnetic stirrer was added 2-amino-3-halo pyridine derivative (1.9 mmol, 1 equiv), MgSO₄ (1715 mg), ketone (7.5 mL), and AcOH (0.109 mL, 1.9 mmol, 1 equiv). The reaction was purged with argon under stirring for 10 min at 22 °C. Then K₃PO₄ (807 mg, 3.8 mmol, 2 equiv) and chloro(2-dicyclohexylphosphino-2′,4′6′-triisopropyl-1,1′biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (56 mg, 0.076 mmol, 0.04 equiv) were added. The vial was closed, purged with argon under stirring for 10 min at 22 °C, and heated to 140 °C. Upon completion, the reaction mixture was filtered through silica that was subsequently rinsed with EtOAc. Concentration in vacuo provided the crude product which was purified as described in the Supporting Information or below.General Procedure BTo a hydrogenation vial flushed with argon was added 2-amino-3-halo pyridine derivative (1.5 mmol, 1 equiv), MgSO₄ (1354 mg), acetone (5.9 mL), AcOH (0.086 mL, 1.5 mmol, 1 equiv), K₃PO₄ (637 mg, 3.0 mmol, 2 equiv), and chloro(2-dicyclohexylphosphino-2′,4′6′triisopropyl-1,1′biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (44 mg, 0.06 mmol, 0.04 equiv). The vial was inserted into the hydrogenation apparatus, purged with nitrogen twice, and heated at 140 °C for 48 h. The reaction mixture was filtered through silica washing with acetone followed by 20% MeOH in acetone. Concentration in vacuo provided the crude product that was purified as described in the Supporting Information or below. Selected examples of azaindoles prepared:Methyl 3-(1-Benzyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propanoate (3a)Prepared following general procedure A, starting from N-benzyl-3-bromopyridin-2-amine (1a) and methyl levulinate. The reaction required 2 h heating at 140 °C. Purification by flash chromatography (20% tert-butyl methyl ether in heptanes, R_f  = 0.18) followed by trituration with 2-methyl pentane gave the product as a white powder (406 mg, 73%). ¹H NMR (400 MHz, CDCl₃): δ = 2.69 (obs. t, J = 7.6 Hz, 2 H), 3.00 (obs. t, J = 7.6 Hz, 2 H), 3.68 (s, 3 H), 5.59 (s, 2 H), 6.27 (s, 1 H), 7.02–7.09 (m, 3 H), 7.19–7.29 (m, 3 H), 7.85 (dd, J = 7.8, 1.5 Hz, 1 H), 8.29 (dd, J = 4.6, 1.6 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 22.2, 32.2, 44.8, 51.8, 97.3, 116.0, 120.3, 126.4, 127.3, 127.6, 128.7, 137.9, 140.0, 142.2, 148.6, 172.7. LC–MS: m/z [M + H]⁺ calcd for C₁₈H₁₉N₂O₂ ⁺: 295.1; found: 295.1.1-Benzyl-2-isobutyl-1H-pyrrolo[2,3-b]pyridine (3c)Prepared following general procedure A, starting from N-benzyl-3-bromopyridin-2-amine (1a) and 4-methylpentan-2-one. The reaction required 6 h heating at 140 °C under microwave irradiation. Purification by flash chromatography (5% EtOAc in heptanes, R_f  = 0.14) gave the product as an off-white solid (418 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (d, J = 6.8 Hz, 6 H), 1.94 (obs. septet, J = 6.8 Hz, 1 H), 2.53 (dd, J = 6.8, 0.8 Hz, 2 H), 5.57 (s, 2 H), 6.28 (obs. s, 1 H), 6.98–7.03 (m, 2 H), 7.06 (dd, J = 7.7, 4.6 Hz, 1 H), 7.18–7.28 (m, 3 H), 7.85 (dd, J = 7.7, 1.6 Hz, 1 H), 8.26 (dd, J = 4.8, 1.5 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 22.6, 27.8, 36.2, 44.8, 98.5, 115.9, 120.5, 126.3, 127.1, 127.2, 128.6, 138.3, 141.1, 141.7, 148.5. LC–MS: m/z [M + H]⁺ calcd for C₁₈H₂₁N₂ ⁺: 265.2; found: 265.2.1-Benzyl-3-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (3g)Prepared following general procedure A, starting from N-benzyl-3-bromopyridin-2-amine (1a) and propiophenone. The reaction required 48 h heating at 140 °C. Purification by reverse-phase flash chromatography (50% MeCN in H₂O to 100% MeCN; R_f  = 0.26, MeCN–H₂O = 8:2) gave the product as an orange oil (150 mg, 26%). ¹H NMR (400 MHz, CDCl₃): δ = 2.25 (s, 3 H), 5.44 (s, 2 H), 6.84–6.88 (m, 2 H), 7.08–7.15 (m, 4 H), 7.24–7.27 (m, 2 H), 7.36–7.41 (m, 3 H), 7.89 (dd, J = 7.8, 1.5 Hz, 1 H), 8.35 (dd, J = 4.8, 1.5 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 9.1, 45.8, 107.5, 115.6, 121.2, 126.6, 126.7, 126.8, 128.2, 128.2, 128.3, 130.5, 131.5, 137.7, 138.7, 143.0, 148.4. LC–MS: m/z [M + H]⁺ calcd for C₂₁H₁₉N₂ ⁺: 299.2; found: 299.2.