Intramolecular Radical Carboaminoxylation of Aryl Amines

Marcel Hartmann; Carolin Gerleve; Armido Studer

doi:10.1055/s-0035-1560770

Synlett, Inhaltsverzeichnis

Synlett 2016; 27(05): 724-730
DOI: 10.1055/s-0035-1560770

cluster

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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Abstract

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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

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Referenzen

References and Notes

1a Galli C. Chem. Rev. 1988; 88: 765
1b Vaillard SE, Schulte B, Studer A In Modern Arylation Methods: Radical Based Arylation Methods . Ackermann L. Wiley-VCH; Weinheim: 2009: 475

For reviews on the Meerwein arylation, see:

2a Rondestvedt CS. Org. React. 1976; 24: 225
2b Heinrich MR. Chem. Eur. J. 2009; 15: 820
2c Kirchstein M, Wetzel A, Heinrich MR. Org. Lett. 2007; 9: 3833

3 Example using photoredox catalysis: Hari DP, Hering T, König B. Angew. Chem. Int. Ed. 2014; 53: 725
4 Tebben L, Studer A. Angew. Chem. Int. Ed. 2011; 50: 5034
5 Hartmann M, Li Y, Studer A. J. Am. Chem. Soc. 2012; 134: 16516

6a Murphy JA. Pure Appl. Chem. 2000; 72: 1327
6b Jasch H, Landais Y, Heinrich MR. Chem. Eur. J. 2013; 19: 8411

7a Mo F, Dong G, Zhang Y, Wang J. Org. Biomol. Chem. 2013; 11: 1582
7b Hari DP, König B. Angew. Chem. Int. Ed. 2013; 125: 4734
7c For a review on in situ diazotation, see: He L, Qui G, Gao Y, Wu J. Org. Biomol. Chem. 2014; 12: 6965

See also:

7d Hartmann M, Daniliuc CG, Studer A. Chem. Commun. 2015; 51: 3121

8a Qui D, Jin L, Zheng Z, Meng H, Mo F, Wang X, Zhang Y, Wang J. J. Org. Chem. 2013; 78: 1923
8b Qui D, Meng H, Jin L, Wang S, Tang S, Wang X, Mo F, Zhang Y, Wang J. Angew. Chem. Int. Ed. 2013; 52: 11581
8c Wang X, Xu Y, Mo F, Ji G, Qui D, Feng J, Ye Y, Zhang S, Zhang Y, Wang J. J. Am. Chem. Soc. 2013; 135: 10330

9 Hartmann M, Studer A. Angew. Chem. Int. Ed. 2014; 53: 8180

10a Studer A. Angew. Chem. Int. Ed. 2000; 39: 1108
10b Wetter C, Jantos K, Woithe K, Studer A. Org. Lett. 2003; 5: 2899
10c Wetter C, Studer A. Chem. Commun. 2004; 174
10d Studer A. Chem. Soc. Rev. 2004; 33: 267
10e Molawi K, Schulte T, Siegenthaler KO, Wetter C, Studer A. Chem. Eur. J. 2005; 11: 2335

