Synlett, Table of Contents Synlett 2022; 33(04): 381-385DOI: 10.1055/a-1705-0247 letter A Mild and Efficient Synthesis of Pyrazolo[1,5-a]pyridines Mediated by Triphenylphosphine/Diiodine Kai Jia‡ , Wenchao Ma‡ , Yintao Yan , Chenming Zhang , Chao Jiang ∗Recommend Article Abstract Buy Article All articles of this category Abstract A synthesis of 2,3-diaryl-substituted pyrazolo[1,5-a]pyridines in moderate to good yields under metal-free and mild conditions is described. The intramolecular cyclization of the oxime substrates is mediated by PPh3/I2, which leads directly to pyrazolo[1,5-a]pyridines without the formation of a 2H-azirine intermediate. Various substituents on the aryl rings are compatible with the method. Key words Key wordspyrazolopyridines - oximes - metal-free synthesis - iodine - triphenylphosphine Full Text References References and Notes For selected examples, see: 1a Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney J, Holmqvist DM, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao Y.-M, Zhou L, Atadja P. J. Med. Chem. 2011; 54: 4752 1b Balkenhohl M, Salgues B, Hirai T, Karaghiosoff K, Knochel P. Org. Lett. 2018; 20: 3114 1c Nirogi R, Mohammed AR, Shinde AK, Gagginapally SR, Kancharla DM, Middekadi VR, Bogaraju N, Ravella SR, Singh P, Birangal SR, Subramanian R, Palacharla RC, Benade V, Muddana N, Jayarajan P. J. Med. Chem. 2018; 61: 4993 1d Möller D, Banerjee A, Uzuneser TC, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P. J. Med. Chem. 2017; 60: 2908 1e Männel B, Hübner H, Möller D, Gmeiner P. Bioorg. Med. Chem. 2017; 25: 5613 1f Yoshida N, Aono M, Tsubuki T, Awano K, Kobayashi T. Tetrahedron: Asymmetry 2003; 14: 529 1g Kojima A, Takita S, Sumiya T, Ochiai K, Iwase K, Kishi T, Ohinata A, Yageta Y, Yasue T, Kohno Y. Bioorg. Med. Chem. Lett. 2013; 23: 5311 1h Takahashi Y, Hibi S, Hoshino Y, Kikuchi K, Shin K, Murata-Tai K, Fujisawa M, Ino M, Shibata H, Yonaga M. J. Med. Chem. 2012; 55: 5255 1i Lu Z, Ott GR, Anand R, Liu R.-Q, Covington MB, Vaddi K, Qian M, Newton RC, Christ DD, Trzaskos J, Duan JJ.-W. Bioorg. Med. Chem. Lett. 2008; 18: 1958 1j Johnston KA, Allcock RW, Jiang Z, Collier ID, Blakli H, Rosair GM, Bailey PD, Morgan KM, Kohno Y, Adams DR. Org. Biomol. Chem. 2008; 6: 175 2a Burja B, Čimbora-Zovko T, Tomić S, Jelušić T, Kočevar M, Polanc S, Osmak M. Bioorg. Med. Chem. 2010; 18: 2375 2b Duan G, Zhang G, Yuan S, Ji R, Zhang L, Ge Y. Spectrochim. Acta, Part A 2019; 219: 173 2c Tang J, Wang B, Wu T, Wan J, Tu Z, Njire M, Wan B, Franzblauc SG, Zhang T, Lu X, Ding K. ACS Med. Chem. Lett. 2015; 6: 814 2d Zhang P, Lv H, Duan G, Dong J, Ge Y. RSC Adv. 2018; 8: 30732 2e Lu X, Tang J, Cui S, Wan B, Franzblauc SG, Zhang T, Zhang X, Ding K. Eur. J. Med. Chem. 2017; 125: 41 2f Insuasty B, Ramírez J, Becerra D, Echeverry C, Quiroga J, Abonia R, Robledo SM, Vélez ID, Upegui Y, Muñoz JA, Ospina V, Nogueras M, Cobo J. Eur. J. Med. Chem. 2015; 93: 401 2g Rashad AE, Hegab MI, Abdel-Megeid RE, Micky JA, Abdel-Megeid FM. Bioorg. Med. Chem. 2008; 16: 7102 3a Umei K, Nishigaya Y, Kondo A, Tatani K, Tanaka N, Kohno Y, Seto S. Bioorg. Med. Chem. 2017; 25: 2635 3b O’Malley DP, Ahuja V, Fink B, Cao C, Wang C, Swanson J, Wee S, Gavai AV, Tokarski J, Critton D, Paiva AA, Johnson BM, Szapiel N, Xie D. ACS Med. Chem. Lett. 2019; 10: 1486 3c Nishigaya Y, Umei K, Saito Y, Watanabe H, Kondo T, Kondo A, Kawamura N, Tatani K, Kohno Y, Tanaka N, Seto S. Bioorg. Med. Chem. Lett. 2017; 27: 4044 3d Ha H.