Metal-Free Directed C–H Borylation of Indoles at the Sterically Congested C2 Position

Abstract

During the past few decades, transition metal-catalyzed C–H borylation has been one of the most notable advances in synthetic chemistry and has been widely employed in the preparation of organoboron reagents. Due to economic and heavy-metal-residue concerns, there is significant interest in the development of metal-free processes to mimic metallic systems. Here, we disclose a highly efficient metal-free approach for the directed C–H borylation of C3-substituted indoles at the sterically congested C2 position that uses the inexpensive boron reagent BBr₃. Compared with the conventional methods using transition metals, this practical protocol provides an ideal pathway to obtain numerous C2-borylated indoles. The benefit of the synthesis of complex molecules and their applicability to medicinal chemistry is also shown through the construction of key intermediates of (–)-goniomitine and bazedoxifene and by a total synthesis of the drug fluvastatin. Mechanistic experiments demonstrate the site selectivity of this C–H borylation process.

Key words

C–H bond activation - borylation - indoles - BBr₃ - site selectivity - metal-free reaction

Publication History

Received: 22 May 2023

Accepted after revision: 10 July 2023

Accepted Manuscript online:
10 July 2023

Article published online:
18 September 2023

• References and Notes

• 1a Indoles, Part 4: The Monoterpenoid Indole Alkaloids: Saxton J. E. The Chemistry ofHeterocyclic Compounds. Vol. 25 Wiley; Chichester: 1983
• 1b Indoles, The Monoterpenoid Indole Alkaloids: Supplement to Part 4 . Saxton JE. The Chemistry of Heterocyclic Compounds, Vol. 25; Wiley; Chichester: 1994
• 1c Sundberg RJ. Indoles . Academic; London: 1996
• 1d Kawasaki T, Higuchi K. Nat. Prod. Rep. 2005; 22: 761
• 1e Miller KA, Williams RM. Chem. Soc. Rev. 2009; 38: 3160
• 1f Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489
• 1g Xu Z, Wang Q, Zhu J. Chem. Soc. Rev. 2018; 47: 7882
• 1h Nagarajua K, Ma D. Chem. Soc. Rev. 2018; 47: 8018
• 2a Robinson B. Chem. Rev. 1969; 69: 227
• 2b Cacchi S, Fabrizi G. Chem. Rev. 2005; 105: 2873
• 2c Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 2d Cacchi S, Fabrizi G. Chem. Rev. 2011; 111: PR215
• 2e Shi Z, Glorius F. Angew. Chem. Int. Ed. 2012; 51: 9220
• 2f Bartoli G, Dalpozzo R, Nardi M. Chem. Soc. Rev. 2014; 43: 4728
• 3a Bandini M, Eichholzer A. Angew. Chem. Int. Ed. 2009; 48: 9608
• 3b Joucla L, Djakovitch L. Adv. Synth. Catal. 2009; 351: 673
• 3c Ping L, Chung DS, Bouffard J, Lee S.-g. Chem. Soc. Rev. 2017; 46: 4299
• 3d Leitch JA, Bhonoah Y, Frost CG. ACS Catal. 2017; 7: 5618
• 3e Prabagar B, Yang Y, Shi Z. Chem. Soc. Rev. 2021; 50: 11249
• 4a Hall DG. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed., Vols. 1 and 2. Wiley–VCH; Weinheim: 2011
• 4b Suzuki A. Angew. Chem. Int. Ed. 2011; 50: 6722
• 4c Neeve EC, Geier SJ, Mkhalid IA. I, Westcott SA, Marder TB. Chem. Rev. 2016; 116: 9091
• 4d Collins BS. L, Wilson CM, Myers EL, Aggarwal VK. Angew. Chem. Int. Ed. 2017; 56: 11700
• 4e Cuenca AB, Shishido R, Ito H, Fernández E. Chem. Soc. Rev. 2017; 46: 415
• 4f Wang M, Shi Z. Chem. Rev. 2020; 120: 7348
• 5a Paul S, Chotana GA, Holmes D, Reichle RC, Maleczka RE, Smith MR. J. Am. Chem. Soc. 2006; 128: 15552
• 5b Stahl T, Müther K, Ohki Y, Tatsumi K, Oestreich M. J. Am. Chem. Soc. 2013; 135: 10978
• 5c Robbins DW, Boebel TA, Hartwig JF. J. Am. Chem. Soc. 2010; 132: 4068
• 5d Huang J, Macdonald SJ. F, Harrity JP. A. Chem. Commun. 2010; 46: 8770
• 5e Feng Y, Holte D, Zoller J, Umemiya S, Simke LR, Baran PS. J. Am. Chem. Soc. 2015; 137: 10160
• 5f Yuan K, Wang S. Org. Lett. 2017; 19: 1462
• 5g Lv J, Zhao B, Liu L, Han Y, Yuan Y, Shi Z. Adv. Synth. Catal. 2018; 360: 4054
