Hypervalent iodine(III) mediated decarboxylative halogenation of indolecarboxylic acids for the synthesis of haloindole derivatives

Article abstract of DOI:10.1055/s-0030-1258585

The treatment of 1-methylindole-2,3-dicarboxylic acid with hypervalent iodine(III) reagent, phenyliodine diacetate (PIDA), in the presence of lithium bromide gave 1-methyl-3,3-dibromooxindole. 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-diiodo-indole derivatives were obtained by the reaction of the indole-2,3-dicarboxylic acids with PIDA in the presence of lithium chloride and iodide. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258585

LETTER
2593
Hypervalent Iodine(III) Mediated Decarboxylative Halogenation of
Indolecarboxylic Acids for the Synthesis of Haloindole Derivatives
Decarboxylative
H
i
aloge
n
r
ationof
o
I
ndolecarbox
m
ylic Acids i Hamamoto, Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Masashi Dohshita, Yasuyoshi Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Fax +81(6)67212505; E-mail: y_miki@phar.kindai.ac.jp
Received 2 July 2010
tion of indoles using bromine, pyridinium tribromide, N-
bromosuccinimide, etc., but the yields or the selectivity
are not satisfactory in general. There is no such report of
indolecarboxylic acids except for the synthesis of the 2,3-
Abstract: The treatment of 1-methylindole-2,3-dicarboxylic acid
with hypervalent iodine(III) reagent, phenyliodine diacetate (PI-
DA), in the presence of lithium bromide gave 1-methyl-3,3-dibro-
mooxindole. However, the reaction of 1-(phenylsulfonyl)indole-
2,3-dicarboxylic acid with PIDA in the presence of lithium bromide diiodoindoles by the decarboxylative iodination of indole-
afforded 2,3-dibromo-1-(phenylsulfonyl)indole. In a similar man-
2-carboxylic acids, but in the case of indole-2-carboxylic
ner, the 2,3-dichloro- and 2,3-diiodo-indole derivatives were ob-
acids without having an electron-donating substituent, the
tained by the reaction of the indole-2,3-dicarboxylic acids with
yield of the 2,3-diiodoindoles are low.10 Recently, we re-
PIDA in the presence of lithium chloride and iodide.
ported the synthesis of the 2,3-dibromoindoles by the de-
Key words: indolecarboxylic acid, decarboxylation, bromination,
chlorination, iodation
carboxylative bromination of indole-2,3-dicarboxylic
acids by using Oxone® and lithium bromide, but 2,3-
dichloro- or 2,3-diiodo-indoles were not obtained.11
We now investigated the Hunsdiecker-type decarboxyla-
The Hunsdiecker reaction, the reaction of heavy-metal
tive halogenation of 1-substituted indole-2,3-dicarboxylic
acids 1 utilizing hypervalent iodine reagent, by the way
the effective strategy for halogenation because hyperval-
salt of carboxylic acids with halogens to give organic ha-
lides, is an example of classical decarboxylative haloge-
nation reaction.1 Thus the decarboxylative halogenation
ent iodine reagents have low toxicity relative to heavy
that can provide halogenated organic compounds from
metals and are readily available and their reactivities are
carboxylic acids, an important class of intermediates, by
simple chemical transformation is very attractive. Recent-
similar to those of heavy metals.12
The reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxyl-
ic acid (1a)13 with 3 equivalents of PIDA14 in the presence
of the same equivalents of lithium bromide in THF gave a
mixture of 3-bromoindole-2-carboxylic acid (2a) and 2,3-
dibromoindole (3a)15 in 36% and 35% yields, respective-
ly, but the treatment of 1a with PIDA (4 equiv) afforded
3a in 86% yield (Table 1, entries 1, 2). However, when the
reaction of 1a with PIDA was carried out using potassium
bromide instead of lithium bromide, 5 equivalents of
PIDA or CH2Cl2 as the solvent, the yields of 3a were rel-
ative low (33–72%, Table 1, entries 3–5, Scheme 1).
