Decarboxylative bromination of indole-2,3-dicarboxylic acids using oxone or can in the presence of lithium bromide

Article abstract of DOI:10.3987/COM-09-11802

The treatment of l-methylindole-2,3-dicarboxylic acid with Oxone and lithium bromide produced 3,3-dibromo-l-methyloxindole. However, the reaction of 1-benzenesulfonylindole-2,3-dicarboxylic acid with Oxone and lithium bromide afforded l-benzenesulfonyl-2,

Full text of DOI:10.3987/COM-09-11802

HETEROCYCLES, Vol. 78, No. 11, 2009
2845
HETEROCYCLES, Vol. 78, No. 11, 2009, pp. 2845 - 2850. © The Japan Institute of Heterocyclic Chemistry
Received, 27th July, 2009, Accepted, 3rd September, 2009, Published online, 7th September, 2009
DOI: 10.3987/COM-09-11802
DECARBOXYLATIVE
BROMINATION
OF
INDOLE-2,3-
DICARBOXYLIC ACIDS USING OXONE® OR CAN IN THE PRESENCE
OF LITHIUM BROMIDE
Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Masashi Dohshita,
Hiroki Tanaka, Syo Hattori, Hiromi Hamamoto, and Yasuyoshi Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae,
Higashi-Osaka 577-8502, Japan
Abstract – The treatment of 1-methylindole-2,3-dicarboxylic acid with Oxone®
and lithium bromide produced 3,3-dibromo-1-methyloxindole. However, the
reaction of 1-benzenesulfonylindole-2,3-dicarboxylic acid with Oxone® and
lithium bromide afforded 1-benzenesulfonyl-2,3-dibromoindole. In a similar
manner, 2,3,5,6-tetrabromoindole was synthesized from 1-benzenesulfonyl-5,6-
dibromoindole-2,3-dicarboxylic acid.
Bromoarenes are an important class of compounds due to their conversion to other functionalities by the
Heck-type reaction in the presence of a palladium catalyst, etc. The bromination of activated arenes is
usually performed by conventional bromination methods typically using toxic bromine. Commercial
available Oxone® (2KHSO5 · KHSO · K2SO4) is an inexpensive, and stable oxidant and in the presence of
sodium bromide or potassium bromide, Oxone® can be used as an efficient bromination reagent for
activated arenes.1 The decarboxylative bromination of aromatic carboxylic acids using Oxone® and
sodium bromide is also a useful method,2 but there is no report about the decarboxylative bromination of
indolecarboxylic acids. Bromoindole alkaloids have also been isolated as secondary metabolites of
marine organisms, such as sponges, tunicates, etc., and are promising sources of new biologically active
molecules.3 2,3,5,6-Tetrabromoindole4,5 having antibacterial and antitumor activities was isolated and
synthesized by Castillo.6 3,6-Dibromoindole also was isolated.7 We have shown that the dimethyl
indole-2,3-dicarboxylates and indole-2,3-dicarboxylic anhydrides are useful synthons in the synthesis of
pratosine,8 hippadine,8 murrayaquinone-A,9 ellipticine,10-12 olivacine,13 caulersin14 and
cryptosanguinolentine.15
In this report we describe the synthesis of bromoindoles by the
decarboxylative bromination of indole-2,3-dicarboxylic acids using a combination of Oxone® or CAN
(ceric ammonium nitrate) 16 and lithium bromide
The reaction of 1-methylindole-2,3-dicarboxylic acid (1a)17 with 0.5 equivalent of Oxone® (2KHSO5 ·

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HETEROCYCLES, Vol. 78, No. 11, 2009
2
KHSO · K2SO4) in the presence of 5 equivalents of sodium bromide and 1 equivalent of sodium
carbonate in MeOH-H2O (1 : 1) gave 3-bromoindole-2-carboxylic acid (2a)18 in 44% yield, but the
treatment of 1a with Oxone® in the presence of lithium bromide and lithium carbonate afforded 2a in 62%
yield. (Entries 1, 2) However, when the reaction of 1a with 2 equivalents of Oxone® in the presence of
10 equivalents of lithium bromide and 2 equivalents of lithium carbonate, 3,3-dibromooxindole (3a)19
was obtained in 36% yield instead of 2a, but the 2,3-dibromoindole (4a) was not isolated. (Entry 3) 1a
was treated with 1 equivalent or 3 equivalents of CAN in the presence of lithium bromide in acetonitrile
to afford a mixture of 2a and 3a in 51-69% and 20-34% yields, respectively. (Entries 4, 5) (Table 1)
Br
Br
Br
CO2H
CO2H
Br
Br
oxidant
+
0°C
O
N
Me
N
Me
N
N
Me
CO2H
0.5 h - 1 h
Me
3a
4a
2a
1a
Scheme 1
Table 1
Yield(%)
Entry
Base
Solvent
Oxidant
MBr
2a
3a
Oxone® (0.5 eq) NaBr (5 eq)1)
Oxone® (0.5 eq) LiBr (5 eq)
44
62
-
1
2
3
4
5
Na2CO3 (1 eq)
MeOH-H2O
MeOH-H2O
MeOH-H2O
CH3CN
-
Li2CO3 (1 eq)
-
Oxone® (2 eq)
LiBr (10 eq)
LiBr (1 eq)
LiBr (3 eq)
36
20
34
Li2CO3 (2 eq)
-
-
CAN
CAN
(1 eq)
(3 eq)
69
51
CH3CN
The treatment of 1-benzenesulfonylindole-2,3-dicarboxylic acid (1b)20 with 1 equivalent of Oxone® in
the presence of lithium bromide and lithium carbonate gave a mixture of 3-bromoindole-2-carboxylic
acid (2b) and 2,3-dibromoindole (4b)21 in 26% or 57% yields, respectively, but 1b was reacted with 2
equivalents of Oxone® to provide 4b in 88% instead of the corresponding 3,3-dibromooxindole (Entries 1,
2) However, treatment of 1b with CAN led to a mixture of 2b and 4b in low yields, respectively.
(Entries 3, 4) (Table 2)
Br
CO2H
Br
oxidant
+
0°C - rt
0.5 - 1 h
Br
N
N
N
CO2H
CO2H
SO2Ph
SO2Ph
SO2Ph
1b
Scheme 2
2b
4b

