Decarboxylative halogenation of indolecarboxylic acids using hypervalent iodine(III) reagent and its application to the synthesis of polybromoindoles

Article abstract of DOI:10.3987/COM-14-13162

Hypervalent iodine mediated decarboxylative halogenation of indoledicarboxylic acid derivatives was studied. The treatment of 1-methylindole-2,3-dicarboxylic acid with phenyliodine diacetate (PIDA) in the presence of lithium bromide gave 1-methyl-3,3-brom

Full text of DOI:10.3987/COM-14-13162

HETEROCYCLES, Vol. 91, No. 3, 2015
561
HETEROCYCLES, Vol. 91, No. 3, 2015, pp. 561 - 572. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 26th December, 2014, Accepted, 26th January, 2015, Published online, 3rd February, 2015
DOI: 10.3987/COM-14-13162
DECARBOXYLATIVE HALOGENATION OF INDOLECARBOXYLIC
ACIDS USING HYPERVALENT IODINE(III) REAGENT AND ITS
APPLICATION TO THE SYNTHESIS OF POLYBROMOINDOLES
Hiromi Hamamoto,a,b* Hideaki Umemoto,a Misako Umemoto,a Chiaki Ohta,a
Emi Fujita,a Akira Nakamura,a Tomohiro Maegawa, a and Yasuyoshi Miki a*
aSchool of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae,
Higashi-Osaka 577-8502, Japan
bFaculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku,
Nagoya 468-8502, Japan; hamam@meijo-u.ac.jp, +81 52 835 7450
Abstract – Hypervalent iodine mediated decarboxylative halogenation of
indoledicarboxylic acid derivatives was studied. The treatment of
1-methylindole-2,3-dicarboxylic acid with phenyliodine diacetate (PIDA) in the
presence of lithium bromide gave 1-methyl-3,3-bromooxindole. However, the
reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxylic acid with PIDA in the
presence of lithium bromide afforded 2,3-dibromo-1-(phenylsulfonyl)indole. In a
similar manner, the 2,3-dichloro- and 2,3-diiodoindole derivatives could be
obtained by the reaction of the indole-2,3-dicarboxylic acids with PIDA in the
presence of lithium chloride and iodide. This method was optimized to the
synthesis of polybromoindole alkaloids.
INTRODUCTION
The decarboxylative halogenation that can provide halogenated organic compounds from carboxylic acids
by simple chemical transformation has become an increasingly important and attractive tool in organic
synthesis.1,2 The Hunsdiecker reaction, the reaction of dry silver (I) salts of aliphatic carboxylic acids with
bromine to give organic bromide, is an example of classical decarboxylative halogenation reaction.1
Because of the difficult preparation of anhydrous silver carboxylates, several Hunsdiecker-type reaction
methods have thereafter been developed to simplify the procedure by using the various reagent conditions

