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Synlett 2016; 27(05): 724-730
DOI: 10.1055/s-0035-1560770
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© Georg Thieme Verlag Stuttgart · New York

Intramolecular Radical Carboaminoxylation of Aryl Amines

Marcel Hartmann
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany   Email: studer@uni-muenster.de
,
Carolin Gerleve
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany   Email: studer@uni-muenster.de
,
Armido Studer*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany   Email: studer@uni-muenster.de
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Publication History

Received: 31 August 2015

Accepted after revision: 28 September 2015

Publication Date:
30 October 2015 (online)

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Abstract

Cyclizing radical carboaminoxylation of various aryl amines is presented. The aryl diazonium salts in situ generated from the corresponding aryl amines are reduced by tetra-n-butylammonium iodide (TBAI) to give the corresponding aryl radicals. These aryl radicals undergo 5-exo and 6-exo cyclization. Subsequent trapping with TEMPO or various other nitroxides provides the corresponding cyclized carboaminoxylated products in moderate to very good yields.

Key words

carboaminoxylation - in situ diazotation - aryl radicals - radical cyclization - nitroxides

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560770.
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  • References and Notes

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  • 11 Indirect proof of TEMPO+I– salt formation was obtained by identifying small amounts of 3-methylbutanal derived from oxidation of isoamyl alcohol.General Procedure for the CarboaminoxylationTo a flame-dried Schlenk tube containing the amine (0.250 mmol, 1.0 equiv), isoamyl nitrite (50.0 μL, 0.375 mmol, 1.5 equiv), methanesulfonic acid (18.0 μL, 0.275 mmol, 1.1 equiv), and nitroxide (0.500 mmol, 2.0 equiv) in MeCN (0.125 M), TBAI (139 mg, 0.375 mmol, 1.5 equiv, 0.5 M in MeCN) was added via syringe pump over 1 h at r.t. After completion, most of the solvent was removed in vacuo, the residue was adsorbed on silica gel and afterwards purified by flash column chromatography.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidine (2a)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2a as yellowish solid (64 mg, 0.22 mmol, 89%); mp 55 °C. 