HETEROCYCLES, Vol. 78, No. 11, 2009
2847
Table 2
Yield(%)
Entry
Oxidant
Base
Solvent
4b
2b
26
-
LiBr
5 eq
10 eq
1 eq
3 eq
1
2
3
4
Oxone® (1 eq)
Oxone® (2 eq)
Li2CO3 (1 eq) MeOH-H2
O
57
88
3
Li2CO3 (2 eq) MeOH-H2O
CAN
CAN
(1 eq)
(3 eq)
-
-
CH3CN
CH3CN
16
13
19
Next, we evaluated the syntheses of the 2,3-dichloroindoles (5) or 2,3-diiodoindoles (6) by the reaction of
1 with Oxone® in the presence of lithium chloride or lithium iodide. The reaction of 1-methylindole-2,3-
dicarboxylic acid (1a) or 1-benzenesulfonylindole-2,3-dicarboxylic acid (1b) with 2 equivalents of
Oxone® and lithium chloride or 3 equivalents of CAN and lithium chloride resulted in a complex mixture.
When 1a or 1b was treated with Oxone® or CAN in the presence of lithium iodide, the corresponding
2,3-diiodoindoles (6) were also not isolated.
CO2H
CO2H
oxidant
THF
Cl
Cl
I
I
N
R
N
R
5
,
N
R
1a,b
6
a: R = Me, b: R = SO2Ph
Scheme 3
The treatment of dimethyl 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylate (7)22 with boron
tribromide gave the corresponding dicarboxylic acid (8) (92%), which was treated with Oxone® (2
equivalents) in the presence of lithium bromide and lithium carbonate to provide
1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9) in 66% yield. 9 could be converted to 2,3,5,6-
6
tetrabromoindole (10) by treatment with tetrabutylammonium fluoride in THF in 92% yield.
CO2H
CO2H
Br
Br
CO2Me
CO2Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Oxone®
BBr3
TBAF
N
N
H
N
N
SO2Ph
SO2Ph
SO2Ph
10
7
9
8
Scheme 4
ACKNOWLEDGEMENTS
This work was supported by a Grand-in-Aid for Scientific Research (C) and also in part “High-Tech