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HETEROCYCLES, Vol. 91, No. 3, 2015
such as thallium(I) or mercury(II) salts. To avoid the use of highly toxic reagents, Suárez introduced the
decarboxylative iodination using hypervalent iodine reagent, phenyliodine diacetate (PIDA), and iodine
under UV photolysis.3-5 Although such metal salt free approaches constitute an important method in
chemistry and several groups also report the devising methodology of hypervalent iodine mediated
decarboxylative halogenations, their utility is limited for the reaction of aliphatic and α,β-unsaturated
carboxylic acids in many cases.6
Halogenated indole derivatives are promising sources of new biologically active molecules.7 Several
halogenated indole derivatives have been isolated as the secondary metabolites of marine organisms
tunicates (Figure 1).8-11 Some of them are known to have a variety of actions including antibiotic and
anticancer activities. Alternatively, halogenated indole derivatives could be attractive synthetic sources
for conversion to other indole alkaloid derivatives.
Br
Br
Br
Br
Br
Br
Br
Br
Br
N
N
Br
N
H
H
H
2,3,5,6-tetrabromoindole
2,3,5-tribromoindole
2,3,6-tribromoindole
Figure 1. Halogenated indole derivatives isolated from marine organisms
In the course of our synthetic studies on indoles and related compounds, we have shown the utilities of
indole-2,3-carboxylic acid derivatives and applied to the synthesis of indole alkaloids such as
murrayaquinone-A, ellipticine, olivacine, caulersin and cryptosanguinolentine.12-19 There is no approach
to halogenated indole derivatives via decarboxylative halogenations except for the synthesis of the
2,3-diiodoindoles by the decarboxylative iodination of indole-2-carboxylic acids, but in the case of
indole-2-carboxylic acids without having an electron-donating substituent, the yields of the
2,3-diiodoindoles are low.20
Previously, we reported the synthesis of the 2,3-dibromoindoles by the decarboxylative bromination of
indole-2,3-dicarboxylic acids by using Oxone® and lithium bromide, but 2,3-dichloro- or
2,3-diiodoindoles were not obtained.21 Very recently, we found the novel ability of hypervalent iodine
(III)-LiX combination in decarboxylative halogenation.22-24 In this paper, we provide a full account of our
studies on the hypervalent iodine mediated decarboxylative halogenation of indolecarboxylic acid
derivatives.22 In addition, an effective utilization of this system for the synthesis of polybromoindole
alkaloids was also described.

HETEROCYCLES, Vol. 91, No. 3, 2015
563
RESULTS AND DISCUSSION
As our initial approach, the decarboxylative halogenation of 1-(phenylsulfonyl)indole-2,3-dicarboxylic
26
acid (1)25 was studied. The reaction using 1-3 equivalents of PhI(OAc)2 in the presence of the same
equivalents of lithium bromide in THF gave a 3-bromoindole-2-carboxylic acid (3a) or a mixture of 3a
and 2,3-dibromoindole (5a),27 but the treatment of 1 with PhI(OAc)2 (4 equivalents) afforded 5a in 86%
yield (Table 1, entries 1-3). However, when the reaction of 1 with PhI(OAc)2 was carried out using
potassium bromide instead of lithium bromide, 5 equivalents of PhI(OAc)2 or CH2Cl2 as the solvent, the
yields of 5a were relative low (33–72%, entries 4-6). The catalytic hypervalent iodine oxidation condition
using m-CPBA (m-chloroperoxybenzoic acid)28 was ineffective for this reaction (entry 7). To extend our
procedure to the decarboxylative iodination and chlorination, the PhI(OAc)2 mediated reaction was
carried out using lithium chloride or iodide, and dichloro- or diiodoindoles 529 was successfully obtained
in good yield, where other reagents such as Oxone® and CAN (Cerium (IV) ammonium nitrate) 21 were
ineffective for these reactions (entries 8-13).
Next, we examined the decarboxylative halogenation of 1-methylindole-2,3-dicarboxylic acid (2).30 The
reaction using 1 equivalent or 2 equivalents of PhI(OAc)2 in the presence of the same equivalents of
lithium bromide in THF gave 3-bromoindole-2-carboxylic acid (4a) in 57% or 74% yields, respectively
(entries 14, 15). When the reaction of 2 with 3 equivalents of PhI(OAc)2 was examined, the corresponding
2,3-dibromoindole (6a), the desired product, was not isolated and 3,3-dibromo-1-methyloxindole (8a)31
was obtained as the sole product in 78% yield (entry 16). In addition, the reaction of 2 with 3 equivalents
of PhI(OAc)2 in CH2Cl2 instead of THF also afforded 8a in slightly lower yield (73%, entry 17). As for
the decarboxylative iodination and chlorination of 2, the PhI(OAc)2 mediated reaction in the presence of
lithium chloride gave 3,3-dichloro-1-methyloxindole (8b)32 in 77 % yield, and 2,3-diiodo-1-methylindole
(6c)33 was isolated in 87% yield in the presence of lithium iodide (entries 18, 21). In each case, other
reagents such as Oxone® and CAN were ineffective for these reactions (entries 19, 20, 22, 23).
One possible explanation for the formation of 3,3-dihalo-1-methyloxindole (8a and 8b) is envisaged as
shown in Scheme 1. The halogenation of 2,3-dihalo-1-methylindole (6), which would obtained after the
second Hunsdiecker-type decarboxylative halogenation of 4, lead to intermediate 9. Treatment of 9 with
water by workup provides 8, where 8c was not obtained, probably due to steric hindrance. The absence of
3,3-dihalo-1-(phenylsulfonyl)oxindole on the reaction with 1, possessing electronwithdrawing
N-substituent may support this explanation. Although the detailed reaction mechanism is still not clear,
the dibromooxindole derivatives could be also potentially attractive synthons in indole alkaloid syntheses.

