Synlett, Table of Contents Synlett 2022; 33(04): 371-375DOI: 10.1055/s-0040-1719865 letter Mild, General, and Regioselective Synthesis of 2-Aminopyridines from Pyridine N-Oxides via N-(2-Pyridyl)pyridinium Salts Authors Hui Xiong∗ Adam T. Hoye ∗ Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Abstract A synthesis of 2-aminopyridines from pyridine N-oxides via their corresponding N-(2-pyridyl)pyridinium salts has been demonstrated and investigated. The reaction sequence features a highly regioselective conversion of the N-oxide into its pyridinium salt followed by hydrolytic decomposition of the pyridinium moiety to furnish the 2-aminopyridine product. The method is compatible with a wide range of functional groups, is scalable, and features inexpensive reagents. 15N-labeling results gave products consistent with a Zincke reaction mechanism. Key words Key wordsaminopyridines - pyridine oxides - pyridylpyridinium compounds - isotopic labeling - Zincke reaction Full Text References References and Notes For selected examples, see: 1a Hagmann WK, Caldwell CG, Chen P, Durette PL, Esser CK, Lanza TJ, Kopka IE, Guthikonda R, Shah SK, MacCoss M, Chabin RM, Fletcher D, Grant SK, Green BG, Humes JL, Kelly TM, Luell S, Meurer R, Moore V, Pacholok SG, Pavia T, Williams HR, Wong KK. Bioorg. Med. Chem. Lett. 2000; 10: 1975 1b Connolly S, Aberg A, Arvai A, Beaton HG, Cheshire DR, Cook AR, Cooper S, Cox D, Hamley P, Mallinder P, Millichip I, Nicholls DJ, Rosenfeld RJ, St-Gallay SA, Tainer J, Tinker AC, Wallace AV. J. Med. Chem. 2004; 47: 3320 1c Hilton S, Naud S, Caldwell JJ, Boxall K, Burns S, Anderson VE, Antoni L, Allen CE, Pearl LH, Oliver AW, Aherne GW, Garrett MD, Collins I. Bioorg. Med. Chem. 2010; 18: 707 1d Malmas MS, Barnes K, Hui Y, Johnson M, Lovering F, Condon J, Fobare W, Solvibile W, Turner J, Hu Y, Manas ES, Fan K, Olland A, Chopra R, Bard J, Pangalos MN, Reinhart P, Robichaud AJ. Bioorg. Med. Chem. Lett. 2010; 20: 2068 1e Younis Y, Douelle F, Feng T.-S, Gonzáles Cabrera D, Le Manach C, Nchinda AT, Duffy S, White KL, Shackleford DM, Morizzi J, Manilla J, Katneni K, Bhamidipati R, Zabiulla KM, Joseph JT, Bashyam S, Waterson D, Witty MJ, Hardick D, Wittlin S, Avery V, Charman SA, Chibale K. J. Med. Chem. 2012; 55: 3479 1f Huang H, Guzman-Perez A, Acuqiviva L, Berry V, Bregman H, Dovey J, Gunaydin H, Huang X, Huang L, Saffran D, Serafino R, Schneider S, Wilson C, DiMauro EF. ACS Med. Chem. Lett. 2013; 4: 1218 1g Wang H.-Y, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 2016; 59: 4913 1h Gerster JF, Lindstrom KJ, Miller RL, Tomai MA, Birmachu W, Bomersine SN, Gibson SJ, Imbertson LM, Jacobson JR, Knafla RT, Maye PV, Nikolaides N, Oneyemi FY, Parkhurst GJ, Pecore SE, Reiter MJ, Scribner LS, Testerman TL, Thompson NJ, Wagner TL, Weeks CE, Andre J.-D, Lagain D, Bastard Y, Lupu M. J. Med. Chem. 2005; 48: 3481 1i González Cabrera D, Douelle F, Younis Y, Feng T.