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, CH_arom), 7.12–6.99 (m, 1 H, CH_arom), 6.84–6.63 (m, 2 H, CH_arom), 4.55 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.31 (dd, J = 9.0, 6.2 Hz, 1 H, OCH_α H_β ), 3.91 (dd, J = 8.6, 6.5 Hz, 1 H, OCH₂CH), 3.81 (t, J = 8.2 Hz, 1 H, NOCH_α H_β), 3.68–3.55 (m, 1 H, NOCH_α H_β ), 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, CH_arom), 7.40 (qd, J = 7.8, 2.1 Hz, 3 H, CH_arom), 7.34–7.27 (m, 1 H, CH_arom), 6.87 (d, J = 8.3 Hz, 1 H, CH_arom), 4.71 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.46 (dd, J = 9.0, 6.3 Hz, 1 H, OCH_α H_β ), 4.05 (dd, J = 8.6, 6.5 Hz, 1 H, OCH₂CH), 3.95 (t, J = 8.3 Hz, 1 H, NOCH_α H_β), 3.81–3.73 (m, 1 H, NOCH_α H_β ), 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, CH_arom), 6.92 (d, J = 8.1 Hz, 1 H, CH_arom), 6.68 (d, J = 8.1 Hz, 1 H, CH_arom), 4.61 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.37 (dd, J = 9.0, 6.3 Hz, 1 H, OCH_α H_β ), 3.96 (dd, J = 8.5, 6.3 Hz, 1 H, NOCH_α H_β), 3.86 (t, J = 8.5 Hz, 1 H, NOCH_α H_β ), 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, CH_arom), 7.86–7.81 (m, 1 H, CH_arom), 6.81 (d, J = 8.4 Hz, 1 H, CH_arom), 4.72 (t, J = 9.2 Hz, 1 H, OCH_α H_β), 4.48 (dd, J = 9.2, 6.1 Hz, 1 H, OCH_α H_β ), 3.98 (dd, J = 8.6, 6.8 Hz, 1 H, NOCH_α H_β), 3.89 (dd, J = 8.6, 7.5 Hz, 1 H, NOCH_α H_β ), 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, CH_arom), 7.18 (d, J = 7.3 Hz, 1 H, CH_arom), 6.76–6.71 (m, 1 H, CH_arom), 4.72 (t, J = 9.1 Hz, 1 H, OCH_α H_β), 4.48 (dd, J = 9.1, 6.1 Hz, 1 H, OCH_α H_β ), 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 × CH_arom), 6.90–6.76 (m, 2 H, 2 × CH_arom), 4.54 (d, J = 8.7 Hz, 1 H, OCH_α H_β), 4.15 (d, J = 8.7 Hz, 1 H, OCH_α H_β ), 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 × CH_arom), 6.91–6.74 (m, 2 H, 2 × CH_arom), 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, NOCH_α H_β), 3.89 (t, J = 8.5 Hz, 1 H, NOCH_α H_β ), 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, CH_arom), 7.11–7.06 (m, 1 H, CH_arom), 6.84 (td, J = 7.4, 1.3 Hz, 1 H, CH_arom), 6.80 (dd, J = 8.1, 1.3 Hz, 1 H, CH_arom), 4.24–4.18 (m, 2 H, OCH₂), 4.00 (dd, J = 8.9, 5.4 Hz, 1 H, NOCH_α H_β), 3.91 (t, J = 8.9 Hz, 1 H, NOCH_α H_β ), 3.12–3.06 (m, 1 H, CH), 2.15–2.05 (m, 2 H, OCH₂CH_α H_β), 2.05–2.01 (m, 2 H, OCH₂CH_α H_β ), 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 × CH_arom), 7.20 (dd, J = 7.6, 5.6 Hz, 3 × CH_arom), 7.14 (d, J = 7.6 Hz, 1 H, CH_arom), 6.97 (td, J = 7.6, 0.9 Hz, 1 H, CH_arom), 4.01 (dd, J = 10.8, 9.4 Hz, 1 H, NCH_α H_β), 3.75 (dd, J = 10.8, 5.7 Hz, 1 H, NCH_α H_β ), 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 × CH_arom), 7.12 (td, J = 7.4, 1.4 Hz, 1 H, CH_arom), 7.01 (td, J = 7.4, 1.4 Hz, 1 H, CH_arom), 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, SCH_α H_β), 3.30 (dd, J = 11.1, 5.7 Hz, 1 H, SCH_α H_β ), 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, CH_arom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CH_arom), 6.89–6.77 (m, 2 H, CH_arom), 4.63 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.39 (dd, J = 9.0, 6.1 Hz, 1 H, OCH_α H_β ), 4.02–3.85 (m, 2 H, OCH₂CH, NOCH_α H_β), 3.70 (ddd, J = 14.7, 8.6, 6.5 Hz, 1 H, NOCH_α H_β ), 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, CH_arom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CH_arom), 6.89–6.77 (m, 2 H, CH_arom), 4.62 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.38 (dd, J = 9.0, 6.0 Hz, 1 H, OCH_α H_β ), 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, CH_arom), 7.15 (td, J = 7.7, 1.4 Hz, 1 H, CH_arom), 6.90–6.77 (m, 2 H, CH_arom), 4.64 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.40 (dd, J = 9.1, 5.8 Hz, 1 H, OCH_α H_β ), 4.12–3.93 (m, 2 H, OCH₂CH, NOCH_α H_β), 3.73 (ddd, J = 14.5, 8.5, 6.4 Hz, 1 H, NOCH_α H_β ), 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, CH_arom), 7.34 (d, J = 8.1 Hz, 2 H, CH_arom), 7.19 (dd, J = 7.4, 1.1 Hz, 1 H, CH_arom), 7.15–7.08 (m, 1 H, CH_arom), 6.88–6.74 (m, 2 H, CH_arom), 4.71 (tt, J = 11.4, 4.7 Hz, 1 H, OCH), 4.60 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.35 (dd, J = 9.0, 5.9 Hz, 1 H, OCH_α H_β ), 3.98–3.81 (m, 2 H, OCH₂CH, NOCH_α H_β), 3.72–3.60 (m, 1 H, NOCH_α H_β ), 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, CH_arom), 7.13 (td, J = 7.7, 1.4 Hz, 1 H, CH_arom), 6.90–6.77 (m, 2 H, CH_arom), 4.62 (tt, J = 9.0, 1.7 Hz, 1 H, OCH_α H_β), 4.39 (dddd, J = 9.2, 6.2, 3.1, 1.7 Hz, 1 H, OCH_α H_β ), 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, CH_arom), 7.14 (td, J = 7.7, 1.4 Hz, 1 H, CH_arom), 6.85 (td, J = 7.4, 1.0 Hz, 1 H, CH_arom), 6.79 (d, J = 8.0 Hz, 1 H, CH_arom), 4.62 (t, J = 9.0 Hz, 1 H, OCH_α H_β), 4.39 (dd, J = 9.0, 6.0 Hz, 1 H, OCH_α H_β ), 4.01–3.82 (m, 3 H, OCH₂CH, OCH, NOCH_α H_β), 3.70 (ddd, J = 14.5, 8.5, 6.4 Hz, 1 H, NOCH_α H_β ), 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.

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