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.20–7.13 (m, 1 H, CHarom), 7.12–6.99 (m, 1 H, CHarom), 6.84–6.63 (m, 2 H, CHarom), 4.55 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.31 (dd, J = 9.0, 6.2 Hz, 1 H, OCHα Hβ ), 3.91 (dd, J = 8.6, 6.5 Hz, 1 H, OCH2CH), 3.81 (t, J = 8.2 Hz, 1 H, NOCHα Hβ), 3.68–3.55 (m, 1 H, NOCHα Hβ ), 1.44–0.95 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 160.3 (C), 128.6 (CH), 128.1 (C), 125.2 (CH), 120.4 (CH), 109.6 (CH), 78.9 (NOCH2), 74.6 (OCH2), 60.1 (2 × C), 41.9 (CH), 39.8 (2 × CH2), 33.4 (CH3), 33.2 (CH3), 20.3 (CH3), 20.2 (CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C18H27NO2H [M + H]+: 290.2115; found: 290.2127. IR (neat): 2973 (m), 2930 (s), 2882 (m), 1598 (w), 1482 (s), 1374 (m), 1232 (m), 1133 (w), 1045 (m), 970 (m), 931 (w), 859 (w), 750 (s) cm–1.1-[(5-Phenyl-2,3-dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidine (2b)Following the general procedure with 4-(allyloxy)-[1,1′-biphenyl]-3-amine (1b; 56 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2b as orange solid (61 mg, 0.17 mmol, 67%); mp 91 °C. 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm) = 7.57–7.48 (m, 3 H, CHarom), 7.40 (qd, J = 7.8, 2.1 Hz, 3 H, CHarom), 7.34–7.27 (m, 1 H, CHarom), 6.87 (d, J = 8.3 Hz, 1 H, CHarom), 4.71 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.46 (dd, J = 9.0, 6.3 Hz, 1 H, OCHα Hβ ), 4.05 (dd, J = 8.6, 6.5 Hz, 1 H, OCH2CH), 3.95 (t, J = 8.3 Hz, 1 H, NOCHα Hβ), 3.81–3.73 (m, 1 H, NOCHα Hβ ), 1.50–1.08 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (101 MHz, CDCl3, 300 K): δ = 159.9 (C), 141.4 (C), 133.9 (C), 128.8 (C), 128.7 (2 × CH), 127.6 (CH), 126.8 (2 × CH), 126.5 (CH), 124.0 (CH), 109.6 (CH), 78.7 (NOCH2), 74.9 (OCH2), 60.0 (2 × C), 41.8 (CH), 39.7 (2 × C), 33.3 (CH3), 33.1 (CH3), 20.2 (CH3), 20.1 (CH3), 17.1 (CH2) ppm. ESI-HRMS: m/z calcd for C24H31NO2H [M + H]+: 366.3428; found: 366.2418. IR (neat): 2929 (s), 2362 (w), 1609 (w), 1476 (s), 1361 (m), 1231 (s), 1131 (m), 1043 (m), 956 (m), 886 (w), 819 (w), 761 (m), 699 (m) cm–1.2,2,6,6-Tetramethyl-1-[(5-methyl-2,3-dihydrobenzofuran-3-yl)methoxy]piperidine (2c)Following general procedure with 2-(allyloxy)-5-methylaniline (1c; 41 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2c as yellowish solid (47 mg, 0.15 mmol, 62%); mp 64 °C. 1H NMR (400 MHz, CDCl3, 300 K): δ = 7.04 (s, 1 H, CHarom), 6.92 (d, J = 8.1 Hz, 1 H, CHarom), 6.68 (d, J = 8.1 Hz, 1 H, CHarom), 4.61 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.37 (dd, J = 9.0, 6.3 Hz, 1 H, OCHα Hβ ), 3.96 (dd, J = 8.5, 6.3 Hz, 1 H, NOCHα Hβ), 3.86 (t, J = 8.5 Hz, 1 H, NOCHα Hβ ), 3.70–3.62 (m, 1 H, CH), 2.27 (s, 3 H, CH3), 1.48–1.02 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (101 MHz, CDCl3, 300 K): δ = 158.2 (C), 129.6 (C), 128.9 (CH), 128.1 (C), 125.8 (CH), 109.1 (CH), 79.0 (OCH2), 74.8 (OCH2), 60.1 (2 × C), 42.0 (CH), 39.8 (2 × CH2), 33.4 (CH3), 33.2 (CH3), 20.9 (CH3), 20.3 (CH3), 20.1 (CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C19H29NO2H [M + H]+: 304.2271; found: 304.2275. IR (neat): 2974 (m), 2931 (s), 2880 (m), 1619 (w), 1492 (s), 1374 (m), 1245 (m), 1210 (m), 1133 (m), 1045 (m), 972 (m), 877 (w), 809 (m), 709 (w) cm–1. Anal. Calcd for C19H29NO2H: C, 75.21; H, 9.63; N, 4.62. Found: C, 75.15; H, 9.80; N, 4.59.1-(3-{[(2,2,6,6-Tetramethylpiperidin-1-yl)oxy]methyl}-2,3-dihydrobenzofuran-5-yl)ethan-1-one (2d)Following the general procedure with 1-[4-(allyloxy)-3-aminophenyl]ethan-1-one (1d; 48 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 25:1 → 10:1 mixture of pentane–EtOAc as an eluent to provide analytically pure product 2d as yellow oil (73 mg, 0.22 mmol, 88%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.91 (t, J = 1.4 Hz, 1 H, CHarom), 7.86–7.81 (m, 1 H, CHarom), 6.81 (d, J = 8.4 Hz, 1 H, CHarom), 4.72 (t, J = 9.2 Hz, 1 H, OCHα Hβ), 4.48 (dd, J = 9.2, 6.1 Hz, 1 H, OCHα Hβ ), 3.98 (dd, J = 8.6, 6.8 Hz, 1 H, NOCHα Hβ), 3.89 (dd, J = 8.6, 7.5 Hz, 1 H, NOCHα Hβ ), 3.77–3.68 (m, 1 H, CH), 2.54 (s, 3 H, CH3), 1.52–1.02 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 169.7 (C), 164.6 (C), 130.9 (CH), 130.7 (C), 129.0 (C), 126.1 (CH), 109.3 (CH), 78.5 (OCH2), 75.7 (OCH2), 60.1 (2 × C), 41.2 (CH), 39.8 (2 × CH2), 33.3 (CH3), 33.2 (CH3), 26.6 (CH3), 20.3 (CH3), 20.2 (CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C20H29NO3H [M + H]+: 332.2220; found: 332.2214. IR (neat): 2974 (m), 2932 (m), 2363 (w), 1677 (s), 1607 (m), 1489 (m), 1435 (w), 1359 (m), 1255 (s), 1131 (w), 1046 (w), 958 (m), 888 (w), 823 (w), 720 (w) cm–1.1-[(7-Bromo-2,3-dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidine (2e)Following the general procedure with 2-(allyloxy)-3-bromoaniline (1e; 57 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2e as yellow solid (78 mg, 0.21 mmol, 85%); mp 64 °C. 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.28 (d, J = 8.0 Hz, 1 H, CHarom), 7.18 (d, J = 7.3 Hz, 1 H, CHarom), 6.76–6.71 (m, 1 H, CHarom), 4.72 (t, J = 9.1 Hz, 1 H, OCHα Hβ), 4.48 (dd, J = 9.1, 6.1 Hz, 1 H, OCHα Hβ ), 3.99–3.85 (m, 2 H, NOCH2), 3.85–3,73 (m, 1 H, CH), 1.52–1.01 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 157.5 (C), 131.7 (CH), 129.7 (C), 124.3 (CH), 121.9 (CH), 102.8 (C), 78.5 (OCH2), 74.9 (OCH2), 60.1 (2 x C), 42.8 (CH), 39.8 (2 x CH2), 33.4 (CH3), 33.2 (CH3), 20.3 (CH3), 20.2 (CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C18H26BrNO2H [M + H]+: 368.1220; found: 368.1228. IR (neat): 2973 (m), 2930 (s), 2876 (m), 1603 (w), 1447 (s), 1374 (m), 1323 (w), 1262 (m), 1217 (m), 1133 (m), 1047 (s), 969 (m), 875 (w), 844 (w), 768 (m), 733 (m), 622 (w), 552 (w) cm–1.2,2,6,6-Tetramethyl-1-[(3-methyl-2,3-dihydrobenzofuran-3-yl)methoxy]piperidine (2f)Following the general procedure with 2-[(2-methylallyl)oxy]aniline (1f; 41 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2f