ly, several Hunsdiecker-type reactions have been investi-
gated using the various reagent conditions, especially
using hypervalent iodine compounds in the point of green
chemistry.2 Camps reported that 2- and 4-nitrobenzoic ac-
ids having electron-withdrawing substituent could be con-
verted into the corresponding bromonitrobenzenes in
moderate yield by decarboxylative bromination using
phenyliodine diacetate (PIDA) and bromine under irradi-
ation, but in the case of 2- and 4-methoxybenzoic acids,
possessing a electron-donating substituent, were recov-
ered and this result shows that the conversion of electron-
rich aromatic carboxylic acid into the corresponding bromo-
benzene is quite difficult.3 Although the decarboxylative
halogenation is an attractive method for the synthesis of
simple halogenated organic compounds, the application
of the Hunsdiecker-type reactions for the synthesis of nat-
ural products or bioactive compounds is still limited.3,4
Br
CO2H
Br
Br
PIDA
+
N
CO2H
N
N
CO2H
SO2Ph
SO2Ph
SO2Ph
3a
1a
2a
Bromoindole alkaloids have been isolated as the second-
ary metabolites of marine organisms, such as sponges,
tunicates, etc., and are promising sources of new biologi-
cally active molecules.5 2,3,6-Tribromoindole,6 2,3,5,6-
tetrabromoindole,7 the polybromo(bisindoles),8 and
bromochloroindoles9 were isolated. The synthesis of the
bromoindoles is usually performed by the direct bromina-
Scheme 1 The reaction of 1a with PIDA in the presence of lithium
bromide
The reaction of 1-methylindole-2,3-dicarboxylic acid
(1b)16 with 1 equiv or 2 equiv of PIDA in the presence of
the same equivalents of lithium bromide in THF gave 3-
bromoindole-2-carboxylic acid (2b)17 in 57% or 74%
SYNLETT 2010, No. 17, pp 2593–2596
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258585; Art ID: U06310ST
© Georg Thieme Verlag Stuttgart · New York

2594
H. Hamamoto et al.
LETTER
yields, respectively (Table 2, entries 1, 2). When the reac-
tion of 1b with 3 equivalents of PIDA was examined, the
corresponding 2,3-dibromoindole (3b), the desired prod-
uct was not isolated and 3,3-dibromo-1-methyloxindole
(4b)18 was obtained as the sole product in 78% yield (en-
try 3). In addition, the reaction of 1b with 3 equivalents of
PIDA in CH2Cl2 instead of THF also afforded 4b in slight-
ly lower yield (73%, entry 4). When 3-bromoindole-2-
carboxylic acid (2b) was treated with with PIDA (2 equiv)
and lithium bromide in THF at room temperature (30
min), 4b was obtained in 90% yield (Scheme 2).
Table 1 Synthesis of 2a and 3a
Entry PIDA
(equiv)
MBr
Solvent
Time Yield of Yield of
(h)
51
2
2a (%) 3a (%)
1
2
3
4
5
3
4
4
5
5
LiBr
LiBr
KBr
LiBr
LiBr
THF
36
–
35
86
72
71
33
THF
THF
22
3
6
THF
–
CH2Cl2
0.5
–
One possible explanation for the formation of 3,3-dibro-
mo-1-methyloxindole (4b) is envisaged as shown in
Scheme 3. The bromination of 1-methyl-2,3-dibromo-
indole (3b), which would obtained after the second
Hunsdiecker-type decarboxylative bromination of 1b,
lead to intermediate 5. Treatment of 5 with water by work-
up provides 4b. The absence of 3,3-dibromo-1-(phenyl-
sulfonyl)oxindole on the reaction with 1a, possessing
electron-withdrawing N-substituent in Table 1 may sup-
port this explanation. Although the detailed reaction
mechanism is still not clear, the dibromooxindole deriva-
tives could be also potentially attractive synthons in in-
dole alkaloid syntheses.
