Aerobic oxidation of indole carbinols using Fe(NO3) 3·9H2O/TEMPO/NaCl as catalysts

Article abstract of DOI:10.1039/c3ob40226f

A practical aerobic oxidation of indole carbinols using Fe(NO ₃)₃·9H₂O/TEMPO/NaCl in DCE at room temperature and atmospheric pressure of oxygen affording aldehydes or ketones in good to excellent yields was developed. Furthermore, when using the industrially favored solvent toluene instead of DCE and air instead of pure oxygen, this protocol also works smoothly, demonstrating its high potential for possible industrial application.

Full text of DOI:10.1039/c3ob40226f

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Aerobic oxidation of indole carbinols using
Fe(NO3)3·9H2O/TEMPO/NaCl as catalysts†
Cite this: DOI: 10.1039/c3ob40226f
Jinxian Liua and Shengming Ma*a,b
A practical aerobic oxidation of indole carbinols using Fe(NO3)3·9H2O/TEMPO/NaCl in DCE at room temp-
erature and atmospheric pressure of oxygen affording aldehydes or ketones in good to excellent yields
was developed. Furthermore, when using the industrially favored solvent toluene instead of DCE and air
instead of pure oxygen, this protocol also works smoothly, demonstrating its high potential for possible
industrial application.
Received 1st February 2013,
Accepted 13th April 2013
DOI: 10.1039/c3ob40226f
www.rsc.org/obc
Introduction
Carbonyl compounds with indole units are important in
organic synthesis since a large number of indole carbonyls
with bioactivity have been found in natural products.1 Tra-
ditionally, such compounds could be obtained by oxidation of
the corresponding alcohols using at least a stoichiometric
amount of oxidants such as MnO2,2 CrO3,3 Pb(OAc)4,4 DMSO,5
hypervalent iodine compounds,6 etc.7 (Scheme 1). However,
from an economical and environmental viewpoint, such proto-
col would produce an almost equivalent amount of oxidant-
derived waste, and place a heavy burden on the environment.
Thus, development of a novel eco-friendly and economic
approach for such a transformation is highly desired.
Scheme 1 Oxidation of indole carbinols.
excellent yields.5 Therefore, we reasoned that such a catalytic
protocol could also be applied to indole carbinols, providing
an efficient alternative.
Molecular oxygen is a clean and cheap oxidant, and releases
water as the sole byproduct, thus it’s an ideal terminal
oxidant, especially for industrial applications. In the last three
decades, numerous aerobic oxidation protocols with metal cata-
lysts or even without a metallic catalyst have been reported.8
2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) has been used
as a catalyst to oxidize alcohols with various oxidants includ-
ing molecular oxygen.8e,9 As we know, there are very limited
reports for the oxidation of indole carbinols using molecular
oxygen as terminal oxidant in the literature.10 Recently, this
group has developed a general and practical approach to
aerobic oxidation of alcohols bearing a wide range of sub-
strates under mild conditions using Fe(NO3)3·9H2O/TEMPO/
NaCl as catalyst, yielding aldehydes or ketones in good to
Results and discussion
We tried to optimize the reaction conditions with regard to
additives, nitrates, solvents and catalyst loading; the results
are summarized in Table 1. A commonly used kitchen chemi-
cal, we found that sodium chloride is an important accelerator
for the Fe(NO3)3·9H2O/TEMPO-catalyzed aerobic oxidation of
alcohols.11 Thus, we first carried out a control experiment to
investigate the effect of chloride ion on this oxidation (Table 1,
entries 1 and 2). We found that when 10 mol% NaCl was
added, the catalytic efficiency was greatly improved, and the
reaction time was reduced from 15 hours to 2 hours. The role
of Cl− in this reaction is not quite clear yet; it probably works
as a ligand to Fe3+ to accelerate the oxidation.11 Copper nitrate
could also catalyze this reaction; however, the reaction is slow
(6 h) (Table 1, entry 3). Therefore, we still chose iron nitrate as
the co-catalyst. We next examined the effect of solvent on the
aerobic oxidation reaction at room temperature (Table 1,
entries 4 and 5) and found that this reaction could be carried
out in ethyl acetate, THF or DCE due to its high reactivity. For
aKey Laboratory of Green Chemistry and Chemical Process, Department of Chemistry,
East China Normal University, 3663 North Zhongshan Lu, Shanghai 200062,
P. R. China. E-mail: masm@sioc.ac.cn; Fax: (+86)-21-6260-9305
bKey Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40226f
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indole ring could bear electron-withdrawing groups such as F
and COOMe (Table 2, entries 2 and 3).
