Logical design and synthesis of indole-2,3-diones and 2-hydroxy-3(2H)- benzofuranones via one-pot intramolecular cyclization

Article abstract of DOI:10.1016/j.tet.2014.05.015

A novel and attractive protocol to synthesis indole-2,3-diones and 2-hydroxy-3(2H)-benzofuranones and via copper(II) oxide catalyzed intramolecular cyclization is described. This method possesses functional-group compatibility, easy workup procedure, shorter reaction time and high yields.

Full text of DOI:10.1016/j.tet.2014.05.015

Accepted Manuscript
Logical design and synthesis of Indole-2,3-diones and 2-hydroxy- 3(2H)-
benzofuranones via one-pot intramolecular cyclization
Fang-Fang Gao , Wei-Jian Xue , Jun-Gang Wang , Anxin Wu
PII:
S0040-4020(14)00675-9
10.1016/j.tet.2014.05.015
TET 25564
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 January 2014
Revised Date: 29 April 2014
Accepted Date: 5 May 2014
Please cite this article as: Gao F-F, Xue W-J, Wang J-G, Wu A, Logical design and synthesis of
Indole-2,3-diones and 2-hydroxy- 3(2H)-benzofuranones via one-pot intramolecular cyclization,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.015.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Logical design and synthesis of Indole-2,3-diones and
2-hydroxy- 3(2H)-benzofuranones via one-pot
intramolecular cyclization
Leave this area blank for abstract info.
Fang-Fang Gao, Wei-Jian Xue, Jun-Gang Wang and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China
O
O
I2. CuO, DBU
O
DMSO, 100oC
NH
R2
N
R2
R1
R1
O
O
I2. CuO, DBU
DMSO, 100oC
OH
OH
O
R
R

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Logical design and synthesis of Indole-2,3-diones and 2-hydroxy- 3(2H)-
benzofuranones via one-pot intramolecular cyclization
Fang-Fang Gao, Wei-Jian Xue, Jun-Gang Wang and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and attractive protocol to synthesis indole-2,3-diones and 2-hydroxy-3(2H)-
benzofuranones and via copper(II) oxide catalyzed intramolecular cyclization is described. This
method possesses functional-group compatibility, easy workup procedure, shorter reaction time
and high yields.
Available online
Keywords:
logical design
2009 Elsevier Ltd. All rights reserved
.
intramolecular cyclization
indole-2,3-diones
2-hydroxy- 3(2H)-benzofuranones
1. Introduction
Indole-2,3-diones (isatins) are important heterocycles found in
many natural products, pharmaceuticals.1 Also Indole-2,3-diones
are commonly used in organic synthesis to construct new
structural frameworks.2 Traditionally, the most practical
approach to this class of compounds is the Sandmeyer method,3
starting from the requisite aniline, chloral hydrate,
hydroxylamine hydrochloride and sulfuric acid, which provided a
useful access to construct isatins. However, in more recent years,
a wider variety of efficient methods have been developed for the
synthesis
intramolecular
of
indole-2,3-diones.
C-H oxidation/acylation
The
copper-catalyzed
of formyl-N-
Scheme 1. In situ trapping of unstable α-ketoaldehyde intermediates
arylformamides has also proven successful in the construction of
indole-2,3-diones with oxygen as oxidant.4 In addition, Jadhav
and co-workers reported a general catalytic Cu(OAc)2/TEMPO
method performed in either air or Cu(OAc)2/O2 systems for the
C-N and C-O cross-coupling reaction to construct indole-2,3-
diones.5 Indoles have also been utilized as substrates for the
synthesis of indole-2,3-diones with selected catalyst.6 Although
each existing method has its own merits for the preparation of
certain indole-2,3-dione derivative(s), further investigation into a
simpler general method remains highly valuable.
strategy to construct diverse compounds through intermolecular reactions.
In recent years, we reported an efficient in situ trapping of
unstable-ketoaldehyde intermediates strategy to construct diverse
compounds through intermolecular reactions (Scheme 1).7 Also,
we suspect to design intramolecular reactions in situ capture α-
ketoaldehyde as a supplement of intermolecular reactions.
Retrosynthetically (Scheme 2), it was envisioned that 1-
methylindoline-2,3-dione could be obtained from 2-(2-
(methylamino)phenyl)-2-oxoacetaldehyde
A
through
an
intramolecular condensation process,8 while A could be furnished
from the α-halogenated ketone through Kornblum Oxidation.9 It
was also suggested that B could be easily prepared from 1-(2-
(methylamino)phenyl)ethanone 1a through
a
halogenation
process.10 Based on the retrosynthetic analysis, it was herein
———
* Corresponding author Tel./fax: +86 027 6786 7773; e-mail: chwuax@mail.ccnu.edu.cn (A. X. Wu)

