Anti-Markovnikov Hydroazidation of Activated Olefins via Organic Photoredox Catalysis

Published as part of the Cluster ‘9th Pacific Symposium on Radical Chemistry’

Abstract

Organic azides serve as synthetically useful surrogates for primary amines, a functional group which is ubiquitous in bioactive and medicinally relevant molecules. Historically, the formal hydroazidation of simple activated olefins and styrenes has proven difficult due to the inherent propensity of these compounds to oligomerize. Herein is disclosed a method for the anti-Markovnikov hydroazidation of activated olefins, catalyzed by an organic acridinium salt under irradiation from blue LEDs. This method is applicable to a variety of substituted and terminal styrenes and several vinyl ethers, yielding synthetically versatile hydroazidation products in moderate to excellent yield.

Key words

photooxidation - alkenes - azides - radicals - regioselectivity

• References and Notes

• 1 Liang L, Astruc D. Coord. Chem. Rev. 2011; 255: 2933
• 2 Bräse S, Gil C, Knepper K, Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188
• 3 Meldal M, Tornøe CW. Chem. Rev. 2008; 108: 2952
• 4 Aldhoun M, Massi A, Dondoni A. J. Org. Chem. 2008; 73: 9565
• 5 Schilling CI, Jung N, Biskup M, Schepers U, Bräse S. Chem. Soc. Rev. 2011; 40: 4840
• 6 Breton GW, Daus KA, Kropp PJ. J. Org. Chem. 1992; 57: 6646
• 7 Waser J, Nambu H, Carreira EM. J. Am. Chem. Soc. 2005; 127: 8294
• 8 Tsuchimochi I, Kitamura Y, Aoyama H, Akai S, Nakai K, Yoshimitsu T. Chem. Commun. 2018; 54: 9893
• 9 Hassner A, Boerwinkle F. J. Am. Chem. Soc. 1968; 90: 216
• 10 Biermann U, Linker U, Metzger JO. Eur. J. Lipid Sci. Technol. 2013; 115: 94
• 11 Zhang P, Sun W, Li G, Hong L, Wang R. Chem. Commun. 2015; 51: 12293
• 12 Wang J, Yu W. Chem. Eur. J. 2019; 25: 3510
• 13 Lonca GH, Ong DY, Tran TM. H, Tejo C, Chiba S, Gagosz F. Angew. Chem. Int. Ed. 2017; 56: 11440
• 14 Li H, Shen S.-J, Zhu C.-L, Xu H. J. Am. Chem. Soc. 2019; 141: 9415
• 15 Shulgin A, Shulgin A. PIHKAL: A Chemical Love Story . Transform Press; Berkeley: 1991
• 16 Romero NA, Nicewicz DA. J. Am. Chem. Soc. 2014; 136: 17024
• 17 Margrey KA, Nicewicz DA. Acc. Chem. Res. 2016; 49: 1997
• 18 Nicewicz D, Hamilton D. Synlett 2014; 25: 1191
• 19 Nguyen TM, Nicewicz DA. J. Am. Chem. Soc. 2013; 135: 9588
• 20 Perkowski AJ, Nicewicz DA. J. Am. Chem. Soc. 2013; 135: 10334
• 21 Wu F, Wang L, Chen J, Nicewicz DA, Huang Y. Angew. Chem. Int. Ed. 2018; 57: 2174
• 22 Brede O, David F, Steenken S. J. Chem. Soc., Perkin Trans. 2 1995; 23
• 23 Johnston LJ, Schepp NP. Pure Appl. Chem. 1995; 67: 71
• 24 Workentin MS, Schepp NP, Johnston LJ, Wayner DD. M. J. Am. Chem. Soc. 1994; 116: 1141
• 25 Johnston LJ, Schepp NP. J. Am. Chem. Soc. 1993; 115: 6564