Table 1 Optimization of the aerobic oxidation of (1-tosyl-1H-indol-2-yl)-
carbinola
N–Ts, Boc or Ac are required for this transformation
(Table 3, entries 1–3). When R1 = Ts or Ac, the substrate could
be oxidized to corresponding aldehyde rapidly with good yield;
when R1 = Boc, 87% isolated yield could be obtained within
5 hours. The R2 group could be aryl, alkyl, a terminal C–C
triple bond or an allene (Table 3, entries 4–7).
Entry
Solvent
Time (h)
Yield of 2a (%)
1
DCE
DCE
DCE
Ethyl acetate
THF
DCE
DCE
2
15
6
3
5
4
43
99
93
95
97
95
96
93
2b
3c
4
Table 3 Aerobic oxidation of indole-3-carbinols to corresponding aldehydes or
ketones – the effect of N-protecting groupa
5
6d
7e
a Standard reaction conditions: 10 mol% Fe(NO3)3·9H2O, 10 mol%
TEMPO, and 10 mol% NaCl in 4 mL of DCE. b Without the addition of
10 mol% NaCl. c Cu(NO3)2·3H2O was used instead of Fe(NO3)3·9H2O.
d The reaction was conducted with 5 mol% Fe(NO3)3·9H2O, 5 mol%
TEMPO, and 5 mol% NaCl in 4 mL of DCE. e The reaction was
conducted with 2 mol% Fe(NO3)3·9H2O, 2 mol% TEMPO, and 2 mol%
NaCl in 4 mL of DCE.
Entry
Substrate
R1
R2
Time (h)
Yield of 2 (%)
1
2
3
4
5
6
7
1f
1g
1h
1i
1j
1k
1l
Ts
Boc
Ac
Ac
Ac
Ac
Ac
H
H
H
Ph
1
5
1.5
5
4.5
9
80 (2f)
83 (2g)
87 (2h)
89 (2i)
89 (2j)
94 (2k)
69 (2l)
the consideration of solubility and efficiency, we chose DCE as
solvent in this reaction. We further investigated the catalyst
loading (Table 1, entries 6 and 7) and found that when 10 mol
% Fe(NO3)3·9H2O, 10 mol% TEMPO, and 10 mol% NaCl were
used, the reaction could be rapidly completed in 2 hours with
an almost quantitative yield; however, when the catalyst
loading of each catalyst was reduced to 5 mol%, the reaction
time doubled; when further reducing the catalyst loading of
Fe(NO3)3·9H2O, TEMPO, and NaCl to 2 mol%, the reaction time
was prolonged to 43 hours.
Therefore, we chose 10 mol% Fe(NO3)3·9H2O, 10 mol%
TEMPO, and 10 mol% NaCl in DCE as standard reaction con-
ditions for further investigation into the substrate scope of
this reaction, with the results being summarized in Table 2.
This protocol could not only be applied to the primary indole-
2-carbinols (Table 2, entries 1–3) but also to the corresponding
secondary alcohols (Table 2, entries 4 and 5) affording alde-
hydes and ketones, respectively, with excellent yields. The
C2H5
HCuC
CHvCvCH2
5
a Standard reaction conditions: 10 mol% Fe(NO3)3·9H2O, 10 mol%
TEMPO, and 10 mol% NaCl in 4 mL of DCE.
We further investigated the usability of air instead of pure
oxygen; the results are summarized in Table 4. The transform-
ation with air could be completed within 3 hours with 97%
yield (Table 4, entry 1). When reducing the catalyst loading to
5 mol% each of Fe(NO3)3·9H2O, TEMPO, and NaCl, the reac-
tion time doubled (Table 4, entry 2); when changing the reac-
tion solvent to toluene,12 the reaction could also be completed
in 10 hours (Table 4, entry 3).
Table 4 Optimization of the aerobic oxidation of (1-tosyl-1H-indol-2-yl)carbi-
nol using air instead of oxygena
Table 2 Room temperature aerobic oxidation of indole-2-carbinols to corres-
ponding aldehydes or ketonesa
Entry
x
Solvent
Time (h)
Yield of 2a (%, NMR)
1
2
3
4
10
5
10
5
DCE
DCE
Toluene
Toluene
3
8
2
97
96
99
99
Entry Substrate R1
R2
Time (h) Yield of 2 (%)
10
1
2
3
4
5
1a
1b
1c
1d
1e
H
H
H
H
5-F
2
3
99 (2a)
90 (2b)
84 (2c)
84 (2d)
92 (2e)
a Standard reaction conditions: 10 mol% Fe(NO3)3·9H2O, 10 mol%
TEMPO, and 10 mol% NaCl in 4 mL of DCE.
5-COOMe 12
H
H
CH3
n-C5H11
14
24
a Standard reaction conditions: 10 mol% Fe(NO3)3·9H2O, 10 mol%
TEMPO, and 10 mol% NaCl in 4 mL of DCE.