2
Tetrahedron
ACCEPTED MANUSCRIPT
assumed that indole-2,3-diones could be obtained from 1-(2-
the reaction was conducted in the absence of the CuO, only 20%
aminophenyl)ethanones
via
the
integration
of
of the product 2a could be obtained (Table 1, entry 15). These
results indicated that I2, DBU and CuO are necessary for the
reaction. Moreover, further examination revealed that
adjustments in temperature resulted in decreased yields (Table 1,
entry 19-22). It was thus determined that the optimum conditions
for this reaction were I2/DBU/CuO (0.5 equiv/0.5 equiv/0.5 equiv)
at a temperature of 100 ꢀin DMSO (Table 1, entry 8).
iodination/oxidation/cyclization sequences.11
Scheme 2. Retrosynthetic analysis and the protocols for one-pot
synthesis of 1-methylindoline-2,3-dione through intramolecular
cyclization.
Table 2. Reaction scope of methyl ketonesa
2. Results and discussion
Our investigation began this reaction with 1-(2-
(phenylamino)phenyl)ethanone 1a as model substrate in DMSO.
The reaction of 1-(2-(methylamino)phenyl)ethanone with I2/CuO
Table 1. Optimization of the reaction conditionsa
Entry
1
2
Yieldsb (%)
1
2
3
4
1c (R1=H, R2=CH3)
1b (R1=H, R2=Ph)
1c (R1=H, R2=Bn)
1d ((R1=[d][1,3]dioxol-5
-yl, R2=CH3)
2a
2b
2c
2d
90
83
85
82
5
6
1e R1=5-I, R2= Ph)
1g (R1=[d][1,3]dioxol-5-yl,
R2= Ph)
2e
2f
91
78
Entry
I2
(equiv)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Base
CuO
(equiv)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Temp
Yield
(%)b
22
35
58
63
80
83
52
90
55
Trace
76
88
67
65
20
38
(
)
7
1h (R1=H, R2=H)
2g
0
1c
2
3
4
5
6
7
8
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
a
Reaction conditions: 1a (1.0 mmol), I2 (0.5 mmol), DBU (0.5 mmol),
NaOH
KOH
Na2CO3
K2CO3
Cs2CO3
Et3N
DBU
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
CuO (0.5 mmol) were heated in DMSO at 100 ℃for 2h.
b Isolated yields.
0.5
0.5
9
10d
11
12
13
14
15e
16
17
18
19
20
21
22
0.25
0.75
1.0
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.75
1.0
1.25
0.5
0.5
0.5
35
32
42
73
87
83
Fig. 1. X-ray crystal structure of compound 2c
80
90
110
0.5
With this optimized result in hand, we next explored the scope
of this reaction, diverse Indole-2,3-diones (2a-2f) was achieved
high yields using optimum condition (Table 2). Much to our
surprise when the substrate was 1-(2-aminophenyl)ethanone, no
deserved product was obtained. (Table 2, 2g), this may be that 1-
a Reaction conditions: 1a (1.0 mmol), CuO (0.5 mmol) were heated in
DMSO for 2h.
b Isolated yields.
c Reaction conditions: 1a (1.0 mmol), I2 (0.5 mmol), CuO (0.5 mmol)
(2-aminophenyl)ethanone
was
oxidized
to
1-(2-
were heated in DMSO at 100 ꢀfor 2h.
nitrophenyl)ethanone under the reaction condition. Fortunately
the target products 2c (Fig. 1)12 and 2e (in Supplementary data)
were further determined by X-ray crystallographic analysis.
d
Reaction conditions: 1a (1.0 mmol), DBU (0.5 mmol), CuO (0.5
mmol) were heated in DMSO at 100 ꢀfor 2h.
e Reaction conditions: 1a (1.0 mmol), I2 (0.5 mmol), DBU (0.5 mmol)
2-hydroxybenzofuran-3(2H)-ones are also compounds which
are recurrent motifs and subunits in organic molecules with
interesting biological activities, such as antimicrobial activity,13,14
antilammatory,14 antifungalactivity.13,16 Therefore, considerable
attention has been paid to their efficient synthetic methods.17
Inspired by the aformentioned results, it was supposed that 2-
hydroxybenzofuran-3(2H)-ones could also be constructed from
1-(2-hydroxyphenyl)ethanones by intramolecular cyclization
under the standard conditions. As depicted in Table 3, the
conditions were mild enough to be compatible with electron-
donating and halogenated substrates (68-83%; 4a-4e). Pleasingly,
were heated in DMSO at 100 ꢀfor 2h.
(0.5 equiv/0.5 equiv) could only afford the desired product in
very low yield at 100ꢀin DMSO (Table 1, entry 1). To improve
the yield of the products, the amount of I2, CuO and various
bases were investigated in further detail in DMSO. First, a series
of bases, such as NaOH, KOH, Na2CO3, K2CO3, Cs2CO3, Et3N,
DBU and DABCO were screened for the reaction (Table 1, entry
2-9). Much to our satisfaction, the reaction efficiency was much
improved to 90% with DBU as the base. When the reaction was
conducted without I2, almost no desired product was obtained
(Table 1, entry 10). However, further increases in the additive
dose to 0.5 equiv could not enhance the yield beyond 90%. When