-S, Le Manach C, Nchinda AT, Street LJ, Scheurer C, Kamber J, White KL, Montagnat OD, Ryan E, Katneni K, Zabiulla KM, Joseph JT, Bashyam S, Waterson D, Witty MJ, Charman SA, Wittlin S, Chibale K. J. Med. Chem. 2012; 55: 11022 2a Bagdi AK, Santra S, Monir K, Hajra A. Chem. Commun. 2015; 51: 1555 ; and references therein 2b Geng J.-B, Wu X.-F. J. Heterocycl. Chem. 2017; 54: 794 2c Venugopal S, Sundaram S. J. Heterocycl. Chem. 2016; 53: 882 2d Meng T, Zhang Z, Hu D, Lin L, Ding J, Wang X, Shen J. J. Comb. Chem. 2007; 9: 739 2e Yang K, Xiang J, Bao G, Dang Q, Bai X. ACS Comb. Sci. 2013; 15: 519 2f Rousseau AL, Matlaba P, Parkinson CJ. Tetrahedron Lett. 2007; 48: 4079 2g Adib M, Sayahi MH, Nosrati M, Zhu L.-G. Tetrahedron Lett. 2007; 48: 4195 2h Chernyak N, Gevorgyan V. Angew. Chem. Int. Ed. 2010; 49: 2743 2i Kopp M, Lancelot J.-C, Dagdag S, Miel H, Rault S. J. Heterocycl. Chem. 2002; 39: 1061 3a Cao S, Xin L, Liu Y, Wan J.-P, Wen C. RSC Adv. 2015; 5: 27372 3b Chen J, Song G, Pan C.-L, Li X. Org. Lett. 2010; 12: 5426 3c Keenan RM, Miller WH, Barton LS, Bondinell WE, Cousins RD, Eppley DF, Hwang S.-M, Kwon C, Lago MA, Nguyen TT, Smith BR, Uzinskas IN, Yuan CC. K. Bioorg. Med. Chem. Lett. 1999; 9: 1801 4 Coleman MD. Role of Metabolism in Drug Toxicity . In Human Drug Metabolism: An Introduction, 2nd ed. John Wiley & Sons; Chichester: 2010: 252-258 5a Londregan AT, Jennings S, Wei L. Org. Lett. 2010; 12: 5254 5b Bollinger JL, Oberholzer M, Frech CM. Adv. Synth. Catal. 2011; 353: 945 ; and references therein 6a Storz T. Org. Process Res. Dev. 2004; 8: 663 6b Storz T, Bartberger MD, Sukits S, Wilde C, Soukup T. Synthesis 2008; 201 7 Yin J, Xiang B, Huffman MA, Raab CE, Davies IW. J. Org. Chem. 2007; 72: 4554 8 Farrell RP, Elipe MV. S, Bartberger MD, Tedrow JS, Vounatsos F. Org. Lett. 2013; 15: 168 9a Kutasevich AV, Perevalov VP, Mityanov VS. Eur. J. Org. Chem. 2021; 357 9b Malykhin RS, Sukhorukov AY. Adv. Synth. Catal. 2021; 363: 3170 9c Wang D, Désaubry L, Li G, Huang M. Adv. Synth. Catal. 2021; 363: 2 9d Wachi K, Terada A. Chem. Pharm. Bull. 1980; 28: 465 9e Abramovitch RA, You-Xiong W. Heterocycles 1987; 26: 2065 9f Medley JW, Movassaghi M. J. Org. Chem. 2009; 74: 1341 9g Vamos M, Cosford ND. P. J. Org. Chem. 2014; 79: 2274 9h Manley PJ, Bilodeau MT. Org. Lett. 2002; 4: 3127 10 Xiong H, Hoye AT, Fan K.-H, Li X, Clemens J, Horchler CL, Lim NC, Attardo G. Org. Lett. 2015; 17: 3726 11a Zincke T, Heuser G, Möller W. Justus Liebigs Ann. Chem. 1904; 330: 361 11b Cheng W.-C, Kurth MJ. Org. Prep. Proced. Int. 2002; 34: 585 12a Seefeld MA, Hamajima T, Jung DK, Nakamura H, Reid PR, Reno MJ, Rouse MB, Heerding DA, Tang J, Wang J. WO 2007/076423, 2007 12b Lam PY. S, Clark CG, Li R, Pinto DJ. P, Orwat MJ, Galemmo RA, Fevig JM, Teleha CA, Alexander RS, Smallwood AM, Rossi KA, Wright MR, Bai SA, He K, Luettgen JM, Wong PC, Knabb RM, Wexler RR. J. Med. Chem. 2003; 46: 4405 12c Pohlmann J, Stieger M, Reinelt S, Lane H. WO 2016/128465, 2016 13a Yakovlev MY, Kadushkin AV, Solov’eva NP, Anisimova OS, Granik VG. Tetrahedron 1998; 5775 13b Krichevsky ES, Alekseeva LM, Granik VG. Chem. Heterocycl. Compd. 