Novel synthesis of 3-indolylquinones catalyzed by molecular iodine under ultrasonic irradiation

Article abstract of DOI:10.1080/00397910701873490

The conjugate addition reactions of indoles with quinones were catalyzed efficiently by molecular iodine under ultrasonic irradiation to afford 3-indolylquinones in good to excellent yields, which provided a novel, mild, convenient approach for the prepar

Full text of DOI:10.1080/00397910701873490

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Novel Synthesis of 3‐Indolylquinones
catalyzed by Molecular Iodine under
Ultrasonic Irradiation
Bing Liu a , Shun‐Jun Ji a , Xiao‐Ming Su a & Shun‐Yi Wang a
a Key Laboratory of Organic Synthesis of Jiangsu Province , College of
Chemistry and Chemical Engineering, Suzhou University , Shzhou Industrial
Park, Suzhou, People's Republic of China
Published online: 17 Apr 2008.
To cite this article: Bing Liu , Shun‐Jun Ji , Xiao‐Ming Su & Shun‐Yi Wang (2008) Novel Synthesis of
3‐Indolylquinones catalyzed by Molecular Iodine under Ultrasonic Irradiation, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:8, 1279-1290, DOI:
10.1080/00397910701873490
To link to this article: http://dx.doi.org/10.1080/00397910701873490
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Synthetic Communicationsw, 38: 1279–1290, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701873490
Novel Synthesis of 3-Indolylquinones
catalyzed by Molecular Iodine under
Ultrasonic Irradiation
Bing Liu, Shun-Jun Ji, Xiao-Ming Su, and Shun-Yi Wang
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry and Chemical Engineering, Suzhou University, Suzhou
Industrial Park, Suzhou, People’s Republic of China
Abstract: The conjugate addition reactions of indoles with quinones were catalyzed
efficiently by molecular iodine under ultrasonic irradiation to afford 3-indolylquinones
in good to excellent yields, which provided a novel, mild, convenient approach for the
preparation of 3-indolylquinones.
Keywords: Indoles, 3-indolylquinones, molecular iodine, ultrasound
1
INTRODUCTION
During recent years, 3-indolylquinones have been attracted considerable
attention for their potent biological and pharmaceutical activities.[1] The
3-indolylquinone is an important component in a wide range of natural
products with diverse biological activities. Among them, the asterriquinones
have been shown a number of biological activities, including antitumor prop-
erties and inhibiton of HIV reverse transcriptase.[2] Recently, demethylaster-
riquinone B1 was reported as a nonprotein and orally active insulin mimetic
Received May 10, 2007
Address correspondence to Shun-Jun Ji, Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou Univer-
sity, Ren’ai Road, Suzhou Industrial Park, Suzhou 215123, People’s Republic of
China. E-mail: chemjsj@suda.edu.cn
1279

1280
B. Liu et al.
with antidiabetic activity.[3] Over the past few years, protic acids have been
used to catalyze the direct coupling of indole compounds with p-quinones,
such as HCl, H2SO, and CH3CO2H.[4] More recently, 3-indolylquinones
could be prepared in water phase without catalyst,[5] but the reaction needed
an extremely long time (up to 48 h) and the yields were relatively low.
Indol-3-yl-quinones were also formed in acetonitrile in the presence of
Lewis acids such InBr3 and Bi(OTf)3.[6,7] However, acetonitrile is not an
environmentally friendly solvent. For these reasons, superior catalytic
systems, which are more efficient, easy to access, and environmentally
friendly, are desirable.
Ultrasound is known to accelerate diverse types of organic reactions, and
it is established as an important technique in organic synthesis.[8] A large
number of classical organic reactions can be accelerated by ultrasonic
irradiation with fast reaction rate, short reaction time, high yields, and good
selectivity.[9]
In recent years, molecular iodine has been extensively used for a
plethora of organic transformations as an inexpensive, nontoxic,
readily available catalyst under very mild and convenient conditions to
afford the corresponding products in excellent yields with high selectiv-
ity.[10] However, the use of molecular iodine as a catalyst in the
synthesis of 3-indolylquinones has not been reported. In continuation of
our work aiming at the sythesis of indole compounds and the use of
molecular iodine,[11] herein we report an ultrasound-accelerated conjugate
addition of indoles to p-quinones employing iodine as a catalyst, which
provides an efficient route to the synthesis of 3-indolylquinones
(Scheme 1).
Scheme 1.