We then applied these optimized reaction conditions using
air as oxidant and toluene as solvent to some indole carbinols;
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the results are summarized in Scheme 2. We found that both spectra were recorded in EI mode. HRMS spectra were
indole-2-carbinols and indole-3-carbinols could be trans- recorded in EI mode.
formed to corresponding carbonyl compounds in excellent
yield under the standard conditions.
General procedure for the synthesis of aldehydes or ketones
using molecular oxygen as oxidant (Method A)
To a 10 mL three-necked flask were added Fe(NO3)3·9H2O
(0.1 mmol), TEMPO (0.1 mmol), NaCl (0.1 mmol) and DCE
(4 mL). Alcohol (1 mmol) was then added to the suspension
and the resulting mixture was placed under an atmosphere of
oxygen from a balloon and stirred at room temperature until
the reaction was complete, as monitored by TLC (eluent: pet-
roleum ether–ethyl acetate = 3 : 1). The resulting mixture was
purified by column chromatography on silica gel (petroleum
ether–ethyl acetate = 10/1) to afford the corresponding alde-
hyde or ketone.
General procedure for the synthesis of aldehydes or ketones
using air as oxidant (Method B)
To a 10 mL three-necked flask were added Fe(NO3)3·9H2O
(0.05 mmol), TEMPO (0.05 mmol), NaCl (0.05 mmol) and
toluene (4 mL). Alcohol (1 mmol) was then added to the sus-
pension and the resulting mixture was stirred at room temp-
erature with an air balloon until the reaction was complete, as
monitored by TLC (eluent: petroleum ether–ethyl acetate =
3 : 1). The resulting mixture was purified by column chromato-
graphy on silica gel (petroleum ether–ethyl acetate = 10/1) to
afford the corresponding aldehyde or ketone.
Scheme 2 Room temperature aerobic oxidation of indole carbinols in toluene
using air as oxidant.
To further show the practicality and efficiency of this cataly-
tic system, a 0.1 mol reaction of (1-tosyl-1H-indol-3-yl)carbinol
was conducted by using 2 mol% each of Fe(NO3)3·9H2O,
TEMPO and NaCl to give 1-tosyl-1H-indole-3-carbaldehyde in
89% isolated yield in 48 h by simple recrystallization.
1. Synthesis of 1-tosyl-1H-indole-2-carbaldehyde (2a).
Method A: the reaction of (1-tosyl-1H-indol-2-yl)carbinol
(301.3 mg, 1 mmol), Fe(NO3)3·9H2O (40.5 mg, 0.1 mmol),
TEMPO (15.6 mg, 0.1 mmol), and NaCl (5.8 mg, 0.1 mmol) in
DCE (4 mL) afforded 1-tosyl-1H-indole-2-carbaldehyde13
(296.3 mg, 99%) as a white solid: m.p. 138–139 °C (hexane–
ethyl acetate).
Conclusions
In summary, we have developed a practical aerobic oxidation
protocol for various types of indole carbinols using Fe-
(NO3)3·9H2O/TEMPO/NaCl as catalysts under mild conditions,
affording the corresponding indole carbonyl compounds in
good to excellent yields. This eco-friendly and economically
oxidation system may be applied in academic laboratories as
well as industrial scale production.
1H NMR (300 MHz, CDCl3) δ 10.54 (s, 1H, CHO), 8.24 (d, J =
8.4 Hz, 1H, Ar-H), 7.66 (d, J = 8.4 Hz, 2H, Ar-H), 7.62 (d, J = 8.4
Hz, 1H, Ar-H), 7.52 (t, J = 7.5 Hz, 1H, Ar-H), 7.47 (s, 1H, Ar-H),
7.31 (t, J = 7.5 Hz, 1H, Ar-H), 7.19 (d, J = 8.4 Hz, 2H, Ar-H), 2.33
(s, 3H, CH3); 13C NMR (75.4 MHz, CDCl3) δ 183.3, 145.6, 138.5,
137.8, 134.6, 130.0, 128.8, 128.2, 126.6, 124.8, 123.6, 118.8,
115.4, 21.6; IR (neat) 2928, 1673, 1595, 1529, 1441, 1409, 1364,
1346, 1229, 1172, 1148, 1120, 1088, 1041 cm−1; MS(EI) m/z (%)
299 (M+, 30.92), 91 (100).
