Intermolecular Photocatalytic C–H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides

Elizabeth C. Swift; Theresa M. Williams; Corey R. J. Stephenson

doi:10.1055/s-0035-1561320

Synlett, Inhaltsverzeichnis

Synlett 2016; 27(05): 754-758
DOI: 10.1055/s-0035-1561320

cluster

Intermolecular Photocatalytic C–H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides

Elizabeth C. Swift

Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA eMail: crjsteph@umich.edu

,

Theresa M. Williams

Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA eMail: crjsteph@umich.edu

,

Corey R. J. Stephenson*

Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA eMail: crjsteph@umich.edu

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Abstract

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Abstract

The coupling of tertiary alkyl halides with electron-rich arenes is promoted by visible-light photoredox catalysis. Tris[2-phenylpyridinato-C ²,N]iridium(III) [Ir(ppy)₃] was the optimal catalyst, enabling direct reduction of the halide from the excited state, and thereby eliminating the requirement for a stoichiometric electron donor. High yields were obtained when the aromatic component was used in excess, although equimolar amounts afforded only slightly diminished yields. The reaction tolerates a number of functional groups, including allyl, ester, amide, or carbamate. The efficiency of this reaction has been improved through demonstration of scale-up in flow, and a new substituted Ir(ppy)₃ derivative was isolated and characterized.

Key words

photoredox - catalysis - alkylation - C–H functionalization - quaternary carbon - flow reaction

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Referenzen

References and Notes

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23 Diethyl 1H-Indol-2-yl(methyl)malonate (7); Typical Procedure A 7 mL vial equipped with magnetic stirrer bar was charged with diethyl-2-bromo-2-methylmalonate (1.0 equiv, 0.40 mmol, 0.10g), 2,6-lutidine (1.0 equiv, 0.40 mmol, 43 mg), Ir(ppy)₃ (1 mol%, 4.0 µmol, 2.6 mg), and indole (5.0 equiv, 2.0 mmol, 0.23 g). Anhyd MeCN (0.5 mL, 0.8 M) was added, and the mixture was sparged with N₂ for 15 min. It was then surrounded by a string of 1 W blue LEDs and stirred under N₂ at r.t. for 24 h. The resulting mixture was diluted with EtOAc and extracted with H₂O. The aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0–5% EtOAc–hexane) to give a white solid; yield: 97 mg (83%); R_f = 0.36 (10% EtOAc–hexane). IR (neat): 3372, 2972, 1732, 1707, 1454, 1263 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.08 (s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.1 Hz, 1 H), 7.09 (t, J = 7.1 Hz, 1 H), 6.47 (s, 1 H), 4.27–4.23 (m, 4 H), 1.95 (s, 3 H), 1.28 (t, J = 7.1 Hz, 6 H). ¹³C NMR (176 MHz, CDCl₃): δ = 170.4, 136.2, 134.7, 127.5, 122.2, 120.5, 119.7, 111.0, 101.4, 62.2, 54.3, 21.2, 14.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₀NO₄: 290.1387; found: 290.1386. Dimethyl (4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)(1H-indol-2-yl)malonate (14) Yellow oil; yield: 0.15 g (89%); R_f = 0.6 (20% EtOAc–hexane). IR (neat): 3426, 2951, 2356, 1729, 1456, 1254 cm^–1. ¹H NMR (700 MHz, CDCl₃): δ = 9.60 (s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 6.44 (s, 1 H), 3.78 (s, 6 H), 3.57 (t, J = 6.3 Hz, 2 H), 2.45–2.43 (m, 2 H), 1.54 (quintet, J = 7.1 Hz, 2 H), 1.29–1.25 (m, 2 H), 0.87 (s, 9 H), 0.02 (s, 6 H). ¹³C NMR (176 MHz, CDCl₃): δ = 170.6, 135.8, 133.9, 127.7, 122.1, 120.5, 119.9, 111.3, 101.3, 62.6, 58.5, 53.2, 36.5, 32.8, 26.0, 21.1, 18.3, –5.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₆NO₅Si: 434.2357; found: 434.2355. Methyl 3-(1H-Indol-2-yl)-2-oxooxepane-3-carboxylate (24) Purple oil; yield: 40 mg (35%); R_f = 0.25 (30% EtOAc–hexane). IR (neat): 3317, 2943, 2360, 1738, 1696, 1454, 1224 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.72 (s, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.38 (dd, J = 8.2, 0.7 Hz, 1 H), 7.20 (td, J = 7.6, 1.1 Hz, 1 H), 7.11 (td, J = 7.5, 0.8 Hz, 1 H), 6.50 (d, J = 1.3 Hz, 1 H), 4.19 (ddd, J = 12.7, 7.6, 1.9 Hz, 1 H), 4.08 (ddd, J = 12.7, 8.1, 1.8 Hz, 1 H), 3.78 (s, 3 H), 2.72 (dt, J = 14.7, 5.8 Hz, 1 H), 2.38 (dt, J = 14.7, 6.6 Hz, 1 H), 2.06 (quintet, J = 6.1 Hz, 2 H), 1.94–1.88 (m, 1 H), 1.85–1.80 (m, 1 H). ¹³C NMR (176 MHz, CDCl₃): δ = 171.6, 169.6, 136.7, 133.6, 127.7, 122.8, 120.8, 120.2, 111.4, 102.3, 69.5, 59.8, 53.5, 31.3, 28.1, 24.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₈NO₄: 288.1230; found: 288.1299. Diethyl Methyl(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)malonate (29) Brown oil; yield: 0.11 g (80%); R_f = 0.5 (20% EtOAc–hexane). IR (neat): 2982, 1724, 1648, 1597, 1558, 1228 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.21 (m, 2 H), 6.08 (t, J = 6.9 Hz, 1 H), 4.24–4.13 (m, 4 H), 3.47 (s, 3 H), 1.74 (s, 3 H), 1.20 (t, J = 7.1 Hz, 6 H). ¹³C NMR (176 MHz, CDCl₃): δ = 170.7, 161.2, 137.5, 135.4, 131.7, 105.0, 61.6, 57.4, 37.8, 20.8, 14.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₉NNaO₅: 304.1155; found: 304.1155.
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Supporting Information