Synthesis of 3-Indolylquinones
1281
Scheme 2.
Scheme 3.
2
RESULTS AND DISCUSSION
Initially, the reactions were carried out using a 1:2 molar ratio of 2-methyl-
1H-indole 1b and 1,4-napthoquinone 2a along with a catalytic amount of I2
in various solvents under ultrasonic irradiation (Schemes 2 and 3). The
results are summarized in Table 1. The reaction proceeded efficiently in the
presence of I2 (10 mol%) and anhydrous ethanol at room temperature,
giving the 2-(2-methyl-1H-indol-3-yl)-1,4-naphthoquinone 3b in excellent
yield (95%) (Table 1, entry 1). In other organic solvents, such as dichloro-
methane, acetonitrile, and 1-butanol, the yields of the product 3b were also
good (Table 1, entries 2–4). Considering the lower toxicity of EtOH, we
carried out this reaction in anhydrous EtOH.
Then, we carried out the reaction of 2-methyl-1H-indole 1b with 1,4-
napthoquinone 2a using different Lewis acids in EtOH under ultrasonic
irradiation at room temperature. As shown in Table 2, the conjugate
addition proceeded efficiently in the presence of I2 (10 mol%), giving the
product 3b in excellent yields (95%) in 15 min (Table 2, entry 1). It has
also been found that the reaction was accelerated under ultrasound irradiation
Table 1. Reaction of 1b with 2a in various solventsa
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
EtOH
CH2Cl2
CH3CN
n-BuOH
15
50
45
40
95
81
88
84
aAll reactions were carried out using a catalytic amount of
I2 (10 mol%) at room temperature.
bIsolated yields.

1282
B. Liu et al.
Table 2. Lewis acid mediated reaction of 2-methyl-1H-indole 1b
with 1,4-napthoquinone 2aa
Entry
Lewis acid
Time (min)
Yield (%)b
1
2
3
4
5
6
7
I2
15
50
95
83
88
82
44
40
10
c
.
I
Fe(NO3)3
2
60
30
.
Bi(NO3)3 5H2O
.
(NH4)2Fe(SO4)2 6H2O
180
120
360
Al2(SO4)3
No catalyst
aAll reactions were carried out using 10% catalyst under sonic
irradiation at room temperature.
bIsolated yields.
cThe reaction was carried out by stirring instead of sonic
irradiation.
condition (Table 2, entries 1 and 2). Furthermore, the reaction could also
be carried out using the other Lewis acids, such as Fe(NO3)3,
.
.
Bi(NO3)3 5H2O, (NH4)2Fe(SO4)2 6H2O, and Al2(SO4)3 (Table 2, entries
3–6), but the yields were lower (40–88%), and it took a prolonged
reaction time (30–180 min). It is noteworthy that the reaction proceeded
even in the absence of the catalyst, though giving the products slowly
(6 h) in a low yield (10%) (Table 2, entry 7). Therefore, iodine was found
to be the superior catalyst in this reaction.
Encouraged by this success, we extended the reaction of 1,4-napthoqui-
none to a wide rage of other substituted indole compounds under similar con-
ditions at room temperature, furnishing the 3-indolyquinones in moderate to
excellent yields (Table 3). As shown in Table 3, the reactions involving
different methyl substituted indoles could proceed smoothly under ultrasonic
irradition to give the desired products in 62–95% yields, and the position of
the methyl group on the indolyl ring also had an influence on the reaction
time and final yields (Table 3, entries 2–6). In addition, our results also
showed that even though 4-(benzyloxy)-1H-indole 1g. 5-(Benzyloxy)-1H-
indole 1h, and 2-phenyl-1H-indole 1i are more sterically hindered than
other indoles, they could react with 1,4-napthoquinone to afford the desired
products in moderate yields (63–82%) (Table 3, entries 7–9). However, the
reactions of indoles bearing electron-withdrawing groups such as 4-bromo-
1H-indole 1j, and 7-nitro-1H-indole 1k with 1,4-napthoquinone were
extremely sluggish (Table 3, entries 10 and 11). We continued to investigate
the reaction of indoles with 1,4-benzoquinone 2b under these
conditions (Table 3, entries 12 and 13). 1,4-Napthoquinone is more active
than 1,4-benzoquinone in this reaction.

