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15 Supporting Information
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17  Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2018
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Deacetylation of Unactivated Amide Bonds in Heterocyclic
23 Systems Using t-BuOK
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25 Minjin Yoo and Kwan-Young Jung*
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General methods.

Unless otherwise stated, all reactions were performed under an inert (N2) atmosphere. Reagents and solvents

were reagent grade and purchased from Sigma-Aldrich, Alfa Aesar and TCI Tokyo. 1H NMR spectra were

recorded on BRUKER ultra-shield 300 MHz and BRUKER ultra-shield 500 MHz NMR spectrometers at 25 ℃.

Chemical shifts are reported in parts per million (ppm). Data for 1H NMR are reported as follows: chemical

shift (δ ppm) (integration, multiplicity, coupling constant (Hz)). Multiplicities are reported as follows: s = singlet,

d = doublet, t = triplet, q = quartet, m = multiplet. The residual solvent peak was used as an internal reference.

The mass spectra were obtained on an AcouityTM waters A06UPD9BM, and Agilent Technologies

SG12109048.

Abbreviations.

EtOAc, ethyl acetate; CH2Cl2, dichloromethane; THF, tetrahydrofuran; MeCN, acetonitrile; DMSO, dimethyl

sulfoxide; DMF, N,N-dimethylformamide; NaH, sodium hydride; t-BuOK, potassium tert-butoxide; EtOH, ethyl

alcohol; H2O, water; Na2S2O4, sodium dithionite; Ac2O, acetic anhydride.

Experimental Section

General procedure for the competition reaction between alkylation and deacetylation of 1-(phenazine-5(10H)-

yl)ethan-1-one (Table 1).

1-(Phenazin-5(10H)-yl)ethan-1-one (1) (100 mg, 0.45 mmol), base (21 mg, 0.54 mmol in case of NaH as a

base; 60 mg, 0.54 mmol in case of t-BuOK as a base), and isobutyl iodide (56 μL, 0.49 mmol) were added to

a flame-dried 25 mL two-necked flask containing appropriate reaction solvent (see table 1) under a nitrogen

atmosphere. The reaction mixture was stirred at 20 ℃ for 3 hrs. The reaction mixture was diluted with EtOAc

and washed with water. The organic layer was concentrated, dried with sodium sulfate and checked the 1H-
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NMR for quantification of compound 3a−d, 4, and 1. In order to identify the synthesized compounds, NMR

analysis of each compound was separately performed after silica gel column chromatography.

General procedure for deacetylation reaction with C−N cleavage from N-acetyl heterocyclic compounds

(Table 2).

Heterocyclic compounds 5a−m (0.62 mmol) was dissolved in freshly distilled EtOAc (7 mL) and potassium

tert-butoxide (0.75 mmol) was added to a flame-dried 25 mL two-necked flask under a nitrogen atmosphere.

The reaction mixture was stirred at 20 ℃ for 30 min and quenched with water. The reaction mixture was

partitioned between water and EtOAc. The organic layer was collected, dried over anhydrous sodium sulfate,

filtered, concentrated, and purified by silica gel column chromatography suing EtOAc/n-hexanes as eluent in

increasing polarity to afford desired compounds 6a−m.

Synthesis of 1-(phenazin-5(10H)-yl)ethan-1-one (1).

Synthesis of 4a, 5, 10, 10a-tetrahydrophenazine. To a boiling solution of phenazine (2.0 g, 11.10 mmol) in

ethanol (50 mL), sodium dithionite (19.3 g, 0.11 mol) in water (200 mL) was added and stirred for 1 hour. The

resulting solid was obtained by filtration and washed with water (50 ml x 2), and dried under high vacuum to

afford the 4a, 5, 10, 10a-tetrahydrophenazine (1.99 g, 98%). 1H-NMR (DMSO-d6, 300 MHz) δ 7.29 (2H, NH,

br), 6.27 (4H, m, Ar), 6.02 (4H, m, Ar).

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Synthesis of 1-(phenazin-5(10H)-yl)ethan-1-one (1). 4a, 5, 10, 10a-tetrahydrophenazine (1.8 g, 9.81 mmol)

in acetic acid (10 mL) were heated boiled for 2 min. The resulting solid was precipitated and washed with

diethyl ether (30 mL x 2) to afford 1-(phenazin-5(10H)-yl)ethan-1-one (1.73 g, 78 %). 1H-NMR (DMSO-d6,

300 MHz) δ 8.93 (1H, br, NH), 7.37 (2H, m, Ar), 7.12 (2H, m, Ar), 6.93 (4H, m, Ar), 2.11 (3H, s, CH 3); 13
C-

NMR (DMSO-d6, 300 MHz) δ 169.8, 140.9, 126.9, 126.6, 120.3, 114.6, 22.7.