Br
Br
CO2H
CO2H
Br
PIDA
LiBr
r.t.
+
N
O
N
N
CO2H
Me
Me
2b
Me
1b
4b
Scheme 2 The reaction of 1b with PIDA in the presence of lithium
bromide
Table 2 Synthesis of 2b and 4b
Entry
PIDA
(equiv)
Solvent
Time
(h)
Yield of 2b Yield of 4b
(%)
57
74
–
(%)
The reaction of 1-(phenylsulfonyl)indole-2-carboxylic
acid (6a) or 1-(phenylsulfonyl)indole-3-carboxylic acid
(7a) with 4 equivalents of PIDA in the presence of the
same equivalents of lithium bromide in THF gave 3a in
81–83% yields (Table 3, entries 1, 2), but from 1-meth-
ylindole-2-carboxylic acid (6b) or 1-methylindole-3-car-
boxylic acid (7b), 4b was isolated in 80% yields (entries
3, 4). The same results were obtained with the reaction of
1 with PIDA and lithium bromide (Scheme 4).
1
2
3
4
1
2
3
3
THF
1
–
THF
2
–
THF
1
78
73
CH2Cl2
0.5
–
Br
Br
Br
Br
Br
Br
H2O
Next, we examined the reactivity of 1 toward lithium
chloride or iodide to synthesize the dichloro- or diiodo-
indoles 8 (Table 4). The reaction of 1-(phenylsulfonyl)
indole-2,3-dicarboxylic acid (1a) with less than 4 equiva-
lents of PIDA in the presence of lithium chloride in THF
gave 2,3-dichloroindole (8a) in low yield, but the treat-
ment of 1a with PIDA (6 equiv) afforded 8a in 80% yield
(entry 1). 2,3-Diiodo-1-(phenylsulfonyl)indole (8b) was
not isolated by the treatment of 1a with 6 equivalents of
PIDA in the presence of lithium iodide in THF, but in a
mixture of 2,2,2-trifluoroethanol and CH2Cl2 (1:1) as a
solvent instead of THF, 8b19 was obtained in 89% yield
(entry 2). The reaction of 1b with PIDA (4 equiv) in the
presence of lithium chloride gave 3,3-dichlorooxindole
920 in 77% yield, and 2,3-diiodo-1-methylindole (8c)21
was isolated in 87% yield in the presence of lithium iodide
(Table 4, entries 3, 4; Scheme 5).
+
N
N
O
Br
N
Me
4b
Me
Me
3b
5
Scheme 3 Plausible reaction mechanism leading to 4b
Table 3 Synthesis of 3 and 4b from Indolecarboxylic Acids 6 and 7
Entry
Compd CO2H
R
Yield of 3 Yield of 4b
(%)
83
81
–
(%)
1
2
3
4
6a
7a
6b
7b
2-
3-
2-
3-
SO2Ph
SO2Ph
Me
–
–
80
80
Me
–
Br
Br
Br
PIDA (4 equiv)
LiBr (4 equiv)
CO2H
+
THF, r.t., 1 h
N
N
Br
N
O
Me
R
SO2Ph
6,7
3a
4b
a: R = SO2Ph
b: R = Me
Scheme 4 The reaction of 6 and 7 with PIDA in the presence of lithium bromide
Synlett 2010, No. 17, 2593–2596 © Thieme Stuttgart · New York

LETTER
Decarboxylative Halogenation of Indolecarboxylic Acids
2595
(7) (a) Vairappan, C. S.; Kawamoto, T.; Miwa, H.; Suzuki, M.
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Tanaka, H.; Hattori, S.; Hamamoto, H.; Miki, Y.
Heterocycles 2009, 78, 2845.
Cl
O
CO2H
CO2H
X
X
PIDA
Cl
+
THF
r.t.