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HETEROCYCLES, Vol. 91, No. 3, 2015
Table 1. The decarboxylative halogenation of indole-2,3-dicarboxylic acids
X
CO2H
X
X
X
X
PhI(OAc)2, MX
0 °C to rt
+
+
N
R
CO2H
N
R
CO2H
N
R
N
R
O
1 (R = SO2Ph)
2 (R = Me)
3 (R = SO2Ph)
4 (R = Me)
5 (R = SO2Ph)
6 (R = Me)
7 (R = SO2Ph)
8 (R = Me)
a : X = Br
c : X = I
b : X = Cl
Yield of
3 or 4
(%)a
Yield of
Yield of
Oxidant
MX
(equivalent)
Time
(h)
Entry
R
Solvent
5 or 6
7 or 8
(%)a
(%)a
(equivalent)
1
2
SO2Ph (1)
SO2Ph (1)
PhI(OAc)2 (1)
LiBr (1)
LiBr (3)
THF
1
3a (80%)
-
-
-
PhI(OAc)2 (3)
PhI(OAc)2 (4)
PhI(OAc)2 (4)
PhI(OAc)2 (5)
PhI(OAc)2 (5)
THF
THF
THF
THF
CH2Cl2
THF
51
2
3a (35%) 5a (36%)
3
4
5
6
7
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
LiBr (4)
KBr (4)
LiBr (5)
LiBr (5)
LiBr (5)
-
5a (86%)
5a (72%)
5a (71%)
5a (33%)
5a (35%)
-
-
-
-
-
22
3
3a (6%)
-
-
-
0.5
5
PhI(OAc)2 (0.2),
m-CPBAb (3.0)
8
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
SO2Ph (1)
Me (2)
PhI(OAc)2 (4)
LiCl (4)
LiCl (6)
LiCl (3)
THF
2
-
5b (86%)
-
9a
MeOH/H2O
MeCN
TFE/CH2Cl2
MeOH/H2O
MeCN
THF
1
-
5b (21%)
Oxone®
(6)
(3)
10
11
12 d
13
14
15
16
17
18
19 d
20
21
22 d
23
CANc
1
-
-
-
-
-
-
-
-
PhI(OAc)2 (6)
LiI
LiI
LiI
(6)
(6)
(3)
8
-
5c (89%)
24
16
1
-
-
Oxone®
(6)
CANcꢀ ꢀ (3)
PhI(OAc)2 (1)
PhI(OAc)2 (2)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (4)
-
-
LiBr (1)
LiBr (2)
LiBr (3)
LiBr (3)
LiCl (4)
LiCl (6)
LiCl (3)
4a (57%)
-
Me (2)
THF
2
4a (74%)
-
Me (2)
THF
1
-
-
8a (78%)
Me (2)
CH2Cl2
THF
0.5
6
-
-
8a (73%)
Me (2)
-
-
8b (77%)
Me (2)
THF
24
24
1.5
3
-
-
-
-
-
-
-
Oxone®
(6)
(3)
Me (2)
CANc
THF
-
-
Me (2)
PhI(OAc)2 (4)
LiI
LiI
LiI
(4)
(6)
(3)
THF
-
6c (87%)
Me (2)
MeOH/H2O
MeCN
4c (88%)
-
-
Oxone®
(6)
(3)
Me (2)
CANc
24
-
aIsolated Yield. bm-CPBA (m-chloroperoxybenzoic acid). cCAN (cerium (IV) ammonium nitrate). dAdditive= Li2CO3 (1 eq).