-H, Kim JS, Kim BM. Bioorg. Med. Chem. Lett. 2008; 18: 653 3e Allen SH, Johns BA, Gudmundsson KS, Freeman GA, Boyd FL. Jr, Sexton CH, Selleseth DW, Creech KL, Moniri KR. Bioorg. Med. Chem. 2006; 14: 944 3f Li A.-R, Johnson MG, Liu J, Chen X, Du X, Mihalic JT, Deignan J, Gustin DJ, Duquette J, Fu Z, Zhu L, Marcus AP, Bergeron P, McGee LR, Danao J, Lemon B, Carabeo T, Sullivan T, Ma J, Tang L, Tonn G, Collins TL, Medina JC. Bioorg. Med. Chem. Lett. 2008; 18: 688 3g Alam M, Beevers RE, Ceska T, Davenport RJ, Dickson KM, Fortunato M, Gowers L, Haughan AF, James LA, Jones MW, Kinsella N, Lowe C, Meissner JW, Nicolas AL, Perry BG, Phillips DJ, Pitt WR, Platt A, Ratcliffe AJ, Sharpe A, Tait LJ. Bioorg. Med. Chem. Lett. 2007; 17: 3463 3h Johns BA, Gudmundsson KS, Allen SH. Bioorg. Med. Chem. Lett. 2007; 17: 2858 3i Zhou H.-J, Wang J, Yao B, Wong S, Djakovic S, Kumar B, Rice J, Valle E, Soriano F, Menon M.-K, Madriaga A, von Soly SK, Kumar A, Parlati F, Yakes FM, Shawver L, Le Moigne R, Anderson DJ, Rolfe M, Wustrow D. J. Med. Chem. 2015; 58: 9480 3j Johns BA, Gudmundsson KS, Turner EM, Allen SH, Samano VA, Ray JA, Freeman GA, Boyd FL. Jr, Sexton CJ, Selleseth DW, Creech KL, Moniri KR. Bioorg. Med. Chem. 2005; 13: 2397 4 Löber S, Hübner H, Gmeiner P. Bioorg. Med. Chem. Lett. 1999; 9: 97 For reviews, see: 5a Priya DD, Nandhakumar M, Roopan SM. Synth. Commun. 2020; 50: 3535 5b Kendall JD. Curr. Org. Chem. 2011; 15: 2481 For recent reports on the synthesis of pyrazolo[1,5a]pyridines, see 5c Yan P, Duan G, Ji R, Ge Y. Tetrahedron Lett. 2018; 59: 2426 5d Ghozlan SA. S, Abdelmoniem DM, Hassaneen HM, Abdelmoniem AM, Abdelhamid IA. J. Heterocycl. Chem. 2018; 55: 1798 5e Meng D, Andre P, Bateman TJ, Berger R, Chen Y.-H, Desai K, Dewnani S, Ellsworth K, Feng D, Geissler WM, Guo L, Hruza A, Jian T, Li H, Metzger J, Parker DL, Reichert P, Sherer EC, Smith CJ, Sonatore LM, Tschirret-Guth R, Wu J, Xu J, Zhang T, Campeau L.-C, Orr R, Poirier M, McCabe-Dunn J, Araki K, Nishimura T, Sakurada I, Hirabayashi T, Wood HB. Bioorg. Med. Chem. Lett. 2015; 25: 5437 6a Mousseau JJ, Bull JA, Ladd CL, Fortier A, Roman DS, Charette AB. J. Org. Chem. 2011; 76: 8243 6b Patnaik S, Dietz HC, Zheng W, Austin C, Marugan JJ. J. Org. Chem. 2009; 74: 8870 6c Supranovich VI, Vorob’ev AY, Borodkin GI, Gatilov VY, Shubin VG. Tetrahedron Lett. 2016; 57: 1093 6d Vorob’ev AY, Supranovich VI, Borodkin GI, Shubin VG. Beilstein J. Org. Chem. 2017; 13: 800 6e Ducray R, Boutron P, Didelot M, Germain H, Lach F, Lamorlette M, Legriffon A, Maudet M, Ménard M, Pasquet G, Renaud F, Simpson I, Young GL. Tetrahedron Lett. 2010; 51: 4755 6f Ding S, Yan Y, Jiao N. Chem. Commun. 