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HETEROCYCLES, Vol. 78, No. 11, 2009
Research Center Project” for Private Universities and matching fund subsidy from the Ministry of
Education, Culture, Sports, Scientific and Technology-Japan (MEXT).
EXPERIMENTAL
Melting points were determined using a Yanagimoto micromelting point apparatus and are uncorrected.
The 1H-NMR spectra were determined by a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as
the internal standard. The IR spectra were recorded by a JASCO FT/IR-7000 spectrophotometer. The
high MS were recorded using a JOEL JMS-HX100 spectrometer. Column chromatography was
performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
General Procedure: Reaction of Indole-2,3-dicarboxylic Acid (1) with Oxone® in the presence of a
lithium halide and lithium carbonate
Indole-2,3-dicarboxylic acid (1)(1 mmol) was added to the mixture of Oxone®, lithium halide, and lithium
carbonate in MeOH-H2O (1 : 1). The mixture was then stirred at room temperature. A 2 % sodium
thiosulfate aqueous solution was added to the reaction mixture and the mixture was extracted with CH2Cl2,
washed with water, and dried over Na2SO4. The extracts were concentrated under reduced pressure to
afford a residue, which was purified by column chromatography.
General Procedure: Reaction of 1 with CANin the presence of a lithium halide
CAN was added to the mixture of indole-2,3-dicarboxylic acid (1)(1 mmol) and lithium halide in MeCN.
The mixture was then stirred at room temperature. A 2 % sodium thiosulfate aqueous solution was
added to the reaction mixture and the aqueous mixture was extracted with CH2Cl2, washed with water,
and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford a residue, which
was purified by column chromatography.
3-Bromo-1-methylindole-2-carboxylic acid (2a); mp 184-186 °C (lit.,18 mp 180 °C (dec). IR (KBr) ꢀ:
1671 cm-1; 1H-NMR (CDCl3) ꢁ: 3.99 (3H, s, CH3), 7.22 (1H, t, J = 8 Hz, H-5 or H-6), 7.40 (1H, t, J = 8 Hz,
H-6 or H-5), 7.54 (1H, d, J = 8 Hz, H-4 or H-7), 7.62 (1H, d, J = 8 Hz, H-7 or H-4).
3,3-Dibromo-1-methyloxindole (3a); mp 202-204 °C (EtOAc) (lit.,19 mp 204-205 °C). IR (CHCl3) ꢀ:
1737 cm-1; 1H-NMR (CDCl3) ꢁ: 3.26 (3H, s, CH3), 6.86 (1H, d, J = 8 Hz, H-4 or H-7), 7.17 (1H, dt, J = 8,
1.5Hz, H-5orH-6), 7.34(1H, dt, J=8, 1.5Hz, H-6orH-5), 7.62(1H, dd, J=8, 1.5Hz, H-7orH-4). 13C-NMR
(DMSO-d6) ꢁ: 169.16, 139.64, 131.87, 130.37, 125.38, 124.05, 110.08, 45.28, 27.03. HRMS (EI) m/z:
Calcd for C9H7NOBr2: 302.8895. Found: 302.8883.
1-Benzenesulfonyl-3-bromoindole-2-carboxylic acid (2b); mp 219-222 °C (EtOAc). IR (Nujol) ꢀ: 1697
cm-1; 1H-NMR (CDCl3) ꢁ: 7.24-7.36 (3H, m, aromatic protons), 7.50-7.68 (3H, m, aromatic protons), 7.91
(1H, dd, J = 8, 1.5 Hz, aromatic protons), 8.25-8.32 (2H, m, aromatic protons). HRMS (EI) m/z: Calcd for
C15H11NSO4Br2S: 379.9592. Found: 379.9602.
1
1-Benzenesulfonyl-2,3-dibromoindole (4b); mp 143 °C (lit.,21 mp 141-143 °C). H-NMR (CDCl3) ꢁ:
7.22-7.40 (5H, m, aromatic protons), 7.46-7.54 (1H, m, aromatic protons), 7.78-7.84 (2H, m, aromatic
protons), 8.19-8.25 (1H, m, aromatic protons).

HETEROCYCLES, Vol. 78, No. 11, 2009
2849
2,3,5,6-Tetrabromoindole (10)
To a solution of dimethyl 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylate (7)22 (531 mg, 1
mmol) in toluene (10 mL) was added 1M boron tribromide in a CH2Cl2 solution (3 mL). The mixture
was then stirred at room temperature overnight. Water was added to reaction mixture and the precipitate
was collected by filtration and washed with water, then with n-hexane.
The
1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylic acid (8) (464 mg, 92%) was used without
purification.
8; IR (KBr) ꢀ: 1763, 1692 cm-1; H-NMR (DMSO-d ) ꢁ: 7.65-7.82 (3H, m, aromatic protons), 8.10-8.15
1
6
(2H, m, aromatic protons), 8.27 (1H, s, H-4 or H-7), 8.33 (1H, s, H-7 or H-4).
1-Benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylic acid (8) (25 mg, 0.05 mmol) was added to the
mixture of Oxone® (62 mg, 0.1 mmol), lithium bromide (47 mg, 0.5 mmol), and lithium carbonate (7 mg,
0.1 mmol) in MeOH-H2O (1 : 1)(2 mL), then the mixture was stirred at room temperature overnight. A
2 % sodium thiosulfate aqueous solution was added to the reaction mixture which was then extracted with
CHCl3, washed with water, and dried over Na2SO4. The extracts were concentrated under reduced
pressure to afford a residue, which was purified by column chromatography (n-hexane : EtOAc = 3 : 1) to
give 1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9)(19 mg, 66%).
1
9; mp 158-161 °C (CHCl3), H-NMR (CDCl3) ꢁ: 7.41-7.60 (3H, m, aromatic protons), 7.64 (1H, s, H-4),
7.80-7.86 (2H, m, aromatic protons), 8.56 (1H, s, H-7).
A 1M solution of tetrabutylammonium fluoride in THF (0.04 mL) was added to a mixture of
1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9)(11 mg, 0.02 mmol) 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 2,3,5,6-tetrabromoindole (10)4 (8 mg, 92%), mp
1
153-154 °C (lit.,4 mp 152.5-154 °C, lit.,6 mp 153-154 °C), H-NMR (CDCl3) ꢁ: 7.61 (1H, s, H-4 or H-7),
7.76 (1H, s, H-7 or H-4), 8.38 (1H, br s, NH).
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