Simple and efficient procedures for selective preparation of 3-haloindoles and 2,3-dihaloindoles by using 1,3-dibromo-5,5-dimethylhydantoin and 1,3-dichloro-5,5-dimethylhydantoin

Article abstract of DOI:10.1016/j.tetlet.2015.01.080

Simple and efficient synthetic procedures for the selective preparation of 3-bromo/3-chloroindoles and 2,3-dibromo/2,3-dichloroindoles by using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) were developed. Using 1,4-dioxane as the solvent, a variety of indoles, treated with 0.55 equiv DBDMH/DCDMH, afford the corresponding 3-bromo/3-chloroindoles selectively in 82-99% yield. In 1,2-dichloroethane (DCE), a series of 2,3-dichloro/2,3-dibromoindoles were selectively obtained in 84-95% yield by treating with DBDMH/DCDMH. All the processes do not need extra catalysts, dry solvents, or harsh reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.01.080

Tetrahedron Letters 56 (2015) 1096–1098
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and efficient procedures for selective preparation
of 3-haloindoles and 2,3-dihaloindoles by using 1,3-dibromo-5,
5-dimethylhydantoin and 1,3-dichloro-5,5-dimethylhydantoin
b
a
Jianwei Yan a, , Tianjun Ni , Fulin Yan
⇑
a School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
b Department of Chemistry, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and efficient synthetic procedures for the selective preparation of 3-bromo/3-chloroindoles and
2,3-dibromo/2,3-dichloroindoles by using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and 1,3-
dichloro-5,5-dimethylhydantoin (DCDMH) were developed. Using 1,4-dioxane as the solvent, a variety
of indoles, treated with 0.55 equiv DBDMH/DCDMH, afford the corresponding 3-bromo/3-chloroindoles
selectively in 82–99% yield. In 1,2-dichloroethane (DCE), a series of 2,3-dichloro/2,3-dibromoindoles
were selectively obtained in 84–95% yield by treating with DBDMH/DCDMH. All the processes do not
need extra catalysts, dry solvents, or harsh reaction conditions.
Received 28 October 2014
Revised 5 January 2015
Accepted 12 January 2015
Available online 19 January 2015
Keywords:
Indole
1,3-Dibromo-5,5-dimethylhydantoin
1,3-Dichloro-5,5-dimethylhydantoin
3-Haloindole
Ó 2015 Elsevier Ltd. All rights reserved.
2,3-Dihaloindole
Indole, as an important class of heterocycles, exists abundantly
in many biologically active natural products and medicinally rele-
vant structures.1 Their synthesis and further functionalization have
been and continue to be a research hotspot for synthetic organic
chemists and medicinal chemists.2 Among numerous efforts,
3-halogenation and 2,3-dihalogenation of indoles attract much
interest due to their versatile synthetic values as organic synthesis
intermediates3 and core structures in many biologically active
indole derivatives, such as antiviral,4 5-HT6 receptor ligands,5
angiotensin II receptor antagonists,6 inhibitors of coagulation
factor Xa, and7 hedgehog agonists.8
To date, the well known chlorination or bromination reagents
for indoles mainly include N-chloropyrrolidine,9 NBS/NCS,10 Br2,11
pyridinium tribromide, polymer supported pyridinium tribro-
mide,12 S2Cl2,13 SO2Cl2,14 and ‘palau’-chlor.’15 Although there are
a lot of papers investigating the 3-position bromination and chlo-
rination of indoles, most of them are limited to special substrates
Li and co-workers reported the selective synthesis of 2,3-dibromo-
indoles by using copper(II) bromide.17
The yields were moderate and the substrates were also few.
Multi-step reaction producing 2,3-dibromoindole derivatives were
also described.11b,18 The reagents for the synthesis of 2,3-dichloro-
indoles mainly include SO2Cl2,13 and S2Cl2.14 The commercially
available 1,3-dibromo-5,5-dimethylhydantion (DBDMH) is an
excellent reagent for the bromination of aromatic rings,19 particu-
larly for phenols and polyphenols.20 However, relatively few
papers have reported on the bromination of aromatic heterocycles
by using DBDMH.21 Bjørsvik and co-worker reported that DCDMH
and DBDMH could react with indole affording 3-chloroindole and
3-bromoindole in moderate yields under catalyzation of a strong
Brønsted acid.21 The systemic research of the halogenation indoles