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General procedure for deacetylation of 1-(phenazin-5(10H)-yl)ethan-1-one (1).

1-(Phenazin-5(10H)-yl)ethan-1-one (1) (100 mg, 0.45 mmol), base (21 mg, 0.54 mmol in case of NaH as a

base; 60 mg, 0.54 mmol in case of t-BuOK as a base), isobutyl iodide (56 μL, 0.49 mmol) were dissolved in

reaction solvent and stirred at 20 ℃ for 3 hrs. The reaction mixture was diluted with EtOAc and washed with

water. The organic layer was concentrated, dried with sodium sulfate and purified by column chromatography.

1-(10-Isobutylphenazin-5(10H)-yl)ethan-1-one (3). 1H-NMR (CDCl3, 300 MHz) δ 7.39 (2H, m, Ar), 7.22

(2H, m, Ar), 7.05 (4H, m, Ar), 3.63 (2H, d, J = 7.2 Hz, CH2), 2.27 (1H, m, CH), 2.22 (3H, s, CH3), 0.96 (3H,

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s, CH3), 0.94 (3H, s, CH3).

Phenazine (4). 1H-NMR (CDCl3, 300 MHz) δ 8.27 (4H, m, Ar), 7.86 (4H, m, Ar)

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General procedure for deacetylation of 5a.

Acetylindoline 5a (100 mg, 0.62 mmol) was dissolved in EtOAc (7 mL) and potassium tert-butoxide (84 mg,

0.75 mmol) was added, stirred at 20 ℃ for 30 min. The reaction mixture was quenched with water and

extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography.

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H-NMR of 6a (DMSO-d6, 300 MHz) δ 7.08 (1H, dd, J = 7.56 Hz, 1.29 Hz, Ar), 6.96 (1H, t, J = 7.53 Hz, Ar),
6.62 (2H, m, Ar), 5.38 (1H, br, NH), 3.47 (2H, t, J = 8.52 Hz, CH2), 2.96 (2H, t, J = 8.49 Hz, CH2).

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H-NMR of 6b (DMSO-d6, 300 MHz) δ 11.0 (1H, br, NH), 7.56 (1H, d, J = 7.8 Hz, Ar), 7.42 (1H, d, J = 7.68
Hz, Ar), 7.34 (1H, m, Ar), 7.11 (1H, td, J = 6.99 Hz, 1.26 Hz, Ar), 7.02 (1H, td, J = 6.81 Hz, 1.17 Hz, Ar), 6.44
(1H, m, Ar).

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H-NMR of 6c (DMSO-d6, 300 MHz) δ 11.48 (1H, br, NH), 8.27 (1H, m, Ar), 7.74 (1H, dd, J = 8.58 Hz, 1.71 Hz,
Ar), 7.49 (2H, m, Ar), 6.60 (1H, m, Ar), 3.84 (3H, s, CH3).

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H-NMR of 6d (DMSO-d6, 300 MHz) δ 8.16 (1H, br, NH), 6.74 (2H, m, Ar), 6.60 (4H, m, Ar), 6.46 (2H, m, Ar).
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H-NMR of 6e (DMSO-d6, 300 MHz) δ 8.57 (1H, br, NH), 7.01 (4H, m, Ar), 6.77 (4H, m, Ar).
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H-NMR of 6f (DMSO-d6, 300 MHz) δ 11.92 (1H, s, NH), 7.19 (1H, t, J = 7.92 Hz, Ar), 7.08 (1H, s, Ar), 7.03
(1H, d, J = 7.92 Hz, Ar), 6.52 (1H, d, J = 7.68 Hz, Ar), 3,86 (3H, s, CH3), 3,84 (3H, s, CH3).

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H-NMR of 6g (DMSO-d6, 300 MHz) δ 11.65 (1H, s, NH), 8.07 (1H, s, Ar), 7.55–7.52 (2H, m, Ar), 7.41 (1H,
d, J = 8.46 Hz, Ar), 6.57 (1H, s, Ar).

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H-NMR of 6h (DMSO-d6, 300 MHz) δ 11.80 (1H, s, NH), 7.12 (1H, t, J = 3.03, Ar), 6.96 (1H, s, Ar), 6.88 (1H,
s, Ar), 6.25 (1H, t, J = 2.01 Hz, Ar), 5.90 (2H, s, OCH2O).