• 5h Tian Y.-M, Guo X.-N, Wu Z, Friedrich A, Westcott SA, Braunschweig H, Radius U, Marder TB. J. Am. Chem. Soc. 2020; 142: 13136
• 6 Nicolaou KC, Dalby SM, Majumder U. J. Am. Chem. Soc. 2008; 130: 14942
• 7 Wooleb H, Wooleb A, van der Schaaf PA, Kolly R, End N. WO 2003018555 2003
• 8a Ishiyama T, Murata M, Miyaura N. J. Org. Chem. 1995; 60: 7508
• 8b Ishiyama T, Miyaura N. Chem. Rec. 2004; 3: 271
• 8c Pilarski LT, Szabó KJ. Angew. Chem. Int. Ed. 2011; 50: 8230
• 8d Kubota K, Iwamoto H, Ito H. Org. Biomol. Chem. 2017; 15: 285
• 9 Zhang Y, Lu BZ, Li G, Rodriguez S, Tan J, Wei H, Liu J, Roschangar F, Ding F, Zhao W, Qu B, Reeves D, Grinberg N, Lee H, Heckmann G, Niemeier O, Brenner M, Tsantrizos Y, Beaulieu PL, Hossain A, Yee N, Farina V, Senanayake CH. Org. Lett. 2014; 16: 4558
• 10a Mkhalid IA. I, Barnard JH, Marder TB, Murphy JM, Hartwig JF. Chem. Rev. 2010; 110: 890
• 10b Hartwig JF. Chem. Soc. Rev. 2011; 40: 1992
• 10c Hartwig JF. Acc. Chem. Res. 2012; 45: 864
• 10d Ros A, Fernández R, Lassaletta JM. Chem. Soc. Rev. 2014; 43: 3229
• 11 Jia Y, Zhou S. Org. Lett. 2014; 16: 3416
• 12 Han S, Movassaghi M. J. Am. Chem. Soc. 2011; 133: 10768
• 13a Sun C.-L, Shi Z.-J. Chem. Rev. 2014; 114: 9219
• 13b Li Y, Wu X.-F. Angew. Chem. Int. Ed. 2020; 59: 1770
• 13c Ingleson MJ. Sci. China Chem. 2019; 62: 1547
• 13d Zhong Q, Qin S, Yin Y, Hu J, Zhang H. Angew. Chem. Int. Ed. 2018; 57: 14891
• 14a Legare M.-A, Courtemanche M.-A, Rochette E, Fontaine F.-G. Science 2015; 349: 513
• 14b Lavergne JL, Jayaraman A, Castro LC. M, Rochette É, Fontaine F.-G. J. Am. Chem. Soc. 2017; 139: 14714
• 14c Rochette É, Desrosiers V, Soltani Y, Fontaine F.-G. J. Am. Chem. Soc. 2019; 141: 12305
• 15a Lv J, Chen X, Xue X.-S, Zhao B, Liang Y, Wang M, Jin L, Yuan Y, Han Y, Zhao Y, Lu Y, Zhao J, Sun W.-Y, Houk KN, Shi Z. Nature 2019; 575: 336
• 15b Wang Z.-J, Chen X, Wu L, Wong JJ, Liang Y, Zhao Y, Houk KN, Shi Z. Angew. Chem. Int. Ed. 2021; 60: 8500
• 16 Iqbal SA, Cid J, Procter RJ, Uzelac M, Yuan K, Ingleson MJ. Angew. Chem. Int. Ed. 2019; 58: 15381
• 17a Lv J, Zhao B, Han Y, Yuan Y, Shi Z. Chin. Chem. Lett. 2021; 32: 691
• 17b Wang D, Xue X.-S, Houk KN, Shi Z. Angew. Chem. Int. Ed. 2018; 57: 16861
• 18 CCDC 2053493 and 2053494 contains the supplementary crystallographic data for compounds 1b and 1c. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 19 Brown H, Rao BC. J. Org. Chem. 1957; 22: 1137
• 20 Zhang F, Spring DR. Chem. Soc. Rev. 2014; 43: 6906
• 21 Lv J, Zhao B, Yuan Y, Han Y, Shi Z. Nat. Commun. 2020; 11: 1316
• 22 Shang Y, Jonnada K, Yedage SL, Tu H, Zhang X, Lou X, Huang S, Su W. Chem. Commun. 2019; 55: 9547
• 23 Fuenfschiling PC, Hoehn P, Muetz J.-P. Org. Process Res. Dev. 2007; 11: 13
• 24 1-(1-Adamantylcarbonyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1c); Typical Procedure A flame-dried 25-mL Schlenk tube was flushed with argon and then charged with indole 1a (58.6 mg, 0.2 mmol, 1.0 equiv) and dry DCM (1 mL, 0.2 M). A 1.0 M solution of BBr₃ in DCM, (0.22 mL, 1.1 equiv) was added slowly under argon. Pyridine (2.0 mmol) and pinacol (0.30 mmol) were then added sequentially, and the resulting mixture was stirred at rt for another 2 h until the reaction was complete (TLC). The solvent was removed directly under vacuum, and the crude product was purified by flash column chromatography [silica gel, EtOAc–PE (1:20)] to give a white solid; yield: 64.9 mg (77%). ATR-FTIR: 3023, 2976, 1685, 1352, 952, 728 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.3 Hz, 1 H), 7.52–7.50 (m, 1 H), 7.28–7.24 (m, 1 H), 7.19–7.15 (m, 1 H), 2.42 (s, 3 H), 2.16 (d, J = 3.0 Hz, 6 H), 2.10–2.08 (m, 3 H), 1.76–1.74 (m, 6 H), 1.36 (s, 12 H). ¹³C NMR (126 MHz, CDCl₃): δ = 183.2, 136.4, 132.5, 125.9, 124.1, 121.6, 119.7, 113.8, 83.1, 44.1, 38.0, 36.3, 28.0, 25.1, 9.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₃₅BNO₃: 420.2705; found: 420.2708.