N
N
R
N
R
Me
8
1a,b
9
a: R = SO2Ph
b: R = Me
a: R = SO2Ph, X = Cl
b: R = SO2Ph, X = I
c: R = Me, X = I
Scheme 5 The reaction of 1 with PIDA in the presence of lithium
chloride or iodide
(12) Wirth, T. Hypervalent Iodine Chemistry, Modern
Developments in Organic Synthesis; Springer: Berlin/
Heidelberg, 2003.
Table 4 Synthesis of 8 and 922
(13) Miki, Y.; Hachiken, H.; Yoshikawa, I. Heterocycles 1997,
45, 1143.
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Chem. 1988, 25, 1905.
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1981, 46, 3278. (b) Moriconi, E. J.; Murray, J. J. J. Org.
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1982, 47, 757.
(20) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Pérez,
M.; Garcia-Martín, M. A.; González, J. M. J. Org. Chem.
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(21) (a) Kellie, A. E.; O’Sullivan, D. G.; Sadler, P. W. J. Chem.
Soc. 1956, 3809. (b) Hantzsch, A. Ber. Dtsch. Chem. Ges.
1921, 54, 1221.
(22) Typical Procedure for the Decarboxylative Halogenation
of Indole-2,3-dicarboxylic Acid(1) with PIDA in the
Presence of Lithium Halide
Entry
R
PIDA
(equiv)
LiX
Time Yield of 8 Yield of 9
(h)
(%)
80
89a
–
(%)
1
2
3
4
SO2Ph
SO2Ph
Me
6
5
4
4
LiCl
LiI
6
–
3
–
LiCl
LiI
6
77
–
Me
1.5
87
a 2,2,2-Trifluoroethanol and CH2Cl2 (1:1) was used as a solvent in-
stead of THF.
In conclusion, we demonstrated the decarboxylative halo-
genation 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 PIDA in the presence of lithium halide prompted us
to extend our procedure to the selective synthesis of in-
dole alkaloids.
Acknowledgment
To a mixture of PIDA and lithium halide in THF (10 mL)
was added indolecarboxylic acids 1, 6, 7 (1 mmol) at r.t., and
then the reaction mixture was stirred. H2O was added to the
reaction mixture, and the mixture was extracted with
CH2Cl2. The combined extracts were washed with 2–3%
Na2S2O3 solution, then H2O, 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 3-halogenoindole-2-carboxylic
acids(2), 2,3-dihalogenoindoles 3, 8, and 3,3-dihalogeno-
oxindoles 4, 9.
1-Phenylsulfonyl-3-bromoindole-2-carboxylic Acid (2a)
Mp 124–125 °C. IR (mull): n = 2856, 2585, 1697 cm–1. 1H
NMR (400 MHz, DMSO-d6): d = 7.24–7.36 (3 H, m), 7.50–
7.68 (3 H, m), 7.91 (1 H, dd, J = 8.0, 1.5 Hz), 8.25–8.32 (2
H, m). HRMS (EI): m/z calcd for C15H11NSO4Br2S:
379.9592; found: 379.9602.
This work was partially supported by a Grant-in-Aid of the Ministry
of Education, Culture, Sport, Science, and Technology and also in
part ‘High-Tech Research Center Project’ for Private Universities
and matching fund subsidy.
References and Notes
(1) Kürti, L.; Czakó, B. Strategic Applications of Named
Reactions in Organic Synthesis, Background and Detailed
Mechanism; Elsevier Academic Press: San Diego, 2005,
218.
(2) For reviews, see: (a) Moriarty, R. M. J. Org. Chem. 2005,
70, 2893. (b) Togo, H.; Katohgi, M. Synlett 2001, 565.
(3) Camps, P.; Lukach, A. E.; Pujol, X.; Vázquez, S.
Tetrahedron 2000, 56, 2703.
(4) Koo, B.-S.; Kim, E.-H.; Lee, K.-J. Synth. Commun. 2002,
32, 2275.
1-Phenylsulfonyl-2,3-dibromoindole (3a)
Mp 143 °C (lit.15 mp 141–143 °C). 1H NMR (400 MHz,
CDCl3): d = 7.22–7.40 (5 H, m), 7.46–7.54 (1 H, m), 7.78–
7.84 (2 H, m), 8.19–8.25 (1 H, m).