2003; 39: 328 13c Borzsonyi G, Alsbaiee A, Beingessner RL, Fenniri H. J. Org. Chem. 2010; 75: 7233 13d Dorsch D, Bertram C, Tsaklakidis C, Mederski W, Gleitz J, Barnes C. WO 2003/013531, 2003 13e Hewawasam P, Fan W, Knipe J, Moon SL, Boissard CG, Gribkoff VK, Starrett JE. Jr. Bioorg. Med. Chem. Lett. 2002; 12: 1779 14a Deev SL, Khalymbadzha IA, Shestakova TS, Charushin VN, Chupakhin ON. RSC Adv. 2009; 9: 26856 ; and references therein 14b Elmore CS. Annu. Rep. Med. Chem. 2009; 44: 515 15 1-(5-Phenylpyridin-2-yl)pyridinium Trifluoroacetate (3d); Typical Procedure TFAA (280 μL, 2.0 mmol, 2.0 equiv) was added to a stirred solution of 3-phenylpyridine 1-oxide (171 mg, 1.0 mmol) and pyridine (400 μL, 5.0 mmol, 5.0 equiv) in CH2Cl2 (5 mL, 0.2 M) at 0 °C, and the resulting mixture was stirred at r.t. until the reaction was complete (LCMS). The mixture was then concentrated, dissolved in a minimal amount of CH2Cl2, and triturated from rapidly stirred Et2O. The crude pyridinium salt was isolated by filtration, washed with Et2O, and purified by chromatography [silica gel (12 g), 0–40% MeOH–CH2Cl2] to give an off-white solid; yield: 312 mg (0.90 mmol, 90%). 1H NMR (400 MHz, CDCl3): δ = 10.15 (d, J = 5.6 Hz, 2 H), 8.73–8.62 (m, 2 H), 8.35 (t, J = 6.4 Hz, 2 H), 8.25 (t, J = 7.8 Hz, 1 H), 8.06–8.01 (m, 3 H), 7.54–7.50 (m, 3 H). 19F NMR (376.5 MHz, CDCl3): δ = –75.2. 13C NMR (100 MHz, CDCl3): δ = 158.1, 151.1, 147.9, 142.6, 142.5, 136.5, 130.8, 129.4, 129.0, 127.3, 123.5, 116.0, (F3CCO2 – signal not included). HRMS (ESI+): m/z [M]+ calcd for C16H13N2: 233.1073; found: 233.1076. 5-Phenylpyridin-2-amine (4b); Typical Procedure TFAA (280 μL, 2.0 mmol, 2 equiv) was added to a stirred solution of 3-phenylpyridine 1-oxide (171 mg. 1.0 mmol) and pyridine (400 μL, 5.0 mmol, 5 equiv) in MeCN (5.0 mL, 0.2 M) at 0 °C, and the resulting mixture was stirred at r.t. until the reaction was complete (LCMS). The reaction was then concentrated, dissolved in a minimal amount of CH2Cl2, and triturated from rapidly stirred Et2O. The crude pyridinium salt was isolated by filtration and washed with Et2O. The off-white solid was treated with hydrazine monohydrate (240 μL, 5.0 mmol, 5 equiv) in EtOH (5.0 mL) at 80 °C for 2 h, The resulting mixture was concentrated over silica gel with excess solid NaHCO3. The residue was purified by column chromatography (silica gel, 0–100% EtOAc–hexane) to give an off-white solid; yield:142 mg (0.84 mmol, 84%). 1H NMR (400 MHz, DMSO-d 6): δ = 8.25 (dd, J = 0.7, 2.5 Hz, 1 H), 7.69 (dd, J = 2.5, 8.6 Hz, 1 H), 7.56–7.54 (m, 2 H), 7.42–7.37 (m, 2 H), 7.28–7.24 (m, 1 H), 6.55 (dd, J = 0.7, 8.6 Hz, 1 H), 6.01 (br s, 2 H). 13C NMR (100 MHz, DMSO-d 6) δ = 159.1, 145.6, 138.1, 135.2, 128.8, 126.1, 125.3, 123.9, 107.9. HRMS (ESI+) m/z [M + H]+ calcd for C11H11N2: 171.0917; found: 171.0917. Supplementary Material Supplementary Material Supporting Information (PDF)