3
Table 3. Reaction scope of methyl ketones and benzylamine
3. Conclusion
ACCEPTED MANUSCRIPT
derivativesa,b
In conclusion, we have reported a new intramolecular
cyclization to construct Indole-2,3-diones and 2-hydroxy- 3(2H)-
benzofuranones
from
easily
available1-(2-aminophenyl)
ethanones and 1-(2-hydroxyphenyl)ethanones via a one-step,
one-pot procedure. This reaction provided significant advantages
in the use of simple substrates, mild reaction conditions and
provision of excellent yields. Further studies on the design of
other complicated compounds and investigations toward the
applications in organic synthesis are currently underway in our
laboratory.
Entry
R
4
Yieldsb (%)
1
2
3
4
5
3a (H)
3b (5-F)
3c (5-Br)
3d (4-F)
3e (5-OCH3)
4a
4b
4c
4d
4e
72
70
79
83
80
4. Experimental
4.1. General
6
4f
81
All substrates and reagents were commercially available and
used without further purification. TLC analysis was performed
using pre-coated glass plates. Column chromatography was
performed using silica gel (200–300 mesh). IR spectra were
recorded on a Perkin-Elmer PE-983 infrared spectrometer as KBr
7
4g
85
1
pellets with absorption in cm–1. H spectra were recorded in
a Reaction conditions: 1a (1.0 mmol), I2 (0.5 mmol), DBU (0.5
mmol), CuO (0.5 mmol) were heated in DMSO at 100 ꢀfor 2h.
b Isolated yields.
CDCl3 or DMSO-d6 on 400/600 MHz NMR spectrometers and
resonances (δ) are given in parts per million relative to
tetramethylsilane. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet),
coupling constants (Hz) and integration. 13C spectra were
recorded in CDCl3 or DMSO-d6 on 100 MHz NMR
spectrometers and resonances (δ) are given in ppm. HRMS were
obtained on a Bruker 7-tesla FT-ICR MS equipped with an
electrospray source. MS was carried out on a Thermo DSQ ꢁ
MS spectrometer (EI, 70 eV). Elemental analyses were
performed using a VARIO EL Ⅲelemental analyzer. The X-ray
crystal-structure determinations were obtained on a Bruker
SMART APEX CCD system. Melting points were determined
using XT-4 apparatus and not corrected.
the desired 2-hydroxybenzofuran-3(2H)-ones could be obtained
in good yields from steric substrates (80%-85%; 4f-4g). To our
delight, product 4e was also further determined by X-ray
crystallographic analysis (Fig. 2).18
4.2. General procedure for synthesis of 2 (2a as an example)
A
sealed
tube
was
charged
with
1-(2-
(methylamino)phenyl)ethanone 1a (74.6 mg, 0.5 mmol), 1,8-
Diazabicyclo[5.4.0]undec-7-ene (38.1 mg, 0.25 mmol), copper
(ꢁ) oxide (20 mg, 0.25 mmol) and iodine (63.5 mg, 0.25 mmol)
at room temperature, and then dried solvent DMSO (3mL)
was added. The resulting mixture was stirred at 100 ꢀ and
monitored to completion by TLC analysis. After cooling to room
temperature, H2O (50 ml) was added and the aqueous mixture
was extracted with EtOAc 3 times (3 × 50 mL). The combined
organic extracts were washed with brine (20 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using petroleum ether/EtOAc as the eluent to give the expected
product 2a as yellow solid (90% yield).
Fig. 2. X-ray crystal structure of compound 4e
In accordance with the results, a plausible mechanism
proposed for the I2/CuO promoted cyclization reaction is
presented in Scheme 3. It is proposed that 1-(2-
(methylamino)phenyl)ethanone 1a with I2 and CuO initially
undertook a halogenation reaction to afford the intermediate α-
iodo-1-(2-(methylamino)phenyl)ethanone B. Subsequently, B
was further converted into the intermediate 2-oxo-2-(2-
(methylamino)phenyl)acetaldehyde A via Kornblum oxidation.19
The addition of the glyoxal group with amine generates
hemiaminal intermediate C.11 Finally, it is proposed that
intermediate C underwent oxidation to provide the desired
product 2a.
4.3. General procedure for synthesis of 4 (4a as an example)
A sealed tube was charged with 1-(2-hydroxyphenyl)ethanone
3a (75.1 mg, 0.5 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene
(38.1 mg, 0.25 mmol), copper(ꢁ) oxide (20 mg, 0.25 mmol)
and iodine (63.5 mg, 0.25 mmol) at room temperature, and
then dried solvent DMSO (3 mL) was added. The resulting
mixture was stirred at 100 ꢀ and monitored to completion by
TLC analysis. After cooling to room temperature, H2O (50 ml)
was added and the aqueous mixture was extracted with EtOAc 3
times (3 × 50 mL). The combined organic extracts were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using petroleum ether/EtOAc as the
Scheme 3. Plausible mechanism for the reaction.