Table 3. Reaction of indoles with quinonesa
Indole
no.
Product
no.
Time
(min)
Yield
(%)b
Entry
1
Indoles
Quinones
Product
Mp(8C)
1a
3a
15
57
177–178
2
1b
3b
15
95
180–182
(180[6]
)
3
4
1c
3c
45
15
77
90
295–297
211–212
1d
3d
(continued)

Table 3. Continued
Indole
no.
Product
no.
Time
(min)
Yield
(%)b
Entry
5
Indoles
Quinones
Product
Mp(8C)
1e
3e
30
45
45
30
60
62
91
63
70
82
245–247
6
7
8
9
1f
3f
197–198
161–162
217–218
213–215
1g
1h
1i
3g
3h
3i

10
11
12
1j
1k
1l
3j
3k
3l
120
180
20
30
nrc
68
282–285
138–140
(106–108[6]
)
13
1m
3m
120
65
224
aAll reactions were carried out in anhydrous ethanol under ultrasonic irradiation at room temperature, employing 10 mol% I2.
bIsolated yields.
cNo reaction.

1286
CONCLUSIONS
B. Liu et al.
3
In conclusion, we have developed a simple, novel, and efficient synthetic
method for the synthesis of 3-indolylbenzoquinones using a catalytic
amount of molecular iodine under ultrasonic irradiation at room temperature.
The method is very fast and efficient, employs cheap, nontoxic molecular
iodine as the catalyst, and involves a simple manipulation in comparision
with current available methodologies. Efforts to develop more active and
available reactive systems are currently in progress.
4
EXPERIMENTAL
4.1 General
Melting points were recorded on an Electrothermal digital melting-point
1
apparatus and are uncorrected. H NMR (400 MHz) spectra were recorded
on a Varian Mercury MHz spectrometer in CDCl3. IR spectra were
obtained on a Nicolet FT-IR500 spectrophotometer using KBr pellets. High-
resolution mass spectra (HRMS) were obtained using a GCT-TOF instrument.
Ultrasound irradiation was performed in a KQ-250E ultrasonic cleaner with a
frequency of 40 KHz and a normal power of 250 W. The reaction flask was
located in the water bath of the ultrasonic cleaner.
4.2 Representative Experimental Procedure
A mixture of 2-methyl-1H-indole 1b (0.066 g, 0.5 mmol), 1,4-napthoquinone
2a (0.158 g, 1 mmol), I2 (0.013 g, 0.05 mmol), and anhydrous EtOH (2 mL)
was irradiated under ultrasound in an open vessel at room temperature until
the disappearance of the starting material (15 min, checked by thin-layer
chromatography, TLC). The residue was washed by saturated Na2S2O4 and
extracted with CH2Cl2 (3 ꢀ 10 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The resulting product was
purified by column chromatography on slica gel (petroleum ether/ethyl
acetate 8:1, gradually increasing ethyl acetate) to afford a pure product.
4.3 Data
2-(1H-Indol-3-yl)-1,4-naphthoquinone (3a). Purple solid; mp 177–178 8C;
1
IR (KBr): n 3246, 2923, 1633, 1435, 1260, 717 cm21; H NMR (400 MHz,
CDCl3): d 7.30–7.33 (m, 2H), 7.48–7.51 (m, 2H), 7.74–7.79 (m, 2H),
7.99–8.02 (m, 1H), 8.13–8.19 (m, 2H), 8.24–8.27 (m, 1H), 8.73 (s, 1H).
HRMS found: m/z, 273.0788 (Mþ); calcd. for C18H11NO2: M, 273.0790.