Experimental section
General experimental methods
1H, 13C and 19F NMR spectra were recorded with a Bruker AN
300 MHz spectrometer. 1H NMR spectra (300 MHz) were
recorded using TMS as an internal standard (δ 0 ppm). 13C
NMR spectra (75 MHz) were recorded using CDCl3 as an
internal standard (δ 77 ppm). 19F NMR spectra (282 MHz) were
recorded using CFCl3 as an internal standard (δ 0 ppm). Infra- Method B: the reaction of (1-tosyl-1H-indol-2-yl)carbinol
red spectra were recorded on an FTIR spectrometer. Mass (300.7 mg, 1 mmol), Fe(NO3)3·9H2O (20.4 mg, 0.05 mmol),
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TEMPO (8.0 mg, 0.05 mmol), and NaCl (3.0 mg, 0.05 mmol) in 140.6, 138.7, 134.4, 130.1, 129.4, 127.8, 126.9, 126.7, 125.9,
toluene (4 mL) afforded 1-tosyl-1H-indole-2-carbaldehyde 118.6, 115.1, 52.3, 21.6; IR (neat) 2988, 2901, 1716, 1669, 1614,
(291.7 mg, 98%) as a white solid.
1596, 1534, 1462, 1436, 1409, 1374, 1307, 1286, 1256, 1233,
2. Synthesis of 5-fluoro-1-tosyl-1H-indole-2-carbaldehyde 1162, 1137, 1086, 1050 cm−1; MS(EI) m/z (%) 357 (M+, 27.95),
(2b).
91 (100); Anal. calcd for C18H15NO5S: C 60.49; H 4.23; N 3.92;
Found: C 60.29; H 4.15; N 3.64.
4. Synthesis of 1-(1-tosyl-1H-indol-2-yl)ethanone (2d).
Method A: the reaction of (5-fluoro-1-tosyl-1H-indol-2-yl)carbi-
nol (319.8 mg, 1 mmol), Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol),
TEMPO (15.6 mg, 0.1 mmol), and NaCl (5.9 mg, 0.1 mmol) in Method A: the reaction of 1-(1-tosyl-1H-indol-2-yl)ethanol
DCE (4 mL) afforded 5-fluoro-1-tosyl-1H-indole-2-carbaldehyde (315.9 mg, 1 mmol), Fe(NO3)3·9H2O (40.1 mg, 0.1 mmol),
(286.7 mg, 90%) as a white solid: m.p. 152–153 °C (hexane– TEMPO (15.7 mg, 0.1 mmol), and NaCl (5.9 mg, 0.1 mmol) in
ethyl acetate).
DCE (4 mL) afforded 1-(1-tosyl-1H-indol-2-yl)ethanone
1H NMR (300 MHz, CDCl3) δ 10.53 (s, 1H, CHO), 8.20 (dd, (263.7 mg, 84%) as a white solid: m.p. 130–131 °C (hexane–
J1 = 9.9 Hz, J2 = 4.2 Hz, 1H, Ar-H), 7.63 (d, J = 8.4 Hz, 2H, Ar- ethyl acetate).
H), 7.41 (s, 1H, Ar-H), 7.30–7.18 (m, 4H, Ar-H), 2.34 (s, 3H,
1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 1H, Ar-H),
CH3); 13C NMR (75.4 MHz, CDCl3) δ 183.2, 160.0 (d, J = 238.0 7.82 (d, J = 8.1 Hz, 2H, Ar-H), 7.55 (d, J = 7.8 Hz, 1H, Ar-H),
Hz), 145.8, 138.9, 134.7, 134.3, 130.0, 129.1 (d, J = 10.4 Hz), 7.44 (t, J = 7.8 Hz, 1H, Ar-H), 7.30–7.18 (m, 3H, Ar-H), 7.10 (s,
126.6, 118.1 (d, J = 4.4 Hz), 117.2 (d, J = 25.8 Hz), 116.8 (d, J = 1H, Ar-H), 2.63 (s, 3H, COCH3), 2.33 (s, 3H, CH3); 13C NMR
9.3 Hz), 108.5 (d, J = 23.7 Hz), 21.6; 19F NMR (282 MHz, CDCl3) (75.4 MHz, CDCl3) δ 191.7, 144.8, 139.9, 138.8, 135.1, 129.4,
δ −117.6; IR (neat) 2928, 1676, 1595, 1529, 1443, 1411, 1362, 128.3, 127.5, 127.3, 124.3, 122.8, 117.3, 115.7, 29.6, 21.5;
1344, 1305, 1239, 1165, 1121, 1086, 1045 cm−1; MS(EI) m/z (%) IR (neat) 1689, 1537, 1442, 1360, 1330, 1312, 1266, 1223,
317 (M+, 26.44), 91 (100); Anal. calcd for C16H12FNO3S: C 1169, 1147, 1125, 1102, 1089, 1018, 969 cm−1
60.56; H 3.81; N 4.41; Found: C 60.49; H 3.81; N 4.22.