4
Tetrahedron
ACCEPTED MANUSCRIPT
4.4.7 2-hydroxybenzofuran-3(2H)-one (4a)
eluent to give the expected product 4a as light yellow solid
(72% yield).
o
Yield 72%; light yellow solid; mp 133–135 C; IR (KBr): 3441,
3221, 1704, 1617, 1463, 1322, 1147, 1128, 998, 762 cm–1; H
1
4.4. Characterization data
4.4.1 1-methylindoline-2,3-dione (2a)
NMR (400 MHz, CDCl3): δ (ppm) = 7.65 (d, J = 8.4 Hz, 1H),
7.62 (s, 1H), 7.09 (d, J = 7.2 Hz, 1H), 5.62 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 198.75, 171.47, 139.45, 125.02,
122.48, 119.00, 113.51, 96.93; MS (70ev): m/z = 150.11; Anal.
Calcd. for C8H6O3: C, 64.00; H, 4.03 %. Found: C, 63.81; H,
4.15 %.
o
Yield 90%; red solid; mp 118-120 C; IR (KBr): 3451, 1749,
1722, 1601, 1475, 1323, 1114, 831, 702, 470 cm–1; 1H NMR (400
MHz, CDCl3): δ (ppm) = 7.61 (s, 1H), 7.28 (s, 1H), 7.14 (s, 1H),
6.91 (d, J = 8.0 Hz, 1H), 3.26 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 183.19, 158.01, 151.22, 138.36, 124.94,
123.65, 117.12, 109.89, 26.04; HRMS (APCI): m/z [M + Na]+
calcd for C9H7NaNO2: 184.0369; found: 184.0371.
4.4.8 5-fluoro-2-hydroxybenzofuran-3(2H)-one (4b)
o
Yield 70%; brown solid; mp 189-192 C; IR (KBr): 3253, 1712,
1493, 1342, 1315, 1245, 1164, 1133, 1109, 1024, 933, 825, 782
4.4.2 1-phenylindoline-2,3-dione (2b)
1
cm–1; H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.66-7.61 (m,
1H), 7.48-7.45 (m, 1H), 5.65 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 198.28, 167.01, 126.48 (d, JCF = 25.0 Hz),
119.87, 114.93, 109.50 (d, JCF = 23.0 Hz), 98.62; MS (70ev): m/z
= 168.11; Anal. Calcd. for C8H5FO3: C, 57.15; H, 3.00 %. Found:
C, 57.02; H, 2.89 %.
o
Yield 85%; red solid; mp 162-164 C; IR (KBr): 3459, 1736,
1609, 1491, 1466, 1471, 1367, 1296, 1193, 926, 854, 810, 760,
698, 485 cm–1; 1H NMR (600 MHz, CDCl3): δ (ppm) = 7.88 (d, J
= 7.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.42 (d, J =
7.2 Hz, 2H), 7.19 (s, 2H); 6.91 (d, J = 4.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 138.99, 138.29, 129.84, 128.70,
127.56, 125.86, 125.62, 125.45, 124.47, 124.21, 110.20, 111.06;
HRMS (APCI): m/z [M + Na]+ calcd for C14H9NaNO2: 246.0530;
found: 246.0526.
4.4.9 5-bromo-2-hydroxybenzofuran-3(2H)-one (4c)
o
Yield 79%; white solid; mp 124-126 C; IR (KBr): 3417, 1716,
1
1613, 1466, 1272, 1145, 1115, 923, 826 cm–1; H NMR (400
MHz, DMSO-d6): δ (ppm) = 7.87 (d, J = 8.8 Hz, 1H), 7.79 (s,
1H), 7.19 (d, J = 8.8 Hz, 1H), 5.65 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 197.34, 169.50, 141.28, 126.51, 121.37,
115.78, 113.51, 98.45; MS (70ev): m/z = 228.04; Anal. Calcd.
for C8H5BrO3: C, 41.95; H, 2.20 %. Found: C, 41.66; H, 2.09 %.
4.4.3 1-benzylindoline-2,3-dione (2c)
o
Yield 85%; yellow solid; mp 163-165 C; IR (KBr): 3450, 1736,
1607, 1491, 1466, 1367, 1296, 1193, 927, 760, 468 cm–1; H
1
NMR (400 MHz, CDCl3): δ (ppm) = 7.86 (s, 1H), 7.76 (d, J = 8.4
Hz, 1H), 7.35-7.31 (m, 6H), 6.58 (d, J = 8.4 Hz, 1H) , 4.91 (s,
2H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 181.81, 157.15,
149.89, 146.26, 133.95, 133.72, 129.07, 128.26, 127.32, 119.10,
113.11, 86.17, 44.05; HRMS (APCI): m/z [M + Na]+ calcd for
C15H11NaNO2: 260.0682; found: 260.0685.
4.4.10 6-fluoro-2-hydroxybenzofuran-3(2H)-one (4d)
Yield 83%; yellow oil; IR (KBr): 3435, 2962, 2831, 1727, 1647,
1509, 1421, 1367, 1259, 1156, 1123, 988, 854, 799, 599, 558
1
cm–1; H NMR (600MHz,): δ (ppm) = 7.39 (d, J = 9.6 Hz ,1H) ,
6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 9.6 Hz, 1H), 6.12 (t, J = 9.0
Hz 1H), 4.81 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm)
= 196.45, 172.20 (d, JCF = 15.0 Hz), 170.33, 167.79, 126.77 (d,
JCF =12.0 Hz), 116.43, 110.47, 100.78 (d, JCF = 26.0 Hz), 98.92 (d,
JCF =13.0 Hz); MS (70ev): m/z = 168.08; Anal. Calcd. for
C8H5FO3: C, 57.15; H, 3.00 %. Found: C, 56.96; H, 2.81 %.
4.4.4 5-methyl-5H-[1,3]dioxolo[4,5-f]indole-6,7-dione (2d)
o
Yield 85%; red solid; mp 192-194 C; IR (KBr): 3426, 1735,
1612, 1479, 1435, 1384, 1344, 1242, 1094, 1036, 934, 807, 487
1
cm–1; H NMR (400 MHz, CDCl3): δ (ppm) = 7.02 (s, 1H), 6.44
(s, H), 6.08 (s, 2H), 3.19 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
(ppm) = 180.66, 159.16, 156.57, 151.13, 144.35, 110.16, 104.84,
102.63, 92.99, 26.25; HRMS (APCI): m/z [M + Na]+ calcd for
C15H12NaNO4: 228.0270; found: 228.0267.
4.4.11 2-hydroxy-5-methoxybenzofuran-3(2H)-one (4e)
o
Yield 80%; light brown solid; mp 190-193 C; IR (KBr): 3253,
1716, 1492, 1342, 1285, 1245, 1164, 1134, 1110, 1025, 933, 825,
4.4.5 1-benzyl-5-iodoindoline-2,3-dione (2e)
1
782 cm–1; H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.36 -7.34
(m, 1H), 7.13 (d, J = 6Hz, 1H), 7.06 (s, 1H), 5.56 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): δ (ppm) = 198.63, 165.76, 154.40,
128.05, 119.28, 114.35, 104.90, 98.18; MS (70ev): m/z = 180.13;
Anal. Calcd. for C9H8O4: C, 60.00; H, 4.48 %. Found: C, 59.72;
H, 4.36 %.
o
Yield 91%; yellow solid; mp 199-201 C; IR (KBr): 3448, 1745,
1731, 1603, 1467, 1434, 1325, 1313, 1176, 1127, 818, 713, 517
1
cm–1; H NMR (400 MHz, CDCl3): δ (ppm) = 7.89 (s, 1H), 7.78
(s, 1H), 7.76 (s, 1H), 7.36-7.29 (m, 5H); 6.57 (d, J = 8.4 Hz, 1H),
4.92 (s, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 181.84,
157.18, 149.92, 146.30, 133.96, 133.80, 129.11, 128.31, 127.35,
119.14, 113.12, 86.20, 44.08; MS (70ev): m/z = 363.21; Anal.
Calcd. for C15H10INO2: C, 49.61; H, 2.78; N, 3.86 %. Found: C,
49.75; H, 2.85; N, 3.69 %.
4.4.12 2-hydroxynaphtho[2,1-b]furan-1(2H)-one (4f)
o
Yield 81%; yellow solid; mp 238-240 C; IR (KBr): 3195, 1669,
1578, 1530, 1449, 1286, 1206, 1139, 1095, 929, 824, 751, 576,
465 cm–1; 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.55 (d, J =
8.0 Hz ,1H), 8.35 (d, J = 8.8Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H),
7.72 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.8
Hz, 1H), 5.71(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm)
= 197.94, 173.55, 141.09, 130.17, 129.12, 128.70, 128.61, 125.29,
121.89, 114.25, 110.79, 98.61; HRMS (APCI): m/z [M + Na]+
calcd for C12H8NaO3: 223.0366; found: 223.0366.
4.4.6 5-benzyl-5H-[1,3]dioxolo[4,5-f]indole-6,7-dione (2f)
o
Yield 78%; red solid; mp 191-193 C; IR (KBr): 3458, 2926,
1741, 1722, 1612, 1494, 1472, 1410, 1386, 1345, 1325, 1247,
1156, 1031, 896, 832, 798, 710, 697, 600, 488, 460 cm–1; H
1
NMR (400 MHz, CDCl3): δ (ppm) = 7.35-7.27 (m, 5H); 7.00 (s,
1H), 6.29 (s, 1H), 6.01 (s, 2H), 4.86 (s, 2H), 6.57 (d, J = 8.4 Hz,
1H), 4.92 (s, 2H); 13C NM.R (100 MHz, CDCl3): δ (ppm) =
220.09, 203.83, 180.43, 159.19, 156.34, 150.25, 144.39, 134.48,
129.02, 128.09, 127.20, 110.39, 104.73, 102.56, 94.00, 43.92;
HRMS (APCI): m/z [M + Na]+ calcd for C16H11NNaO4: 304.0580;
found: 304.0582.
4.4.13 2-hydroxynaphtho[1,2-b]furan-3(2H)-one (4g)
o
Yield 85%; light yellow solid; mp 179-182 C; IR (KBr): 3445,
1633, 1467, 1434, 1307, 1284, 1257, 1210, 1091, 792, 764 cm–1;
1H NMR (600 MHz, DMSO-d6): δ (ppm) = 7.96-7.92 (m, 1H),