as yellowish oil (50 mg, 0.16 mmol, 66%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.20–7.09 (m, 2 H, 2 × CHarom), 6.90–6.76 (m, 2 H, 2 × CHarom), 4.54 (d, J = 8.7 Hz, 1 H, OCHα Hβ), 4.15 (d, J = 8.7 Hz, 1 H, OCHα Hβ ), 3.81 (s, 2 H, NOCH2), 1.51–0.98 (m, 21 H, 3 × CH2, 5 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 159.9 (C), 133.2 (C), 128.5 (CH), 123.8 (CH), 120.4 (CH), 109.7 (CH), 81.8 (OCH2), 80.9 (OCH2), 60.3 (2 × C), 46.7 (C), 40.0 (2 × CH2), 33.4 (CH3), 33.1 (CH3), 22.9 (CH3), 20.5 (CH3), 20.3 (CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C19H29NO2H [M + H]+: 304.2271; found: 304.2286. IR (neat): 2972 (m), 2929 (s), 2875 (m), 2245 (w), 1598 (m), 1481 (s), 1376 (m), 1232 (m), 1193 (m), 1133 (m), 1048 (m), 981 (m), 926 (m), 875 (w), 834 (m), 795 (w), 747 (s), 708 (w), 623 (w) cm–1.1-[(2-Allyl-2,3-dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidine (2g)Following the general procedure with 2-(hexa-1,5-dien-3-yloxy)aniline (1g; 47 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2g as yellowish oil (63 mg, 0.19 mmol, 77%) with a dr of trans/cis = 10:1. Analytical data are given for the major diastereoisomer: 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.24 – 7.09 (m, 2 H, 2 × CHarom), 6.91–6.74 (m, 2 H, 2 × CHarom), 5.99–5.79 (m, 1 H, CH2=CH), 5.27–5.11 (m, 2 H, CH=CH2 ), 4.63 (q, J = 6.4 Hz, 1 H, OCH), 4.02 (dd, J = 8.5, 6.2 Hz, 1 H, NOCHα Hβ), 3.89 (t, J = 8.5 Hz, 1 H, NOCHα Hβ ), 3.47–3.40 (m, 1 H, NOCH2CH), 2.58 (t, J = 6.4 Hz, OCHCH2 ), 1.53–1.02 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 159.7 (C), 133.8 (CH), 128.6 (CH), 127.9 (C), 125.1 (CH), 120.3 (CH), 118.0 (CH2), 109.6 (CH), 86.3 (OCH), 79.0 (OCH2), 60.1 (2 × C), 46.6 (CH), 40.1 (CH2), 39.8 (2 × CH2), 33.4 (CH3), 33.2 (CH3), 20.4 (2 × CH3), 17.2 (CH2) ppm. ESI-HRMS: m/z calcd for C21H31NO2H [M + H]+: 330.2428; found: 330.2428. IR (neat): 3077 (w), 2975 (m), 2930 (s), 1597 (m), 1479 (s), 1374 (m), 1238 (s), 1179 (w), 1133 (m), 1044 (m), 994 (m), 958 (m), 919 (m), 880 (m), 804 (w), 750 (s), 628 (w), 577 (w) cm–1.1-(Chroman-4-ylmethoxy)-2,2,6,6-tetramethylpiperidine (2h)Following the general procedure with 2-(but-3-en-1-yloxy)aniline (1h; 41 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2h as yellowish oil (33 mg, 0.11 mol, 43%). 1H NMR (600 MHz, CDCl3, 300 K): δ = 7.20–7.15 (m, 1 H, CHarom), 7.11–7.06 (m, 1 H, CHarom), 6.84 (td, J = 7.4, 1.3 Hz, 1 H, CHarom), 6.80 (dd, J = 8.1, 1.3 Hz, 1 H, CHarom), 4.24–4.18 (m, 2 H, OCH2), 4.00 (dd, J = 8.9, 5.4 Hz, 1 H, NOCHα Hβ), 3.91 (t, J = 8.9 Hz, 1 H, NOCHα Hβ ), 3.12–3.06 (m, 1 H, CH), 2.15–2.05 (m, 2 H, OCH2CHα Hβ), 2.05–2.01 (m, 2 H, OCH2CHα Hβ ), 1.54–0.98 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (151 MHz, CDCl3, 300 K): δ = 