;
MS(EI)
m/z (%) 313 (M+, 25.73), 91 (100); Anal. calcd for C17H15-
NO3S: C 65.16; H 4.82; N 4.47; Found: C 65.09; H 4.78;
N 4.17.
Method B: the reaction of (5-fluoro-1-tosyl-1H-indol-2-yl)carbi-
nol (319.6 mg, 1 mmol), Fe(NO3)3·9H2O (20.8 mg, 0.05 mmol),
TEMPO (7.9 mg, 0.1 mmol), and NaCl (2.7 mg, 0.1 mmol) in
toluene (4 mL) afforded 5-fluoro-1-tosyl-1H-indole-2-carbalde-
hyde (304.6 mg, 96%) as white solid.
Method B: the reaction of 1-(1-tosyl-1H-indol-2-yl)ethanol
(315.2 mg, 1 mmol), Fe(NO3)3·9H2O (20.0 mg, 0.05 mmol),
TEMPO (7.9 mg, 0.05 mmol), and NaCl (3.0 mg, 0.05 mmol) in
toluene (4 mL) afforded 1-(1-tosyl-1H-indol-2-yl)ethanone
(278.2 mg, 89%) as a white solid.
3. Synthesis of methyl 2-formyl-1-tosyl-1H-indole-5-carboxy-
late (2c).
5. Synthesis of 1-(1-tosyl-1H-indol-2-yl)hexan-1-one (2e).
Method A: the reaction of methyl 2-(hydroxymethyl)-1-tosyl-1H-
indole-5-carboxylate (357.5 mg,
1 mmol), Fe(NO3)3·9H2O Method A: the reaction of 1-(1-tosyl-1H-indol-2-yl)hexan-1-ol
(40.3 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), and NaCl (370.1 mg, 1 mmol), Fe(NO3)3·9H2O (40.1 mg, 0.1 mmol),
(5.7 mg, 0.1 mmol) in DCE (4 mL) afforded methyl 2-formyl-1- TEMPO (15.6 mg, 0.1 mmol), and NaCl (5.6 mg, 0.1 mmol) in
tosyl-1H-indole-5-carboxylate (298.0 mg, 84%) as a white solid: DCE (4 mL) afforded 1-(1-tosyl-1H-indol-2-yl)hexan-1-one
m.p. 139–140 °C (hexane–ethyl acetate).
(340.2 mg, 92%) as a white solid: m.p. 97–98 °C (hexane–ethyl
1H NMR (300 MHz, CDCl3) δ 10.53 (s, 1H, CHO), 8.34 (s, acetate).
1H, Ar-H), 8.27 (d, J = 8.7 Hz, 1H, Ar-H), 8.17 (dt, J1 = 8.8 Hz,
1H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H, Ar-H),
J2 = 1.4 Hz, 1H, Ar-H), 7.67 (d, J = 8.4 Hz, 2H, Ar-H), 7.50 (s, 1H, 7.85 (d, J = 8.4 Hz, 2H, Ar-H), 7.54 (d, J = 7.8 Hz, 1H, Ar-H),
Ar-H), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 3.93 (s, 3H, OCH3), 2.33 (s, 7.43 (t, J = 7.8 Hz, 1H, Ar-H), 7.31–7.20 (m, 3H, Ar-H), 7.03 (s,
3H, CH3); 13C NMR (75.4 MHz, CDCl3) δ 182.9, 166.4, 146.0, 1H, Ar-H), 2.96 (t, J = 7.4 Hz, 2H, COCH2), 2.35 (s, 3H, COCH3),
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1.82–1.65 (m, 2H, CH2), 1.43–1.25 (m, 4H, CH2CH2), 0.91 (t, J = dried over anhydrous MgSO4, concentrated in vacuo and recrys-
6.6 Hz, 3H, CH3); 13C NMR (75.4 MHz, CDCl3) δ 195.4, 144.8, tallized (DCM/petroleum ether) to afford 1-tosyl-1H-indole-3-
140.0, 138.4, 135.1, 129.4, 128.5, 127.4, 127.1, 124.2, 122.6, carbaldehyde (26.5628 g, 89%) as a white solid.
115.9, 115.5, 42.5, 31.3, 24.3, 22.4, 21.5, 13.9; IR (neat) 1686,
1597, 1535, 1356, 1332, 1299, 1255, 1234, 1217, 1187, 1169, (2g).
1123, 1092, 1046 cm−1; MS(EI) m/z (%) 369 (M+, 22.37), 91
(100); Anal. calcd for C21H23NO3S: C 68.27; H 6.27; N 3.79;
Found: C 68.19; H 6.13; N 3.51.