5
6562; (b) Zhu, Y. P.; Liu, M. C.; Jia, F. C.; Yuan, J. J.; Gao, Q. H.;
7.84 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.5
Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6): δ (ppm) = 173.06, 160.38, 136.82,
131.49, 129.45, 127.68, 125.97, 124.89, 124.13, 123.20, 118.44,
106.05; MS (70ev): m/z = 200.15; Anal. Calcd. for C12H8O3: C,
72.00; H, 4.03 %. Found: C, 71.83; H, 3.89 %.
ACCEPTED MANUSCRIPT
Lian, M.; Wu, A. X. Org. Lett. 2012, 14, 3392-3395; (c) Jiang, H. F.;
Huang, H. W.; Cao, H.; Qi, C. R. Org. Lett. 2010, 12, 5561-5563; (d)
Xue, W. J.; Guo, Y. Q.; Gao, F. F.; Li, H. Z.; Wu, A. X. Org. Lett. 2013,
15, 890-893; (e) Zhu, Y. P.; Fei, Z.; Liu, M. C.; Jia, F. C.; Wu, A. X.
Org. Lett. 2013, 15, 378-381; (f) Zhu, Y. P.; Cai, Q.; Gao, Q. H.; Jia, F.
C; Liu, M. C; Gao, M.; Wu, A. X. Tetrahedron 2013, 69, 6392-6398; (g)
Lian, M.; Li, Q.; Zhu, Y. P.; Yin, G. D.; Wu, A. X. Tetrahedron 2012,
69, 9598-9605; (h) Gao, Q. H.; Wu, X.; Jia, F. C.; Liu, M. C.; Zhu, Y.
P.; Cai, Q.; Wu, A. X. J. Org. Chem. 2013, 78, 2792−2797.
Acknowledgments
10. (a) Pavlinac, J.; Stavber, S.; Zupan, M. J. Org. Chem. 2006, 71, 1027-
1032; (b) Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan, Y.
J. Synthesis 2007, 20, 3113-3116; (c) Wang, Z. H.; Yin, G. D.; Qin, J.;
Gao, M.; Cao, L. P.; Wu, A. X. Synthesis 2008, 22, 3675-3681; (d) Zhu,
Y. P.; Gao, Q. H.; Lian, M.; Yuan, J. J.; Liu, M. C.; Zhao, Q.; Yang, Y.;
Wu, A. X. Chem. Commun. 2011, 47, 12700-12702.
11. During our preparation of this manuscript Deng and co-workers reported
the same starting materials as ours: Selenium-Promoted Intramolecular
Oxidative Amidation of 2-(Arylamino)-acetophenones for the Synthesis
of N-Arylisatins Liu, Y.; Chen, H.; Hu, X.; Zhou, W.; Deng, G. J. Eur. J.
Org. Chem. 2013, 20, 4229–4232.
12. Crystal structure data for compound 2c: CCDC number 948705, C15
H11NO2, Monoclinic, space group P2(1)/c, a = 6.592(4), b = 4.916(3), c
= 18.359(10) Å, α = 90°, β = 98.768(7)°, γ = 90°, V = 588.0(6) Å3, T =
296(2) K, Z = 2, Dc= 1.340 Mg/m3, ꢀ = 0.090 mm-1, λ = 0.71073 Å,
F(000) 248, crystal size 0.12 x 0.10 x 0.10 mm3, 2191 independent
reflections [R(int) = 0.0445], reflections collected 4304, refinement
method: Full-matrix least-squares on F2: goodness-of-fit on F2 1.055,
final R indices [I > 2σ(I)], R1 = 0.0472, wR2 = 0.1286, largest diff. peak
and hole 0.188and -0.197e.Å-3.
This work was supported by Central China Normal University,
the National Natural Science Foundation of China (Grant
21032001 and 21272085). We thank Dr. Xianggao Meng
(Central China Normal University) for performing X-ray
crystallographic analysis and Dr. Chuanqi Zhou (Hebei
University) for performing the HRMS analysis.
Supplementary data
1
The X-ray crystal structures of compound 2f and H and 13C
NMR spectra of compounds are available in Supplementary data.
Supplementary data related to this article can be found online at
doi:
References and notes
13. Luo, J.; Liu, X. Y.; Li, E. W.; Guo, L. D.; Chen, Y. S. J. Nat. Prod.
2013, 76, 107-112 .
1. (a) Daisley, R. W.; Shah, V. K. J. Pharm. Sci. 1984, 73, 407-408; (b)
Chapman, J. G.; Magee, W. P.; Stukenbrok, H. A.; Beckius, G. E.;
Milici, A. J.; Tracey, W. R. Eur. J. Pharmacol. 2002, 456, 59-68; (c)
Lee, D.; Long, S. A.; Murray, J. H.; Adams, J. L.; Nutall, M. E.; Nadeau,
D. P.; Kikly, K.; Winkler, J. D.; Sung, C. M.; Ryan, M. D.; Levy, M. A.;
Keller, P. M.; DeWolf, W. E. J. Med. Chem. 2001, 44, 2015-2026; (e)
Silva, J. F. M. D.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001,
12 , 273-324.
2. For selected examles, see: (a) Kiyota, H.; Shimizu, Y.; Oritani, T.