HETEROCYCLES, Vol. 91, No. 3, 2015
565
X
X
X
X
X
X
X
H2O
N
N
N
O
Me
Me
Me
6a (X = Br)
or
6b (X = Cl)
8a (X = Br)
or
8b (X = Cl)
9
Scheme 1. Plausible reaction mechanism leading to 8
The reaction of 1-(phenylsulfonyl)indole-2-carboxylic acid (10) or 1-(phenylsulfonyl)indole-3-carboxylic
acid (11) with 4 equivalents of PhI(OAc)2 in the presence of 4 equivalents of lithium bromide in THF
gave 5a in 81-83% yields (Table 2, entries 1, 2), but from 1-methylindole-2-carboxylic acid (12) or
1-methylindole-3-carboxylic acid (13), 8a was isolated in 80% yields (entries 3, 4). Thus, the same results
were obtained with the reaction of indole-2,3-dicarboxylic acids (1 and 2) with PhI(OAc)2 and lithium
bromide. The reaction of 3a with 2 equivalents of PhI(OAc)2 in the presence of 2 equivalents of lithium
bromide gave 5a in 80% yield, while the reaction of 4a with 2 equivalents of PhI(OAc)2 in the presence
of 2 equivalents of lithium bromide gave 8a in 90% yield (entries 5, 6).
Table 2. The reaction indolecarboxylic acids with PhI(OAc)2-LiBr
Condi-
tionsa
Products
Yield
(%)b
Condi-
tionsa
Products
Yield
(%)b
Entry
Substrates
Entry
Substrates
Br
Br
Br
CO2H
Br
1c
4
N
CO2H
N
A
B
B
83
81
80
N
80
80
90
A
A
N
O
SO2Ph
SO2Ph
Me
Me
10
13
5a
8a
Br
Br
Br
Br
CO2H
Br
2 d
5
6
N
N
N
N
CO2H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
11
5a
3a
5a
Br
Br
Br
CO2H
Br
Br
3
N
CO2H
A
N
N
O
N
O
Me
Me
Me
Me
12
4a
8a
8a
aCondition A: PhI(OAc)2 (4 equivalents), LiBr (4 equivalents), THF, rt, 1 h; Condition B: PhI(OAc)2 (2 equivalents), LiBr (1 equivalent),
b
c
THF, rt, 1 h. Isolated Yield. The reaction with 1 equivalent of PhI(OAc)2 in the presence of 1 equivalent of LiBr gave 3a in 80% yield.
dThe reaction with 1 equivalent of PhI(OAc)2 in the presence of 1 equivalent of LiBr gave 3-bromo-1-(phenylsulfonyl)indole in 45% yield
(recovery of 11:53%).