7. Synthesis of tert-butyl 3-formyl-1H-indole-1-carboxylate
6. Synthesis of 1-tosyl-1H-indole-3-carbaldehyde (2f).
Method A: the reaction of tert-butyl 3-(hydroxymethyl)-1H-
indole-1-carboxylate (248.6 mg, mmol), Fe(NO3)3·9H2O
1
(40.0 mg, 0.1 mmol), TEMPO (15.7 mg, 0.1 mmol), and NaCl
(5.9 mg, 0.1 mmol) in DCE (4 mL) afforded tert-butyl 3-formyl-
1H-indole-1-carboxylate15 (204.0 mg, 83%) as a white solid: m.
p. 129–130 °C (hexane–ethyl acetate).
Method A: the reaction of (1-tosyl-1H-indol-3-yl)carbinol
(301.3 mg, 1 mmol), Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol),
TEMPO (15.8 mg, 0.1 mmol), and NaCl (5.9 mg, 0.1 mmol) in
DCE (4 mL) afforded 1-tosyl-1H-indole-3-carbaldehyde14
(238.4 mg, 80%) as a white solid (elute: petroleum ether–ethyl
acetate = 5/1): m.p. 151–152 °C (hexane–ethyl acetate).
1H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H, CHO), 8.25 (d, J =
8.4 Hz, 1H, Ar-H), 8.23 (s, 1H, Ar-H), 7.95 (d, J = 7.5 Hz, 1H, Ar-
H), 7.85 (d, J = 8.7 Hz, 2H, Ar-H), 7.45–7.32 (m, 2H, Ar-H), 7.28
(d, J = 8.7 Hz, 2H, Ar-H), 2.36 (s, 3H, CH3); 13C NMR
(75.4 MHz, CDCl3) δ 185.3, 146.1, 136.2, 135.1, 134.2, 130.3,
127.2, 126.24, 126.21, 125.0, 122.5, 122.3, 113.2, 21.6; IR (neat)
1662, 1595, 1538, 1479, 1444, 1399, 1372, 1279, 1237, 1168,
1126, 1098, 1082, 1016 cm−1; MS(EI) m/z (%) 299 (M+, 49.19),
91 (100).
1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H, CHO), 8.29 (dd,
J1 = 6.9 Hz, J2 = 1.8 Hz, 1H, Ar-H), 8.23 (s, 1H, Ar-H), 8.15 (d,
J = 7.5 Hz, 1H, Ar-H), 7.45–7.34 (m, 2H, Ar-H), 1.71 (s, 9H,
C(CH3)3); 13C NMR (75.4 MHz, CDCl3) δ 185.7, 148.8, 136.5,
135.9, 126.1, 126.0, 124.6, 122.1, 121.5, 115.1, 85.6, 28.0; IR
(neat) 1740, 1675, 1556, 1482, 1449, 1396, 1355, 1327, 1310,
1273, 1238, 1153, 1131, 1099, 1044, 1016 cm−1; MS(EI) m/z (%)
245 (M+, 12.63), 57 (100).
8. Synthesis of 1-acetyl-1H-indole-3-carbaldehyde (2h).
Method A: the reaction of 1-(3-(hydroxymethyl)-1H-indol-1-yl)
ethanone (176.3 mg, 1 mmol), Fe(NO3)3·9H2O (40.3 mg,
0.1 mmol), TEMPO (15.4 mg, 0.1 mmol), and NaCl (5.9 mg,
0.1 mmol) in DCE (4 mL) afforded 1-acetyl-1H-indole-3-carbal-
dehyde16 (151.2 mg, 87%) as a pink solid (elute: petroleum
ether–ethyl acetate = 3/1): m.p. 167–169 °C (hexane–ethyl
acetate).
Method B: the reaction of (1-tosyl-1H-indol-3-yl)carbinol
(301.8 mg, 1 mmol), Fe(NO3)3·9H2O (20.8 mg, 0.05 mmol),
TEMPO (7.9 mg, 0.05 mmol), and NaCl (2.9 mg, 0.05 mmol) in
toluene (4 mL) afforded 1-tosyl-1H-indole-3-carbaldehyde
(294.2 mg, 98%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H, CHO), 8.41 (d, J =
7.5 Hz, 1H, Ar-H), 8.28 (dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 1H, Ar-H),
8.08 (s, 1H, Ar-H), 7.50–7.36 (m, 2H, Ar-H), 2.75 (s, 3H, CH3);
13C NMR (75.4 MHz, CDCl3) δ 185.6, 168.5, 136.3, 135.1, 126.8,
126.0, 125.4, 122.6, 121.9, 116.3, 23.9; IR (neat) 1731, 1670,
1548, 1479, 1445, 1405, 1371, 1341, 1319, 1253, 1206, 1170,
1125, 1086, 1040, 1010 cm−1; MS(EI) m/z (%) 187 (M+, 40.60),
144 (100).