Tetrahedron Lett. 2000, 41, 5887-5890; (b) Elsinghorst, P. W.; Cavlar, T.;
Müller, A.; Braune, A.; Blaut, M.; Gütschow, M. J. Nat. Prod. 2011, 74,
2243-2249; (c) Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett. 2011,
13, 2876-2879.
3. Sandmeyer, T. Helv. Chim. Acta. 1919, 2, 234–242; (b) Pinto, A. C.;
Lapis, A. A. M.; Silva, B. V. D.; Bastos, R. S.; Dupont, J.; Neto, B. A. D.
Tetrahedron Lett. 2008, 49, 5639-5641.
4. Tang, B, X.; Song, R. J.; Wu, C. Y.; Liu, Y.; Zhou, M. B.; Wei, W. T.;
Deng, G. B.; Yin, D. L.; Li, J. H. J. Am. Chem. Soc. 2010, 132, 8900–
8902.
14. Trisuwan, K.; Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit, S.;
Preedanon, S.; Sakayaroj, J. Tetrahedron 2010, 66, 4484-4489.
15. Chen, J. J.; Tsai, Y. C.; Hwang, T. L.; Wang, T. C. J. Nat. Prod. 2011,
74, 1021–1027.
16. Viturro, C. I.; Fuente, J. R. D. L; Maier, M. S. J. Nat. Prod. 2004, 67,
778-782.
17. (a) Loser, R.; Chlupacova, M.; Marecek, A.; Opletalova, V.; Gutschow,
M. Helvetica Chimica Acta. 2004, 87, 2597-2004; (b) Kiyota, H.;
Shimizu, Y.; Oritani, T. Tetrahedron Lett. 2000, 41, 5887-5890; (c)
Fan, R. H.; Sun, Y.; Ye, Y. Org. Lett. 2009ꢂ11, 5174-5177.
18. Crystal structure data for compound 4b: CCDC number 948707, C9 H8
O4, Orthorhombic, space group Pna2(1), a = 20.870(5), b = 3.9446(9),
c = 9.784(2) Å, α = 90°, β = 90 °, γ = 90°, V = 805.3(6) Å3, T = 296(2)
K, Z = 4, Dc = 1.486 Mg/m3, ꢀ = 0.118 mm-1, λ = 0.71073 Å, F(000)
376, crystal size 0.12 x 0.10 x 0.10 mm3, 2427 independent reflections
[R(int) = 0.0435], reflections collected 4304, refinement method: Full-
matrix least-squares on F2: goodness-of-fit on F2 1.055, final R indices
[I > 2σ(I)], R1 = 0.0434, wR2 = 0.9875, largest diff. peak and hole 0.172
and -0.141e.Å-3.
5. Yadav, J. S., Reddy, S. B. V., Reddy, S. C.; Krishna, A. D.,
Tetrahedron Lett. 2007, 48, 693–696.
19. Halogenation reaction and Kornblum oxidation processes are well
investigated in our previous studies. See refs 8b-8h and 9b-9d.
6.
For selected examples, see: (a) Yadav, J. S., Reddy, S. B. V., Reddy, S.
C.; Krishna, A. D. synthesis 2007, 5, 693-696; (b)Chebolu, N. S. S. P.
K.; Chebrolu, L. D.; Vaidya, J. R.; Srinivasan, P. Synlett 2008, 13, 2023
–2027.
7. (a) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao, Q. H.;
Wu, A. X. Chem. Commun. 2012, 9086-9088; (b) Zhu, Y. P.; Liu, M. C.;
Jia, F. C.; Yuan, J. J.; Gao, Q. H.; Lian, M.; Wu, A. X. Org. Lett. 2012,
14, 3392-3395; (c) Xue, W. J.; Li, Q.; Zhu, Y. P.; Wang, J. G.; Wu, A.
X. Chem. Commun. 2012, 3485-3487; (d) Yin, G. D.; Zhou, B. H.;
Meng, X. G.; Wu, A. X.; Pan, Y. J. Org. Lett. 2006, 8, 2245-2248; (e)
Yin, G. D.; Wang, Z. H.; Chen, A. H.; Gao, M.; Wu, A. X.; Pan, Y. J. J.
Org. Chem. 2008, 73, 3377-3383; (f) Gao, M.; Yin, G. D.; Wang, Z. H.;
Wu, Y. D.; Guo, C.; Pan, Y. J.; Wu, A. X. Tetrahedron 2009, 65, 6047-
6049; (g) Gao, M.; Yang, Y.; Wu, Y. D.; Deng, C.; Cao, L. P.; Meng, X.
G.; Wu, A. X. Org. Lett. 2010, 12, 1856-1859; (h) Yang, Y.; Gao, M.;
Zhang, D. X.; Wu, L. M.; Shu, W. M.; Wu, A. X. Tetrahedron 2012, 68,
7338-7344; (i) Yang, Y.; Gao, M.; Deng, C.; Zhang, D. X.; Wu, L. M.;
Shu, W. M.; Wu, A. X. Tetrahedron 2012, 68, 6257-6262; (j) Zhu, Y. P.;
Jia, F. C.; Liu, M. C.; Wu, A. X. Org. Lett. 2012, 14, 4414-4417; (k)
Gao, Q. H.; Fei, Z,; Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; She, N.
F.; Wu, A. X. Tetrahedron 2013, 69, 22-28; (l) Fei, Z.; Zhu, Y. p.; Liu,
M. C.; Jia, F. C; Wu, A. X. Tetrahedron Lett. 2013, 54, 1222-1226.
8. Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61, 10153-10202.
9. (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson,
H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562-