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HETEROCYCLES, Vol. 91, No. 3, 2015
The attractive results obtained in the hypervalent iodine mediated decarboxylative halogenation of
indole-2,3-dicarboxylic acid derivatives prompted us to extent our procedure to the synthesis of
polybromoindole alkaloids. When the reaction of 5,6-dibromo-1-(phenylsulfonyl)indole-2,3-dicarboxylic
acid (14)21 with 4 equivalents of PhI(OAc)2 in the presence of 4 equivalents of lithium bromide (optimal
condition in Table 1) was examined, 1-(phenylsulfonyl)-2,3,5,6-tetrabromoindole (16), the desired
product, was obtained in low yield and 3,5,6-tribromo-1-(phenylsulfonyl)indole-2-carboxylic acid (15)
was obtained as a major product (Table 3, entry 1). Further optimization of the reaction conditions
revealed that the use of 5 equivalents of PhI(OAc)2 in the presence of 5 equivalents of potassium bromide
in THF-TFE (trifluoroethanol) afforded 16 in 83% yield (entries 2-7). The conversion of 16 to
2,3,5,6-tetrabromoindole9 was achieved by treatment with tetrabutylammonium fluoride (TBAF) in THF
in 92% yield (Scheme 2).
Table 3. The reaction 1-(phenylsulfonyl)lindole-2,3-dicarboxylic acid with PhI(OAc)2-MX
Br
CO2H
Br
Br
Br
Br
Br
PhI(OAc)2, MX
0 °C to rt
+
Br
N
CO2H
Br
N
CO2H
Br
N
SO2Ph
SO2Ph
SO2Ph
14
15
16
Yield of 15
Yield of 16
PhI(OAc)2
(equiv)
Entry
MBr (equiv)
Solvent
Time (h)
(%)a
(%) a
1
4
5
5
5
5
5
5
LiBr (4)
LiBr (5)
NaBr (5)
KBr (5)
KBr (5)
KBr (5)
KBr (5)
THF
24
24
20
20
20
2
67
17
2
3
4
5
6
7
THF
50
71
48
-
31
17
45
73
THF
THF
MeCN
TFE
(complex mixture)
83
THF-TFE b
3
-
aIsolated Yield. b THF (0.5 h) then TFE (2.5 h).
Br
Br
Br
Br
Br
Br
Br
TBAF, THF
-20 °C, 4 h
N
Br
N
H
SO2Ph
2,3,5,6-tetrabromoindole (92%)
16
Scheme 2. Synthesis of 2,3,5,6-tetrabromoindole

HETEROCYCLES, Vol. 91, No. 3, 2015
567
The encouraging results obtained in Table 3 and Scheme 2 prompted us to extend our procedure to
several polybromoindole alkaloid syntheses. Dimethyl bromoindole-2,3-dicarboxylates (17 and 18) were
prepared according to the reported method.34 The treatment of 17 boron tribromide gave the
corresponding dicarboxylic acids (19) in 65% yield (Scheme 3A). The PhI(OAc)2 mediated
decarboxylative bromination of 19 afforded tribromo-1-(phenylsulfonyl)indole (20) in 80% yield. 20
could be converted to 2,3,5-tribromoindole8 by treatment with tetrabutylammonium fluoride in 83%. In a
similar manner, the synthesis of 2,3,6-tribromoindole8 from 18 was also successfully completed via
PhI(OAc)2 mediated decarboxylative bromination (Scheme 3B).
(A)
Br
Br
Br
Br
CO2Me
CO2Me
N
N
H
SO2Ph
17
2,3,5-tribromoindole (83%)
BBr3
TBAF
toluene
rt, 3 h
THF
-20 °C, 3 h
Br
CO2H
CO2H
Br
Br
PhI(OAc)2 (5 eq), KBr (5 eq)
THF-TFE
rt, 3 h
N
N
Br
SO2Ph
SO2Ph
20 (80%)
19 (65%)
(B)
Br
Br
CO2Me
CO2Me
Br
N
Br
N
H
SO2Ph
18
2,3,6-tribromoindole (87%)
BBr3
TBAF
toluene
rt, 3 h
THF
-20 °C, 3 h
Br
CO2H
CO2H
PhI(OAc)2 (5 eq), KBr (5 eq)
THF-TFE
rt, 3 h
Br
N
Br
N
Br
SO2Ph
SO2Ph
22 (79%)
21 (70%)
Scheme 3. Synthesis of tribromoindoles