2013; 49: 4250 6g Mousseau JJ, Fortier A, Charette AB. Org. Lett. 2010; 12: 516 6h Ravi C, Samanta S, Mohan D, Reddy N, Adimurthy S. Synthesis 2017; 49: 2513 6i Shi F, Wu C, Wang Q, Zhao J, Li P. Synthesis 2012; 44: 3033 6j Ling L, Chen J, Song J, Zhang Y, Li X, Song L, Shi F, Li Y, Wu C. Org. Biomol. Chem. 2013; 11: 3894 6k Motornov VA, Tabolin AA, Nelyubina YV, Nenajdenko VG, Ioffe SL. Org. Biomol. Chem. 2020; 18: 1436 6l Ravi C, Mohan DC, Reddy NN. K, Adimurthy S. RSC Adv. 2015; 5: 42961 6m Cao W, Zhang H, Huang Q, He D, Han J, Chen J, He W, Deng H, Shao M. Synthesis 2018; 50: 3731 7a Tamura Y, Ikeda M. Adv. Heterocycl. Chem. 1981; 29: 71 7b Harju K, Kylnlähti I, Paananen T, Polamo M, Nielsen J, Yli-Kauhaluoma J. J. Comb. Chem. 2006; 8: 344 7c Chen Z, Su M, Yu X, Wu J. Org. Biomol. Chem. 2009; 7: 4641 7d Yu X, Ye S, Wu J. Adv. Synth. Catal. 2010; 352: 2050 7e Chen Z, Wu J. Org. Lett. 2010; 12: 4856 8 Hoashi Y, Takai T, Kotani E, Koike T. Tetrahedron Lett. 2013; 54: 2199 9 Xie F, Qi Z, Li X. Angew. Chem. Int. Ed. 2013; 52: 11862 10 Tang H.-T, Zeng J.-H, Chen J.-J, Zhou Y.-B, Li R.-H, Zhan Z.-P. Org. Chem. Front. 2017; 4: 1513 11a Johns BA, Gudmundsson KS, Turner EM, Allen SH, Jung DK, Sexton CJ, Boyd FL, Peel MR. Tetrahedron 2003; 59: 9001 11b Gudmundsson KS, Johns BA, Allen SH. Bioorg. Med. Chem. Lett. 2008; 18: 1157 11c Gudmundsson KS, Johns BA, Wang Z, Turner EM, Allen SH, Freeman GA, Boyd FL. Jr, Sexton CJ, Selleseth DW, Moniri KR, Creech KL. Bioorg. Med. Chem. 2005; 13: 5346 11d Stevens KL, Jung DK. M, Alberti J, Badiang JG, Peckham GE, Veal JM, Cheung M, Harris PA, Chamberlain SD, Peel MR. Org. Lett. 2005; 7: 4753 12 6-Methyl-2,3-diphenylpyrazolo[1,5-a]pyridine (2c); Typical ProcedureA mixture of oxime 1c (60 mg, 0.2 mmol), PPh3 (79 mg, 0.3 mmol), I2 (76 mg, 0.3 mmol), imidazole (27 mg, 0.4 mmol), and THF (2.0 mL) was added under air to a high-pressure tube. The tube was sealed and the mixture was stirred at 30 °C for 40 min, then cooled to R.T., and filtered through a pad of silica gel that was subsequently washed with 1:1 EtOAc–PE (100 mL). The solvents were removed under reduced pressure, and the residue was purified by chromatography [silica gel, EtOAc–PE (1:20)] to give a white solid; yield: 29 mg (52%); mp 110.1 °C.1H NMR (500 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.62–7.57 (m, 2 H), 7.48 (d, J = 9.0 Hz, 1 H), 7.41–7.34 (m, 4 H), 7.32 (d, J = 6.1 Hz, 4 H), 6.98 (d, J = 9.1 Hz, 1 H), 2.36 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 150.3, 138.3, 133.4, 133.4, 129.9, 128.9, 128.7, 128.4, 128.0, 126.9, 126.5, 126.3, 122.1, 116.6, 109.9, 18.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H16N2: 285.1392; found: 285.1388. 13a Appel R. Angew. Chem. Int. Ed. 1975; 14: 801 13b Desmaris L, Percina N, Cottier L, Sinou D. Tetrahedron Lett. 2003; 44: 7589 13c Baughman TW, Sworen JC, Wagener KB. Tetrahedron 2004; 60: 10943 13d Årstad E, Barrett AG. M, Hopkins BT, Köbberling J. Org. Lett. 2002; 4: 1975 Supplementary Material Supplementary Material Supporting Information