ACCEPTED MANUSCRIPT
Supporting Information
Logical design and synthesis of Indole-2,3-diones and 2-hydroxy-
3(2H)-benzofuranones via one-pot intramolecular cyclization
Fang-Fang Gao, Wei-Jian Xue, Jun-Gang Wang and An-Xin Wu*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal
University,
Wuhan 430079, People’s Republic of China
E-mail: chwuax@mail.ccnu.edu.cn
Table of Contents
page
1. General.………………………………………………........…............... S2
2. Synthesis of 2a-2g, 4a-4g.........................................................................S2
3. Control experimental…………………………………………………….S2-S3
4. Crystallographic data and molecular structure of compounds 2e…......... S4
5. Appendix: spectral copies of 1H NMR, and 13C NMR …………….…....S5-S17
S1

ACCEPTED MANUSCRIPT
1. General
All substrates and reagents were commercially available and used without
further purification. TLC analysis was performed using pre-coated glass plates.
Column chromatography was performed using silica gel (200–300 mesh). IR
spectra were recorded on a Perkin-Elmer PE-983 infrared spectrometer as KBr
pellets with absorption in cm–1. 1H spectra were recorded in CDCl3 or DMSO-d6 on
400/600 MHz NMR spectrometers and resonances (δ) are given in parts per
million relative to tetramethylsilane. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constants
(Hz) and integration. 13C spectra were recorded in CDCl3 or DMSO-d6 on 100 MHz
NMR spectrometers and resonances (δ) are given in ppm. HRMS were obtained on
a Bruker 7-tesla FT-ICR MS equipped with an electrospray source. MS was
carried out on a Thermo DSQ ꢀ MS spectrometer (EI, 70 eV) Elemental
analyses were performed using a VARIO EL ꢁ elemental analyzer. The X-ray
crystal-structure determinations were obtained on a Bruker SMART APEX CCD
system. Melting points were determined using XT-4 apparatus and not corrected.
2. Synthesis of 2a-2g, 4a-4g
2.1. General procedure for synthesis of 2a-2g (2a as an example)
General
procedure:
A
sealed
1a
tube
(80.6
was
mg,
charged
0.5
with
mmol),
1-(2-(methylamino)phenyl)ethanone
1,8-Diazabicyclo[5.4.0]undec-7-ene (38.1 mg, 0.25 mmol), copper (Ⅱ) oxide (20 mg,
0.25 mmol) and iodine (63.5 mg, 0.25 mmol) at room temperature, and then
dried solvent DMSO (3mL) was added. The resulting mixture was stirred at 110 ℃
and monitored to completion by TLC analysis. After cooling to room temperature,
H2O (50 ml) was added and the aqueous mixture was extracted with EtOAc 3
times (3 × 50 mL). The combined organic extracts were washed with brine (20
mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using petroleum
ether/EtOAc as the eluent to give the expected product 2a as yellow solid (90%
yield).
2.2 . General procedure for synthesis of 4a-4g (4a as an example)
General procedure: A sealed tube was charged with 1-(2-hydroxyphenyl)ethanone
3a (75.1 mg, 0.5 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (38.1 mg, 0.25 mmol),
copper(Ⅱ) oxide (20 mg, 0.25 mmol) and iodine (63.5 mg, 0.25 mmol) at room
temperature, and then dried solvent DMSO (3mL) was added. The resulting
mixture was stirred at 100 ℃and monitored to completion by TLC analysis. After
cooling to room temperature, H2O (50 ml) was added and the aqueous mixture was
extracted with EtOAc 3 times (3 × 50 mL). The combined organic extracts were
washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using petroleum ether/EtOAc as the eluent to give the expected product
4a as light yellow solid (72% yield).
S2