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HETEROCYCLES, Vol. 91, No. 3, 2015
In conclusion, we have demonstrated the decarboxylative halogenation of indolecarboxylic acid
derivatives using the Hunsdiecker-type reaction. The exciting result obtained with the reaction of the
indole-2,3-dicarboxylic acids (1) with PhI(OAc)2-MX system prompted us to extend our procedure to the
synthesis of polybromoindole alkaloids such as 2,3,5,6-tetrabromoindole, 2,3,5-tribromoindole, and
2,3,6-tribromoindole. Further studies along this line are now in progress.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micromelting point apparatus and are uncorrected.
1H NMR spectra were recorded at 300 MHz. Infrared (IR) absorption spectra (cm-1) were recorded using
a JASCO FT/IR-7000 spectrophotometer. The high MS were recorded by a JEOL-HX100 spectrometer.
Column chromatography was performed on Silica gel 60 N (Kanto Chemical Co., Inc.). Compounds
10-13 were commercially available. Compounds 1,25 2,30 14,21 17,34 and 1834 were prepared by known
methods.
Compounds 3a, 4a, 5a, 8a, 16, and 2,3,5,6-Tetrabromoindole have been previously reported by us and the
spectral data were in full agreement with those reported.21
Typical Procedure for the decarboxylative halogenation of indole-2,3-dicarboxylic acid with
PhI(OAc)2 in the presence of lithium halide: To a mixture of PhI(OAc)2 and lithium halide in THF (10
mL) was added indole-2,3-dicarboxylic acids (1 mmol) at 0 °C and then the reaction mixture was stirred
at room temperature. Water was added to the reaction mixture and the mixture was extracted with CH2Cl2.
The combined extracts were washed with 2-3% sodium thiosulfate solution, then water, and dried over
Na2SO4. The extracts were concentrated under reduced pressure to give a solid, which was purified by
column chromatography on silica gel to afford the halogenoindole derivatives.
1
2,3-Dichloro-1-(phenylsulfonyl)indole (5b). Mp 122 °C; H NMR (CDCl3) δ: 7.30-7.63 (6H, m),
7.84-7.92 (2H, m), 8.28 (1H, br d, J = 8.0 Hz, H-7 or H-4); 13C NMR (DMSO-d6) δ: 168.80, 140.58,
131.85, 129.16, 125.13, 124.70, 124.14, 109.08, 26.98; HRMS (EI) m/z: Calcd for C14H9NO2Cl2S:
324.9677. Found: 324.9737; CAS Registry Number [1260070-91-4].
2,3-Diiodo-1-(phenylsulfonyl)indole (5c).29 Mp 165-167 °C (lit.,29 mp 166-167 °C); 1H NMR (CDCl3) δ:
7.25-7.60 (6H, m), 7.90 (2H, br d, J = 8.0 Hz), 8.28 (1H, br d, J = 8.0 Hz, H-7); CAS registry number
[80360-26-5].
1
3,3-Dichloro-1-methyloxindole (8b).32 Mp 144-147 °C (lit.,32 143 °C); IR (Nujol) n: 1740 cm-1; H
NMR (CDCl3) δ: 3.25 (3H, s, CH3), 6.85 (1H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1H, t, J = 8.0 Hz, H-5 or
H-6), 7.39 (1H, t, J = 8.0, 1.5 Hz, H-6 or H-5), 7.61 (1H, d, J = 8 Hz, H-7 or H-4); 13C NMR (DMSO-d6)
δ: 168.80, 140.58, 131.85, 129.16, 125.13, 124.70, 124.14, 109.08, 26.98; CAS registry number
[114380-33-5].