9. Synthesis of 1-(3-benzoyl-1H-indol-1-yl)ethanone (2i).
To a 250 mL three-necked flask were added Fe(NO3)3·9H2O
(0.8090 g, 2.0 mmol), TEMPO (0.3130 g, 2.0 mmol), NaCl
(0.1180 g, 2.0 mmol) and DCE (100 mL). (1-tosyl-1H-indol-3-yl)-
carbinol (30.1984 g, 0.1 mol) was then added to the suspen-
sion and the resulting mixture was stirred at room temperature
with an oxygen balloon until the reaction was complete, as
monitored by TLC (eluent: petroleum ether–ethyl acetate = Method A: the reaction of 1-(3-(hydroxy(phenyl)methyl)-1H-
3/1). The resulting mixture was washed with saturated brine, indol-1-yl)ethanone (265.3 mg,
1
mmol), Fe(NO3)3·9H2O
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(40.0 mg, 0.1 mmol), TEMPO (15.7 mg, 0.1 mmol), and NaCl Method B: the reaction of 1-(3-(1-hydroxypropyl)-1H-indol-1-yl)-
(5.8 mg, 0.1 mmol) in DCE (4 mL) afforded 1-(3-benzoyl-1H- ethanone (207.0 mg, 1 mmol), Fe(NO3)3·9H2O (20.6 mg,
indol-1-yl)ethanone (233.3 mg, 89%) as a white solid (elute: 0.05 mmol), TEMPO (7.6 mg, 0.05 mmol), and NaCl (2.9 mg,
petroleum ether–ethyl acetate = 5/1): m.p. 109–110 °C (hexane– 0.05 mmol) in toluene (4 mL) afforded 1-(1-acetyl-1H-indol-3-
ethyl acetate).
yl)propan-1-one (180.7 mg, 88%) as a white solid.
11. Synthesis of 1-(1-acetyl-1H-indol-3-yl)prop-2-yn-1-one
(2k).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 7.5 Hz, 1H, Ar-H),
8.26 (d, J = 7.2 Hz, 1H, Ar-H), 7.90–7.83 (m, 3H, Ar-H),
7.66–7.38 (m, 5H, Ar-H), 2.67 (s, 3H, CH3); 13C NMR
(75.4 MHz, CDCl3) δ 191.1, 168.6, 139.4, 136.0, 132.5, 132.2,
128.9, 128.6, 128.1, 126.4, 125.1, 122.4, 120.8, 116.2, 24.0; IR
(neat) 1732, 1637, 1597, 1549, 1472, 1441, 1375, 1349, 1320,
1262, 1208, 1177, 1143, 1115, 1077, 1036, 1008 cm−1; MS(EI)
m/z (%) 263 (M+, 49.69), 144 (100); Anal. calcd for C17H13NO2:
C 77.55; H 4.98; N 5.32; Found: C 77.12; H 4.97; N 4.95.
Method A: the reaction of 1-(3-(1-hydroxyprop-2-ynyl)-1H-indol-
1-yl)ethanone (212.9 mg, 1 mmol), Fe(NO3)3·9H2O (40.4 mg,
0.1 mmol), TEMPO (15.4 mg, 0.1 mmol), and NaCl (5.5 mg,
0.1 mmol) in DCE (4 mL) afforded 1-(1-acetyl-1H-indol-3-yl)
prop-2-yn-1-one (198.2 mg, 94%) as a white solid (elute: pet-
roleum ether–ethyl acetate = 5/1): m.p. 151–152 °C (hexane–
ethyl acetate).
1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 7.5 Hz, 1H, Ar-H),
8.33 (d, J = 7.8 Hz, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 7.48–7.35 (m,
2H, Ar-H), 3.31 (s, 1H, CH), 2.76 (s, 3H, CH3); 13C NMR
(75.4 MHz, CDCl3) δ 171.2, 168.5, 136.1, 135.1, 126.6, 126.0,
125.4, 122.3, 122.0, 116.2, 80.5, 77.4, 23.8; IR (neat) 2097, 1731,
1630, 1543, 1477, 1444, 1385, 1373, 1348, 1319, 1259, 1207,
1177, 1152, 1139, 1101, 1017 cm−1; MS(EI) m/z (%) 211 (M+,
50.12), 169 (100); Anal. calcd for C13H9NO2: C 73.92; H 4.29;
N 6.63; Found: C 73.60; H 4.32; N 6.21.