155.1 (C), 129.9 (CH), 127.7 (CH), 123.1 (C), 120.2 (CH), 116.9 (CH), 80.3 (OCH2), 63.7 (OCH2), 60.1 (C), 60.0 (C), 39.8 (2 × CH2), 33.8 (CH), 33.3 (CH3), 33.2 (CH3), 25.5 (CH2), 20.4 (CH3), 20.3 (CH3), 17.3 (CH2) ppm. ESI-HRMS: m/z calcd for C19H29NO2H [M + H]+: 304.2271; found: 304.2277. IR (neat): 2973 (m), 2930 (s), 2875 (m), 1582 (m), 1490 (s), 1452 (m), 1373 (m), 1308 (w), 1258 (m), 1225 (s), 1132 (m), 1027 (s), 790 (w), 753 (s), 727 (w), 614 (w), 571 (w) cm–1.3-{[(2,2,6,6-Tetramethylpiperidin-1-yl)oxy]methyl}-1-tosylindoline (2i)Following the general procedure with N-allyl-N-(2-aminophenyl)-4-methylphenylsulfonamide (1i; 72 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv) Crude product was purified by flash column chromatography on silica gel by using a 10:1 mixture of pentane–EtOAc as an eluent to provide analytically pure product 2i as colorless oil (82 mg, 0.19 mmol, 77%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.67 (t, J = 7.6 Hz, 3 H, 3 × CHarom), 7.20 (dd, J = 7.6, 5.6 Hz, 3 × CHarom), 7.14 (d, J = 7.6 Hz, 1 H, CHarom), 6.97 (td, J = 7.6, 0.9 Hz, 1 H, CHarom), 4.01 (dd, J = 10.8, 9.4 Hz, 1 H, NCHα Hβ), 3.75 (dd, J = 10.8, 5.7 Hz, 1 H, NCHα Hβ ), 3.72–3.58 (m, 2 H, OCH2), 3.39 (m, 1 H, CH), 2.35 (s, 3 H, CH3), 1.44–0.97 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 144.1 (C), 142.1 (C), 134.0 (C), 132.6 (C), 129.8 (2 × CH) 128.4 (CH), 127.4 (2 × CH), 125.5 (CH), 123.6 (CH), 114.8 (CH), 78.9 (OCH2), 60.0 (2 × C), 53.3 (NCH2), 39.9 (CH), 39.7 (2 × CH2), 33.2 (CH3), 33.1 (CH3), 21.6 (CH3), 20.3 (CH3), 20.2 (CH3), 17.1 (CH2) ppm. ESI-HRMS: m/z calcd for C25H34N2O3SH [M + H]+: 443.2363; found: 443.2349. IR (neat): 2930 (m), 1599 (w), 1478 (m), 1358 (s), 1245 (w), 1167 (s), 1105 (m), 1049 (m), 922 (w), 813 (w) 753 (m), 665 (m) cm–1.1-[(2,3-Dihydrobenzo[b]thiophen-3-yl)methoxy]-2,2,6,6-tetramethylpiperidine (2j)Following the general procedure with 2-(allylthio)aniline (1j; 41 mg, 0.25 mmol, 1.0 equiv) and TEMPO (76 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 50:1 mixture of pentane–Et2O as an eluent to provide analytically pure product 2j as pale yellow solid (60 mg, 0.20 mmol, 79%); mp 66 °C. The NMR spectra show small amounts of impurities which could not be removed by column chromatography. 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.23–7.15 (m, 2 H, 2 × CHarom), 7.12 (td, J = 7.4, 1.4 Hz, 1 H, CHarom), 7.01 (td, J = 7.4, 1.4 Hz, 1 H, CHarom), 4.00–3.88 (m, 2 H, OCH2), 3.78–3.66 (m, 1 H, CH), 3.52 (dd, J = 11.1, 7.7 Hz, 1 H, SCHα Hβ), 3.30 (dd, J = 11.1, 5.7 Hz, 1 H, SCHα Hβ ), 1.49–1.07 (m, 18 H, 3 × CH2, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 142.0 (C), 140.5 (C), 128.0 (CH), 125.0 (CH), 124.2 (CH), 122.4 (CH), 77.6 (OCH2), 60.0 (2 × C), 47.9 (CH), 