HETEROCYCLES, Vol. 91, No. 3, 2015
569
2,3-Diiodo-1-methylindole (6c).33 Mp 76-77 °C (lit.,33 76-78 °C); 1H NMR (CDCl3) δ: 3.89 (3H, s, CH3),
7.1-7.42 (2H, m); 13C NMR (DMSO-d6) δ: 138.11, 131.15, 122.71, 120.80, 120.50, 111.06, 99.78, 71.72,
36.09; HRMS (EI) m/z: Calcd for C9H7NI2: 382.8668. Found: 382.8671; CAS registry number
[180623-97-6].
Preparation of bromo-1-(phenylsulfonyl)indole-2,3-dicarboxylic acids: To a solution of dimethyl
bromo-1-(phenylsulfonyl)indole-2,3-dicarboxylate derivative (1 mmol) in toluene (10 mL) was added 1M
boron tribromide in a CH
2
Cl solution (3 mL). The mixture was then stirred at room temperature
2
overnight. Water was added to reaction mixture and the precipitate was collected by filtration and washed
with water, then with n-hexane. The bromo-1-(phenylsulfonyl)indole-2,3-dicarboxylic acid was used
without further purification.
1
5-Bromo-1-(phenylsulfonyl)indole-2,3-dicarboxylic acid (19). H NMR (CDCl3) δ: 7.45-7.62 (5H, m,
arom), 7.86 (1H, s, H-6), 7.87 (1H, d, J = 8.0 Hz, H-4), 8.17 (1H, d, J = 9.2 Hz, H-7).
1
6-Bromo-1-(phenylsulfonyl)indole-2,3-dicarboxylic acid (21). H NMR (CDCl3) δ: 7.30-7.64 (5H, m,
arom), 7.86 (1H, s, H-6), 7.91 (2H, d, J = 7.6 Hz, H-4, 5), 8.50 (1H, s, H-7).
Typical Procedure for the decarboxylative bromination of bromoindole-2,3-dicarboxylic acid with
PhI(OAc)2 in the presence of potassium bromide: To a mixture of PhI(OAc)2 and potassium bromide
in THF (10 mL) was added bromoindole-2,3-dicarboxylic acids (1 mmol) at 0 °C. After 0.5 h of stirring,
the solvent was exchanged to TFE (10 mL) and the reaction mixture was stirred for 2.5 h at room
temperature. Water was added to the reaction mixture and the mixture was extracted with CH2Cl2. The
combined extracts were washed with 2-3% sodium thiosulfate solution, then water, and dried over
Na2SO4. The extracts were concentrated under reduced pressure to give a solid, which was purified by
column chromatography on silica gel to afford the bromoindole derivatives.
1
2,3,5-Tribromo-1-(phenylsulfonyl)indole. H NMR (CDCl3) δ: 7.45-7.62 (5H, m, arom), 7.86 (1H, s,
H-6), 7.87 (1H, d, J = 8.0 Hz, H-4), 8.17 (1H, d, J = 9.2 Hz, H-7).
1
2,3,6-Tribromo-1-(phenylsulfonyl)indole: H NMR (CDCl3) δ: 7.30-7.64 (5H, m, arom), 7.86 (1H, s,
H-6), 7.91 (2H, d, J = 7.6 Hz, H-4, 5), 8.50 (1H, s, H-7).
Syntheses of polybromoindoles: A 1M solution of tetrabutylammonium fluoride in THF (0.04 mL) was
added to a mixture of polybromo-1-(phenylsulfonyl)indole in THF (1 mL) at -20 °C under argon and the
reaction mixture was stirred for 1 h at the same temperature. Hydrochloric acid (2 %) was added to the
mixture and then extracted with CHCl3. The extracts were washed with water, dried over Na2SO4, then
concentrated under reduced pressure to afford a residue, which was purified by column chromatography
(n-hexane : AcOEt = 3:1) to give the polybromoindole.
2,3,5-Tribromoindole.8 Mp 150-151 °C from EtOAc/hexane (lit.,8 mp 150-151 °C); IR(KBr) ν: 2918,
1
2850, 1635, 1456, 1434 cm-1 ; H NMR (CDCl3) δ: 7.13 (1H, d, J = 8.8 Hz, H-7), 7.29 (1H, dd, J = 8.8,

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HETEROCYCLES, Vol. 91, No. 3, 2015
1.8, H-6), 7.61 (1H, d, J = 1.1 Hz, H-4), 8.34 (1H, br s, N-H); CAS Registry Number [918529-97-2].
2,3,6-Tribromoindole.8 Mp 74-75 °C from EtOAc/hexane (lit.,8 mp 74-75 °C); IR(KBr) ν: 2918, 2850,
1635, 1456, 1434 cm-1; 1H NMR (CDCl3) δ: 7.61 (1H, s, H-4 or H-7), 7.76 (1H, s, H-7 or H-4), 8.38 (1H,
br s, NH); CAS Registry Number [918530-08-2].
ACKNOWLEDGEMENTS
This work was partially supported by Grant-in-Aid for Scientific Research (C) from the Japan Society for
the Promotion of Science (JSPS) (25460027), Kinki University Research Grant Project, the Research
Institute of Meijo University, and also in part “High-Tech Research Center Project” for Private
Universities and matching fund subsidy.
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