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H-NMR of 6i (DMSO-d6, 300 MHz) δ 10.84 (1H, s, NH), 7.03 (1H, t, J = 2.31 Hz, Ar), 6.48 (1H, s, Ar), 6.30
(1H, dt, J = 2.1 Hz, 0.84 Hz, Ar), 6.13 (1H, d, J = 1.92 Hz, Ar), 3.79 (3H, s, CH3), 3.72 (3H, s, CH3).

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H-NMR of 6j (DMSO-d6, 300 MHz) δ 11.81 (1H, s, NH), 8.56 (1H, d, J = 2.31 Hz, Ar), 7.99 (1H, dd, J = 8.99
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Hz, 2.31 Hz, Ar), 7.60 (1H, d, J = 3.18 Hz, Ar), 7.55 (1H, d, J = 9.01 Hz, Ar), 6.72 (1H, d, J = 3.18 Hz).

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H-NMR of 6k (DMSO-d6, 300 MHz) δ 10.87 (1H, s, NH), 7.46 (1H, m, Ar), 7.35 (1H, d, J = 1.47 Hz, Ar), 7.22
(1H, t, J = 8.37 Hz, Ar), 6.92 (2H, m, Ar), 6.70 (1H, m, Ar), 2.38 (3H, s, CH3).

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H-NMR of 6l (DMSO-d6, 300 MHz) δ 11.52 (1H, s, NH), 7.85 (2H, m, Ar), 7.52-7.40 (4H, m, Ar), 7.31 (1H,
m, Ar), 7.09 (1H, ddd, J = 8.17 Hz, 7.01 Hz, 1.27 Hz, Ar), 6.98 (1H, ddd, J = 8.06 Hz, 7.02 Hz, 1.12 Hz, Ar),
6.89 (1H, dd, J = 2.24 Hz, 0.90 Hz, Ar).

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H-NMR of 6m (DMSO-d6, 300 MHz) δ 5.10 (2H, p, J = 6.82 Hz, CH2), 2.92 (2H, ddt, J = 11.57 Hz, 9.73 Hz,
5.68 Hz, CH2), 2.74 (1H, td, J = 10.08 Hz, 5.05 Hz, CH), 1.84 (1H, m, CH), 1.69 (1H, ddt, J = 12.32 Hz, 9.77
Hz, 6.78 Hz, CH), 1.45 (5H, m, CH2), 1.22 (3H, m, CH2).

Table 3. Deacetylation of N-acetylphenazine without alkyl halide.

Solvent Toluene Dioxane THF Acetone MeCN DMSO EtOAc

Deacetylation product 32.9% 20.1% 58.5% 65.3% 67.1% 74.5% 100%

General experimental procedure of deacetylation of N-acetylphenazine without alkyl halide.

1-(Phenazin-5(10H)-yl)ethan-1-one (1) (100 mg, 0.45 mmol) and t-BuOK (60 mg, 0.54 mmol) were added to

the reaction vessel containing appropriate reaction solvent, and stirred at 20 ℃ for 30 min. The reaction

mixture was diluted with EtOAc and washed with water. The organic layer was concentrated and checked by
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H-NMR.

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Table 4. Deacetylation of N-acetylphenazine using t-BuOLi, t-BuONa and MeONa.

1-(Phenazin-5(10H)-yl)ethan-1-one (1) (100 mg, 0.45 mmol), isobutyl iodide (62 μL, 0.54 mmol), and

appropriate base (0.54 mmol) were added to the reaction vessel containing EtOAc, and stirred at 20 ℃ for

30 min. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was

concentrated and checked by 1H-NMR.

Entry Base Yield 3a Yield 4 Remain 1

1 t-BuOLi 17% 48% 35%
2 t-BuONa 8% 61% 31%
3 MeONa 0% 28% 72%

Time-dependent deacetylation for the reaction of comp 1 with t-BuOK. Reaction time: 3 min.

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Time-dependent deacetylation for the reaction of comp 1 with t-BuOK. Reaction time: 10 min.

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Time-dependent deacetylation for the reaction of comp 1 with t-BuOK. Reaction time: 30 min.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 3 min.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 10 min.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 30 min.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 1 h.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 2 h.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 3 h.

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Time-dependent deacetylation for the reaction of comp 1 with NaH. Reaction time: 6 h.
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