Method B: the reaction of 1-(3-(hydroxy(phenyl)methyl)-1H-
indol-1-yl)ethanone (265.0 mg,
1 mmol), Fe(NO3)3·9H2O
(20.0 mg, 0.05 mmol), TEMPO (7.7 mg, 0.05 mmol), and NaCl
(3.0 mg, 0.05 mmol) in toluene (4 mL) afforded 1-(3-benzoyl-
1H-indol-1-yl)ethanone (223.9 mg, 85%) as a white solid.
10. Synthesis of 1-(1-acetyl-1H-indol-3-yl)propan-1-one (2j).
12. Synthesis of 1-(1-acetyl-1H-indol-3-yl)butyl-2,3-dien-1-
one (2l).
Method A: the reaction of 1-(3-(1-hydroxypropyl)-1H-indol-1-yl)-
ethanone (217.9 mg, 1 mmol), Fe(NO3)3·9H2O (40.0 mg,
0.1 mmol), TEMPO (15.7 mg, 0.1 mmol), and NaCl (5.9 mg,
0.1 mmol) in DCE (4 mL) afforded 1-(1-acetyl-1H-indol-3-yl)
propan-1-one (192.1 mg, 89%) as a white solid (elute: pet-
roleum ether–ethyl acetate = 5/1): m.p. 136–137 °C (hexane–
ethyl acetate).
1H NMR (300 MHz, CDCl3) δ 8.37–8.25 (m, 2H, Ar-H), 7.93
(s, 1H, Ar-H), 7.41–7.27 (m, 2H, Ar-H), 2.87 (q, J = 7.3 Hz, 2H,
CH2), 2.65 (s, 3H, COCH3), 1.22 (t, J = 7.2 Hz, 3H, CH3); 13C
NMR (75.4 MHz, CDCl3) δ 196.8, 168.6, 135.8, 130.3, 127.2,
126.0, 125.0, 122.3, 121.0, 116.0, 33.1, 23.9, 8.1; IR (neat) 1713,
1664, 1605, 1549, 1481, 1446, 1392, 1370, 1355, 1325, 1252,
1218, 1187, 1140, 1074, 1027 cm−1; MS(EI) m/z (%) 215 (M+,
20.52), 144 (100); Anal. calcd for C13H13NO2: C 72.54; H 6.09; N
6.51; Found: C 72.35; H 5.93; N 6.30.
Method A: the reaction of 1-(1-acetyl-1H-indol-3-yl)butyl-2,3-
dien-1-ol (227.0 mg, 1 mmol), Fe(NO3)3·9H2O (40.0 mg,
0.1 mmol), TEMPO (15.7 mg, 0.1 mmol), and NaCl (5.7 mg,
0.1 mmol) in DCE (4 mL) afforded 1-(1-acetyl-1H-indol-3-yl)
butyl-2,3-dien-1-one (154.7 mg, 69%) as a yellow solid: m.p.
126–128 °C (hexane–ethyl acetate).
1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 7.5 Hz, 1H, Ar-H),
8.33 (d, J = 7.5 Hz, 1H, Ar-H), 8.19 (s, 1H, Ar-H), 7.45–7.35 (m,
2H, Ar-H), 6.36 (t, J = 6.5 Hz, 1H, CvCvCH), 5.33 (d, J = 6.6
Hz, 2H, CvCvCH2), 2.71 (s, 3H, CH3); 13C NMR (75.4 MHz,
CDCl3) δ 215.7, 184.9, 168.5, 135.6, 130.9, 127.6, 126.2, 125.1,
122.4, 120.9, 116.0, 94.4, 79.5, 23.8; IR (neat) 1963, 1934, 1703,
1633, 1538, 1480, 1448, 1420, 1381, 1349, 1326, 1254, 1217,
1188, 1140, 1020 cm−1; MS(EI) m/z (%) 225 (M+, 12.74), 144
(100); Anal. calcd for C14H11NO2: C 74.65; H 4.92; N 6.22;
Found: C 74.24; H 4.94; N 6.03.
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Acknowledgements
We greatly acknowledge the financial support from the Major
State Basic Research Development Program of China (No.
2009CB825300) and the National Natural Science Foundation
of China (21232006). We thank Xiaobing Zhang in our group
for reproducing the results of entry 5 in Table 2, and entries 3
and 6 in Table 3 presented in this study.
7 S. Kobayashi, H. Miyamura, R. Akiyama and T. Ishida,
J. Am. Chem. Soc., 2005, 127, 9251.
8 For reviews, see: (a) J.-E. Bäckvall, Modern Oxidation
Methods, Wiley-VCH, Weinheim, Germany, 2nd edn, 2010;
(b) C. Parmeggiani and F. Cardona, Green Chem., 2012, 14,
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Ketones: A Guide to Current Common Practice, ed. G. Tojo,
M. I. Fernandez, Springer, 2006.
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