39.8 (2 × CH2), 36.4 (SCH2), 33.5 (CH3), 33.1 (CH3), 20.4 (2 × CH3), 17.3 (CH2) ppm. ESI-HRMS: m/z calcd for C18H27NOSH [M + H]+: 306.1886; found: 306.1914. IR (neat): 3061 (w), 2972 (m), 2929 (s), 1586 (w), 1464 (m), 1374 (m), 1261 (m), 1209 (w), 1132 (m), 1056 (m), 932 (w), 866 (w), 749 (s), 625 (w) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-4-methoxy-2,2,6,6-tetramethylpiperidine (4a)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and 4-methoxy-TEMPO (93 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 25:1 mixture of pentane–EtOAc to provide analytically pure product 4a as yellow oil (45 mg, 0.14 mmol, 56%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.23 (dt, J = 7.3, 1.2 Hz, 1 H, CHarom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CHarom), 6.89–6.77 (m, 2 H, CHarom), 4.63 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.39 (dd, J = 9.0, 6.1 Hz, 1 H, OCHα Hβ ), 4.02–3.85 (m, 2 H, OCH2CH, NOCHα Hβ), 3.70 (ddd, J = 14.7, 8.6, 6.5 Hz, 1 H, NOCHα Hβ ), 3.43 (tt, J = 11.3, 4.1 Hz, 1 H, OCH), 3.32 (s, 3 H, OCH3), 1.85 (dd, J = 12.5, 4.0 Hz, 2 H, CH2), 1.38 (t, J = 11.9 Hz, 2 H, CH2), 1.22–1.11 (m, 12 H, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 160.3 (C), 128.7 (CH), 128.0 (C), 125.2 (CH), 120.4 (CH), 109.7 (CH), 79.0 (OCH2), 74.5 (OCH2), 71.8 (CH), 60.3 (2 × C), 55.9 (OCH3), 44.7 (CH2), 42.0 (2 × CH2), 33.6 (CH3), 33.4 (CH3), 21.3(CH3), 21.2 (CH3). ESI-HRMS: m/z calcd for C19H29NO3H [M + H]+: 320.2220; found: 320.2232. IR (neat): 2974 (m), 2935 (m), 2884 (m), 1597 (w), 1482 (m), 1375 (m), 1228 (m), 1169 (w), 1096 (s), 1043 (m), 972 (m), 895 (w), 861 (w), 750 (s) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethyl-4-(prop-2-yn-1-yloxy)piperidine (4b)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and 4-propargyloxy-TEMPO (98 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 10:1 mixture of pentane–EtOAc to provide analytically pure product 4b as yellow oil (58 mg, 0.18 mmol, 71%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.23 (d, J = 7.4 Hz, 1 H, CHarom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CHarom), 6.89–6.77 (m, 2 H, CHarom), 4.62 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.38 (dd, J = 9.0, 6.0 Hz, 1 H, OCHα Hβ ), 4.16 (d, J = 2.4 Hz, 2 H, OCH2), 4.02–3.65 (m, 4 H, OCH2CH, NOCH2, OCH), 2.41 (t, J = 2.4 Hz, 1 H, CCH), 1.85 (dd, J = 12.7, 4.0 Hz, 2 H, nitroxide CH2), 1.43 (t, J = 11.8 Hz, 2 H, CH2), 1.17 (d, J = 11.8 Hz, 12 H, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): d = 160.3 (C), 128.7 (CH), 128.0 (C), 125.2 (CH), 120.4 (CH), 109.7 (CH), 80.3 (C), 79.0 (OCH2), 74.5 (OCH2), 74.2 (CH), 69.8 (OCH), 60.4 (2 × C), 55.4 (2 × CH2), 44.8 (OCH2), 41.9 (CH), 33.5 (CH3), 33.3 (CH3), 21.3 (CH3), 21.2 (CH3) ppm. ESI-HRMS: m/z calcd for C21H29NO3H [M + H]+: 344.2220; found: 344.2225. IR (neat): 3291 (w), 2975 (m), 2938 (m), 2887 (m), 1597 (w), 1482 (m), 1360 (m), 1230 (m), 1195 (w), 1086 (s), 1044 (m), 971 (w), 752 (s) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidin-4-one (4c)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and 4-oxo-TEMPO (85 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 8:1 mixture of pentane–EtOAc to provide analytically pure product 4c as yellow oil (49 mg, 0.16 mmol, 65%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.24 (dt, J = 7.3, 1.2 Hz, 1 H, CHarom), 7.15 (td, J = 7.7, 1.4 Hz, 1 H, CHarom), 6.90–6.77 (m, 2 H, CHarom), 4.64 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.40 (dd, J = 9.1, 5.8 Hz, 1 H, OCHα Hβ ), 4.12–3.93 (m, 2 H, OCH2CH, NOCHα Hβ), 3.73 (ddd, J = 14.5, 8.5, 6.4 Hz, 1 H, NOCHα Hβ ), 2.59 (d, J = 13.2 Hz, 2 H, CH2), 2.19 (d, J = 13.0 Hz, 2 H, CH2), 1.23 (dd, J = 36.7, 7.1 Hz, 12 H, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 207.6 (C), 160.2 (C), 128.7 (CH), 127.5 (C), 125.1 (CH), 120.4 (CH), 109.7 (CH), 79.0 (OCH2), 74.2 (OCH2), 63.2 (2 × C), 53.4 (2 × CH2), 41.7 (CH), 32.8 (CH3), 32.5 (CH3), 22.3 (CH3), 22.3 (CH3) ppm. ESI-HRMS: m/z calcd for C18H25NO3H [M + H]+: 304.1907; found: 340.1907. IR (neat): 2975 (m), 2937 (w), 2884 (w), 1722 (s), 1597 (w), 1483 (s), 1377 (w), 1305 (m), 1231 (s), 1042 (m), 969 (w), 752 (s) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidin-4-yl-4-methylbenzenesulfonate (4d)Following the general procedure with 2-(allyloxy)aniline (1a; 38.0 mg, 0.250 mmol, 1.0 equiv) and 4-tosyloxy-TEMPO (163 mg, 0.500 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 10:1 mixture of pentane–EtOAc to provide analytically pure product 4d as yellow oil (50 mg, 0.11 mmol, 44%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.85–7.73 (m, 2 H, CHarom), 7.34 (d, J = 8.1 Hz, 2 H, CHarom), 7.19 (dd, J = 7.4, 1.1 Hz, 1 H, CHarom), 7.15–7.08 (m, 1 H, CHarom), 6.88–6.74 (m, 2 H, CHarom), 4.71 (tt, J = 11.4, 4.7 Hz, 1 H, OCH), 4.60 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.35 (dd, J = 9.0, 5.9 Hz, 1 H, OCHα Hβ ), 3.98–3.81 (m, 2 H, OCH2CH, NOCHα Hβ), 3.72–3.60 (m, 1 H, NOCHα Hβ ), 2.45 (s, 3 H, CH3), 1.79–1.59 (m, 4 H, 2 × CH2), 1.17–1.05 (m, 12 H, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 160.3 (C), 144.7 (C), 134.6 (C), 129.9 (2 × CH), 128.7 (CH), 127.7 (C, 2 × CH), 125.1 (CH), 120.4 (CH), 109.7 (CH), 79.0 (OCH2), 75.2 (OCH), 74.4 (OCH2), 60.5 (2 × C), 44.9 (2 × CH2), 41.9 (CH), 33.2 (CH3), 33.0 (CH3), 21.8 (CH3), 21.0 (CH3), 20.9 (CH3) ppm. ESI-HRMS: m/z calcd for C25H33NO5SH [M + H]+: 460.2152; found: 460.2155. IR (neat): 2976 (w), 2933 (w), 2886 (w), 1597 (w), 1482 (m), 1360 (m), 1229 (w), 1174 (s), 1097 (m), 1044 (m), 927 (s), 864 (w), 814 (m), 751 (m), 668 (s), 556 (m) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,6-diethyl-2,3,6-trimethylpiperidine (4e)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and 2,6-diethyl-2,3,6-trimethylpiperidine N-oxyl radical (99 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 10:1 mixture of pentane–CH2Cl2 to provide analytically pure product 4e as yellow oil (38 mg, 0.12 mmol, 46%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.22 (dd, J = 7.3, 1.3 Hz, 1 H, CHarom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CHarom), 6.90–6.77 (m, 2 H, CHarom), 4.62 (tt, J = 9.0, 1.7 Hz, 1 H, OCHα Hβ), 4.39 (dddd, J = 9.2, 6.2, 3.1, 1.7 Hz, 1 H, OCHα Hβ ), 4.00–3.62 (m, 3 H, OCH2CH, NOCH 2), 1.75–1.57 (m, 3 H, CH, CH2), 1.47–0.74 (m, 21 H, 3 × CH2, 5 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 160.4 (C), 128.6 (CH), 128.1 (C), 125.2 (CH), 120.4 (CH), 109.6 (CH), 77.0 (OCH2), 74.9 (OCH2), 65.8 (C), 62.2 (C), 42.2 (CH), 36.0 (CH2), 35.0 (CH), 34.4 (CH2), 30.5 (CH2), 24.7 (CH2), 19.5 (CH3), 17.2 (CH3), 15.9 (CH3), 8.4 (CH3), 7.9 (CH3) ppm. ESI-HRMS: m/z calcd for C21H33NO2H [M + H]+: 332.2584; found: 332.2591. IR (neat): 2964 (w), 1597 (w), 1481 (m), 1366 (w), 1232 (m), 1162 (w), 969 (w), 907 (s), 731 (s) cm–1.1-[(2,3-Dihydrobenzofuran-3-yl)methoxy]-2,2,6,6-tetramethylpiperidin-4-ol (4f)Following the general procedure with 2-(allyloxy)aniline (1a; 38 mg, 0.25 mmol, 1.0 equiv) and 4-hydroxy-TEMPO (86 mg, 0.50 mmol, 2.0 equiv). Crude product was purified by flash column chromatography on silica gel by using a 5:1 mixture of pentane–EtOAc to provide analytically pure product 4f as brown oil (35 mg, 0.12 mmol, 46%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.23 (dt, J = 7.4, 1.1 Hz, 1 H, CHarom), 7.14 (td, J = 7.7, 1.4 Hz, 1 H, CHarom), 6.85 (td, J = 7.4, 1.0 Hz, 1 H, CHarom), 6.79 (d, J = 8.0 Hz, 1 H, CHarom), 4.62 (t, J = 9.0 Hz, 1 H, OCHα Hβ), 4.39 (dd, J = 9.0, 6.0 Hz, 1 H, OCHα Hβ ), 4.01–3.82 (m, 3 H, OCH2CH, OCH, NOCHα Hβ), 3.70 (ddd, J = 14.5, 8.5, 6.4 Hz, 1 H, NOCHα Hβ ), 1.80 (dd, J = 12.5, 4.2 Hz, 2 H, CH2), 1.45 (t, J = 11.9 Hz, 2 H, CH2), 1.36–1.30 (m, 1 H, OH), 1.16 (d, J = 11.9 Hz, 12 H, 4 × CH3) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 160.1 (C), 128.6 (CH), 127.8 (C), 125.1 (CH), 120.3 (CH), 109.5 (CH), 78.8 (OCH2), 74.4 (OCH2), 63.2 (OCH), 60.3 (2 × C), 48.2 (2 × CH2), 41.7 (CH), 33.3 (CH3), 33.1 (CH3), 21.1 (CH3), 21.0 (CH3) ppm. ESI-HRMS: m/z calcd for C18H27NO3Na [M + Na]+: 328.1883; found: 328.1872. IR (neat): 2975 (m), 1934 (m), 2884 (m), 1611 (w), 1597 (m), 1482 (s), 1374 (m), 1360 (m), 1228 (m), 1195 (w), 1165 (w), 1097 (w), 1044 (s), 1033 (s), 969 (m), 954 (m), 931 (w), 899 (w), 862 (w), 837 (m), 750 (s), 735 (s) cm–1.