• 26 General Procedure (CAUTION: use care when handling TMS-N₃): A flame-dried 2-dram borosilicate vial (purchased from Fisher Scientific, catalogue # 03-339-22D), equipped with a stir bar, was charged with 3,6-di-tert-butyl-9-mesityl-10-phenylacridin-10-ium tetrafluoroborate (0.01 equiv, 0.01 mmol) and 2,5,6-triisopropylthiophenol (0.10 mmol, 0.20 equiv). For solid/non-volatile substrates, the substrate (0.50 mmol) was then added. 2,2,2-Trifluoroethanol (5.0 mL) was added and the vials were capped tightly with a Teflon-lined phenolic resin septum cap (purchased through VWR international, Microliter Product # 15-0060K). The reaction mixture was then sparged by bubbling with nitrogen or argon for 5 minutes. Trimethylsilylazide (0.625 mmol, 1.25 equiv) was added by using a microliter syringe. Prior to irradiation, vials were sealed with Teflon tape and electrical tape to ensure maximal oxygen exclusion. The reaction vial was then placed into the reactor and irradiated for 18 hours unless otherwise noted. Following irradiation, the reaction mixture was concentrated under reduced pressure and the desired products were isolated by flash column chromatography (see the Supporting Information substrate/product details for solvent information). Unless otherwise noted, all reaction yields are reported as the average of two separate trials (including chromatography). Example products 4-(2-Azidopropyl)-1,1′-biphenyl (11): Following irradiation, the crude reaction mixture was concentrated under reduced pressure and dry-loaded onto silica gel. The desired product was isolated as a pale-yellow oil following column chromatography (100% hexane to 1% EtOAc/hexane). Yield: 97% (n = 2). ¹H NMR (600 MHz, CDCl₃): δ = 7.63 (dd, J = 26.1, 7.7 Hz, 4 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 3.77 (h, J = 6.6 Hz, 1 H), 2.92 (dd, J = 13.7, 7.3 Hz, 1 H), 2.82 (dd, J = 13.7, 6.4 Hz, 1 H), 1.35 (d, J = 6.5 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 140.90, 139.73, 136.91, 129.79, 128.84, 127.29, 127.10, 59.04, 42.24, 19.22. HRMS (APCI, positive mode): m/z [M + H, – N₂] calcd: 210.1277; found: 210.1278. 1-(2-Azidopropyl)-2-chlorobenzene (14): Following irradiation, the crude reaction mixture was concentrated under reduced pressure and dry-loaded onto silica gel. The desired product was isolated as a pale-yellow oil following column chromatography (100% hexane to 3% EtOAc/hexane). Yield: 64% (n = 2). ¹H NMR (600 MHz, CDCl₃): δ = 7.40 (dd, J = 7.2, 1.9 Hz, 1 H), 7.28 (dd, J = 7.1, 2.3 Hz, 1 H), 7.25–7.19 (m, 2 H), 3.85 (h, J = 6.7 Hz, 1 H), 3.00–2.84 (m, 2 H), 1.33 (d, J = 6.5 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 135.70, 134.32, 131.85, 129.74, 128.42, 126.95, 57.57, 40.40, 19.43. MS (EI): m/z [M]⁺ calcd: 195.056; found: 195.05. 1-(2-Azidopropyl)-4-phenoxybenzene (23) Following irradiation, the crude reaction mixture was concentrated under reduced pressure and dry-loaded onto silica gel. The desired product was isolated as a clear oil following purification by column chromatography (100% hexane to 1% EtOAc/hexane). Yield: 91% (n = 2). ¹H NMR (600 MHz, CDCl₃): δ = 7.38–7.30 (m, 2 H), 7.16 (d, J = 8.5 Hz, 2 H), 7.13–7.06 (m, 1 H), 7.01 (dd, J = 8.7, 1.1 Hz, 2 H), 6.96 (d, J = 8.5 Hz, 2 H), 3.77–3.47 (m, 1 H), 2.80 (dd, J = 13.8, 7.4 Hz, 1 H), 2.72 (dd, J = 13.8, 6.3 Hz, 1 H), 1.28 (d, J = 6.5 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 157.31, 156.03, 132.62, 130.57, 129.72, 123.18, 118.96, 118.78, 59.14, 41.87, 19.16. HRMS (APCI, positive mode): m/z [M + H, – N₂] calcd: 226.1226; found: 226.1227.