ACCEPTED MANUSCRIPT
3. Control experimental
To confirm the reaction process, the reaction of intermediate
1-(2-hydroxyphenyl) -2-iodoethanone was carried out. A mixture of
1-(2-hydroxyphenyl)ethanone 3a (1 equiv), CuO (1 equiv), and iodine (1 equiv) in
methanol was heated at 80 °C for 1 h. compound 3aa was obtained (Scheme s1).
Then the reaction was carried out with the mixture as substrate under the
optimum condition, we have also gotten the target compound 4a (Fig. s1).
Scheme s1. iodination of 1-(2-hydroxyphenyl)ethanone
Fig. s1. 1H NMR spectroscopic monitoring of the present reaction.
3a
mixture
4a
S3

ACCEPTED MANUSCRIPT
3. Crystallographic data and molecular structure of compounds 2e
Fig. s2. X-ray crystal structure of compound 2e
Crystal structure data for compound 2e: CCDC number: 960539, C15H10INO2
,
Orthorhombic, space group P2(1)2(1)2(1), a = 4.5682(12), b = 13.600(4), c = 22.338(6) Å, α = 90°,
β = 90°, γ = 90°, V = 1387.8(7) Å3, T = 296(2)K, Z = 4, Dc = 1.738Mg/m3, µ = 2.304 mm-1, λ =
0.71073Å, F(000) 704, crystal size 0.15 x 0.12 x 0.10 mm3, 2827 independent reflections [R(int) =
0.0726], reflections collected 10305, refinement method: Full-matrix least-squares on F2:
goodness-of-fit on F2 1.037, final R indices [I > 2σ(I)], R1 = 0.0611, wR2 = 0.1517, largest diff.
peak and hole 1.261 and -1.536e.Å-3. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
S4

ACCEPTED MANUSCRIPT
4. Appendix: spectral copies of 1H NMR, and 13C NMR
S5

ACCEPTED MANUSCRIPT
S6

ACCEPTED MANUSCRIPT
S7

ACCEPTED MANUSCRIPT
S8

ACCEPTED MANUSCRIPT
S9

ACCEPTED MANUSCRIPT
S10

ACCEPTED MANUSCRIPT
S11

ACCEPTED MANUSCRIPT
S12

ACCEPTED MANUSCRIPT
S13

ACCEPTED MANUSCRIPT
S14

ACCEPTED MANUSCRIPT
S15

ACCEPTED MANUSCRIPT
S16

ACCEPTED MANUSCRIPT
S17

ACCEPTED MANUSCRIPT
S18