Synthesis of 3-Indolylquinones
1287
2-(2-Methyl-1H-indol-3-yl)-1,4-naphthoquinone (3b). Purple solid; mp
180–182 8C IR (KBr): n 3303, 2925, 1652, 1459, 1250, 718 cm21 1H
;
NMR (400 MHz, CDCl3): d 2.49 (s, 3H), 7.11 (s, 1H), 7.14–7.21 (m, 2H),
7.34 (d, J ¼ 7.6 Hz, 1H), 7.55 (d, J ¼ 7.6 Hz, 1H), 7.70–7.79 (m, 2H),
8.15–8.21 (m, 2H), 8.31 (s, 1H). HRMS found: m/z, 287.0930 (Mþ); calcd.
for C19H13NO2: M, 287.0946. Anal. calcd. for C19H13NO2: C, 79.43; H,
4.56; N, 4.88. Found: C, 79.40; H, 4.26; N, 4.61.
2-(4-Methyl-1H-indol-3-yl)-1,4-naphthoquinone (3c). Purple solid; mp
295–297 8C IR (KBr): n 3334, 1650, 1598, 1382, 718 cm21 1H NMR
;
(400 MHz, CDCl3): d 2.42 (s, 3H), 6.99 (s, 2H), 7.19–7.26 (m, 1H), 7.46
(s, 2H), 7.78 (s, 2H), 8.18 (d, J ¼ 16 Hz, 2H), 8.49 (s, 1H). HRMS found:
m/z, 287.0930 (Mþ); calcd. for C19H13NO2: M, 287.0946.
2-(5-Methyl-1H-indol-3-yl)-1,4-naphthoquinone (3d). Purple solid; mp
1
211-212 8C IR (KBr): n 3265, 2925, 1667, 1420, 1459, 1289, 718 cm21; H
NMR (400 MHz, CDCl3): d 2.51 (s, 3H), 7.12 (d, J ¼ 8.0 Hz, 1H), 7.35
(d, J ¼ 8.0 Hz, 1H), 7.46 (s, 1H), 7.75–7.78 (m, 3H), 8.13–8.22 (m, 3H),
8.70 (s, 1H). HRMS found: m/z, 287.0917 (Mþ); calcd. for C19H13NO2: M,
287.0946.
2-(6-Methyl-1H-indol-3-yl)-1,4-naphthoquinone (3e). Purple solid; mp
1
245-247 8C IR (KBr): n 3218, 2932, 1667, 1451, 1297, 787 cm21; H NMR
(400 MHz, CDCl3): d 2.50 (s, 3H), 7.13 (d, J ¼ 8.0 Hz, 1H), 7.45 (s, 1H),
7.75-7.89 (m, 4H), 8.12-8.23 (m, 3H), 8.59 (s, 1H). HRMS found: m/z,
287.0931 (Mþ); calcd. for C19H13NO2: M, 287.0946.
2-(7-Methyl-1H-indol-3-yl)-1,4-naphthoquinone (3f). Purple solid; mp
197–198 8C IR (KBr): n 3226, 2956, 1675, 1451, 1297, 741 cm21 1H
;
NMR (400 MHz, CDCl3): d 2.56 (s, 3H), 7.13 (s, 1H), 7.22–7.26 (m, 1H),
7.48 (s, 1H), 7.78–7.86 (m, 3H), 8.14–8.26 (m, 3H), 8.62 (s, 1H). HRMS
found: m/z, 287.0934 (Mþ); calcd. for C19H13NO2: M, 287.0946.
2-(4-(Benzyloxy)-1H-indol-3-yl)-1,4-naphthoquinone (3g). Black solid; mp
1
161–162 8C IR (KBr): n 3296, 3033, 2964, 1659, 1088, 733, 710 cm21; H
NMR (400 MHz, CDCl3): d 5.10 (s, 2H), 6.68 (d, J ¼ 7.6 Hz, 1H), 7.04–
7.28 (m, 8H), 7.47 (s, 1H), 7.62–7.71 (m, 2H), 7.96–8.05 (m, 2H), 8.66
(s, 1H). HRMS found: m/z, 379.1163 (Mþ); calcd. for C25H17NO3: M,
379.1208.
2-(5-(Benzyloxy)-1H-indol-3-yl)-1,4-naphthoquinone (3h). Black solid; mp
217–218 8C IR (KBr): n 3226, 2948, 1659, 1088, 733 cm21 1H NMR
;
(400 MHz, CDCl3): d 5.16 (s, 2H), 7.03 (d, J ¼ 8.8 Hz, 1H), 7.36–7.51
(m, 8H), 7.76 (s, 2H), 8.15–8.21 (m, 3H), 8.64 (s, 1H). HRMS found: m/z,
379.1158 (Mþ); calcd. for C25H17NO3: M, 379.1208.
2-(2-Phenyl-1H-indol-3-yl)-1,4-naphthoquinone (3i). Purple solid; mp
213–215 8C IR (KBr): n 3350, 3064, 2902, 1659, 1451, 1289, 695 cm21
;