(5) For reviews, see: (a) Gribble, G. W. Prog. Chem. Org. Nat.
Prod. 2010, 91, 1. (b) Gribble, G. W. Environ. Sci. Pollut.
Res. 2000, 7, 37. (c) Gribble, G. W. Chem. Soc. Rev. 1999,
28, 335. (d) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141.
(e) Alvarez, M.; Salas, M.; Joule, J. A. Heterocycles 1991,
32, 1391.
3-Bromo-1-methylindole-2-carboxylic Acid (2b)
Mp 184–186 °C [lit.17 mp 180 °C (dec)]. IR (KBr): n = 1671
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 3.99 (3 H, s,
CH3), 7.22 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.40 (1 H, t,
J = 8.0 Hz, H-6 or H-5), 7.54 (1 H, d, J = 8.0 Hz, H-4 or H-
7), 7.62 (1 H, d, J = 8.0 Hz, H-7 or H-4).
(6) Maruya, K. A. Chemosphere 2003, 52, 409.
Synlett 2010, No. 17, 2593–2596 © Thieme Stuttgart · New York

2596
H. Hamamoto et al.
LETTER
3,3-Dibromo-1-methyloxindole (4b)
1-Phenylsulfonyl-2,3-diiodoindole (8b)
Mp 202–204 °C (lit.18 mp 204–205 °C). IR (CHCl3): n =
1737 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 3.26 (3 H,
s, CH3), 6.86 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, dt,
J = 8.0, 1.5 Hz, H-5 or H-6), 7.34 (1 H, dt, J = 8.0, 1.5 Hz,
H-6 or H-5), 7.62 (1 H, dd, J = 8.0, 1.5 Hz, H-7 or H-4).
13C NMR (100 MHz, DMSO-d6): d = 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.
Mp 165–167 °C (lit.19 mp 166–167 °C). 1H NMR (400 MHz,
CDCl3): d = 7.25–7.60 (6 H, m), 7.90 (2 H, br d, J = 8.0 Hz),
8.28 (1 H, br d, J = 8.0 Hz, H-7).
2,3-Diiodo-1-methylindole (8c)
Mp 76–77 °C (lit.20 mp 76–78 °C). 1H NMR (400 MHz,
CDCl3): d = 3.89 (3 H, s, CH3), 7.10–7.42 (4 H, m). 13
C
NMR (100 MHz, DMSO-d6): d = 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.
3,3-Dichloro-1-methyloxindole (9)
1-Phenylsulfonyl-2,3-dichloroindole (8a)
Mp 122 °C. 1H NMR (400 MHz, CDCl3): d = 7.30–7.63 (6
H, m), 7.84–7.92 (2 H, m), 8.28 (1 H, br d, J = 8.0 Hz, H-7
or H-4). 13C NMR (100 MHz, DMSO-d6): d = 137.59,
134.70, 134.40, 129.30, 126.94, 126.54, 126.14, 124.57,
121.24, 118.15, 114.98, 113.78. HRMS (EI): m/z calcd for
C14H9NO2Cl2S: 324.9677; found: 324.9737.
Mp 144–147 °C (lit.21 143 °C). IR (KBr): n = 1740 cm–1. 1H
NMR (400 MHz, CDCl3): d = 3.25 (3 H, s, CH3), 6.85 (1 H,
d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, t, J = 8.0 Hz, H-5 or
H-6), 7.39 (1 H, t, J = 8.0, 1.5 Hz, H-6 or H-5), 7.61 (1 H, d,
J = 8.0 Hz, H-7 or H-4). 13C NMR (100 MHz, CDCl3): d =
168.80, 140.58, 131.85, 129.16, 125.13, 124.70, 124.14,
109.08, 26.98.
Synlett 2010, No. 17, 2593–2596 © Thieme Stuttgart · New York

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