1288
B. Liu et al.
1H NMR (400 MHz, CDCl3): d 7.19–7.28 (m, 3H), 7.35–7.37 (m, 3H), 7.43–
7.48 (m, 3H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.71–7.76 (m, 2H), 7.98
(d, J ¼ 7.6 Hz, 1H), 8.14 (d, J ¼ 7.2 Hz, 1H), 8.62 (s, 1H). HRMS found:
m/z, 349.1087 (Mþ); calcd. for C24H15NO2: M, 349.1103.
2-(4-Bromo-1H-indol-3-yl)-1,4-naphthoquinone (3j). Yellow solid; mp
282–285 8C IR (KBr): n 3319, 1659, 1598, 1297, 718 cm21 1H NMR
;
(400 MHz, CDCl3): d 7.07 (s, 1H), 7.12 (t, J ¼ 8.0 Hz, 1H), 7.36
(d, J ¼ 7.6 Hz, 1H), 7.41–7.46 (m, 2H), 7.77–7.80 (m, 2H), 8.14–8.16
(m, 1H), 8.20–8.22 (m, 1H), 8.60 (s, 1H). HRMS found: m/z, 352.9866
(Mþ); calcd. for C18H Br NO2: M, 352.9874.
81
10
2-(2-Methyl-1H-indol-3-yl)-1,4-benzoquinone (3l). Purple solid; mp 138–
140 8C IR (KBr): n 3303, 3064, 2925, 1636, 1574, 1289, 1088, 741 cm21
;
1H NMR (400 MHz, CDCl3): 2.35 (s, 3H), 6.76–6.84 (m, 3H), 7.06–7.13
(m, 2H), 7.24 (d, J ¼ 7.6 Hz, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 8.25 (s, 1H).
HRMS [found: m/z, 237.0782 (Mþ); calcd. for C15H11NO2: M, 237.0790].
2-(2-Phenyl-1H-indol-3-yl)-1,4-benzoquinone (3m). Purple solid; mp
224 8C IR (KBr): n 3404, 2964, 1652, 1598, 1297, 1088, 803, 756,
1
702 cm21; H NMR (400 MHz, CDCl3): 6.76–6.84 (m, 2H), 6.99 (s, 1H),
7.20–7.27 (m, 2H), 7.37–7.47 (m, 6H), 7.58 (d, J ¼ 7.6 Hz, 1H), 8.90
(s, 1H). HRMS found: m/z, 299.0913 (Mþ); calcd. for C20H13NO2: M,
299.0946.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (Nos. 20472062 and 20672079) the Natural Science Foundation of
Jiangsu Province (Nos. BK2004038 and BK2006048), and the Key Labora-
tory of Organic Synthesis of Jiangsu Province (No. S8109108), Nature
Science Key Basic Research of Jiangsu Province for Higher Education
(Nos. 06KJA15007 and 05KJB150116), the Key Laboratory of Fine
Petroleum Chemistry of Jiangsu Province (No. KF0402), and a research
grant from the Innovation Project for Graduate Students of Jiangsu Province.
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