is needed. Below, we describe the results of our investigation for
selective 3-bromination/3-chlorimination and 2,3-dibromination/
2,3-dichlorimination of a variety of indoles through the simple
control of solvents and temperature.
with
a few substituents and substituted modes. Meanwhile,
overhalogenation, lower yields, sensitivity to air/water, and nar-
row functional tolerance limited the application scopes of these
synthetic methods. Few examples of the synthesis of 2,3-dibromo-
indoles were reported. Langer and co-worker reported the prepara-
tion of 2,3-dibromo-1-methyl-1H-indole by using NBS at À78 °C.16
Initially, N-methyl indole was selected as a model substrate to
detect the 3-position bromination. 0.55 equiv DBDMH was
selected as bromination partner. The choice of solvent influenced
the activity and selectivity of bromination of indoles. When the
reaction was conducted in CH2Cl2, CHCl3, and acetonitrile, the
desired 3-bromoindole product was obtained in lower yields
accompanying the generation of the by-product of N-methyl-2,
3-dibromoindole and others, the solvents THF and 1,4-dioxane give
⇑
Corresponding author. Tel.: +86 187 3855 7612; fax: +86 373 302 9879.
E-mail address: jwyansimm@163.com (J. Yan).
http://dx.doi.org/10.1016/j.tetlet.2015.01.080
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. Yan et al. / Tetrahedron Letters 56 (2015) 1096–1098
1097
Table 1
Table 3
Synthesis of 3-bromoindoles
Synthesis of 3-chloromoindoles
Cl
Br
DBDMH (0.55 eq)
dioxane
DCDMH(0.55 eq)
R1
R1
Br
R1
R1
N
R2
N
N
N
dioxane
R2
R2
R2
1
1
4a
2
Cl
Cl
Cl
Br
Br
Br
O2N
Br
N
N
N
N
H
N
H
N
H
H
H
4b (93%)b
4a (96%)
4c (95%)
2a
2b
2c
(84%)
(92%)
(87%)
Cl
Cl
Cl
Br
Br
Br
O
F
F
F
O
N
N
H
N
Cl
N
H
N
N
H
H
Cl
H
H
4f (84%)b
4d
4e
(94%)
(92%)
2e (95%)
2d (90%)
2f (91%)
Br
Cl
Cl
Cl
Br
Br
Br
Br
N
H
N
N
Br
N
H
N
H
Br
H
F
N
H
H
4g (99%)
4h (94%)
4i (88%)
2h (90%)
2g (85%)
2i (93%)
O
O
Cl
Cl
Br
Br
Br
Cl
O2N
N
H
N
N
N
H
N
H
N
H
Bn
4j (97%)b
Cl
4l (86%)c
4k (96%)
2j
2k
2l
(86%)
Br
(83%)
Br
(85%)
Br
Cl
Cl
N
N
N
N
N
Bn
Boc
Ts
N
H
N
Ts
Boc
d
d
(85%)e
Cl
4m
4n
4o
(93%)
(86%)
Cl
2n (89%)
2m (82%)
2o (85%)
Cl
Br
Br
Ph
Ph
N
N
N
N
N
H
N
H
H
H
H
4r (92%)g
f
g
4p
4s
(85%)
(92%)
2q (93%)
2p (95%)
a Reaction conditions: 1 (1 mmol) and DCDMH (0.55 mmol) in dioxane (10 mL) was
stirred at 25 °C for 3 h.
Table 2
Synthesis of 2,3-dibromoindoles
b Reaction was stirred at 25 °C for 6 h.
c Reaction was stirred at 25 °C for 0.5 h.
d Reaction was stirred at 25 °C for 10 min.
e Reaction was stirred at 80 °C for 3 h.
f Reaction was stirred at 80 °C for 0.5 h.
g Reaction was stirred at 25 °C for 24 h.
the only product of 3-bromoindole, and the latter gives the higher
yield (see Table 1 in SI). So, the optimal reaction condition was that
N-methyl indole reacted with 0.55 equiv DBDMH in 1,4-dioxane at
10 °C for ten minutes, and the DBDMH should be added portion-
wise. The generality of this bromination method was examined
(Table 1). To our delight, we found this transformation to be very
general for a wide range of indoles, and provided easy access to
diverse substituted 3-bromoindoles. Employment of different
indole substrates, bearing fluoro, chloro, bromo, methyl, methoxy,
nitro groups on the phenyl ring at different positions, 2-methyl
indole, and 2-phenyl indole produced corresponding 3-bromoin-
doles in good to excellent yields (2b–2k, 2p, and 2q). Among them,
3,6-dibromoindole22 (2h) and 3,4-dibromoindole23 (2i) are marine
natural products, and exhibit antibacterial activities. Indoles con-
taining different electrical properties N-substituents, including
benzyl, Boc, and tosyl groups, also reacted with DBDMH smoothly

1098
J. Yan et al. / Tetrahedron Letters 56 (2015) 1096–1098
Acknowledgments
Cl
DCDMH (1.1 eq)
DCE, 80 °C, 4h
5a (96%)
Cl
N
Boc
This work was supported by the key project of Henan Provincial
Department of Education (14A350006) and post-doctoral research
projects of Henan Province (2013039).
N
Boc
Cl
DCDMH(2.2 eq)
DCE, 80 °C, 12h
Supplementary data
5b (90%)
Cl
N
Ts
N
Supplementary data (Experimental procedures and spectral
data for all new compounds were provided.) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.01.080.
Ts
Figure 1. Synthesis of 2,3-dichloromoindoles.
and provided corresponding 3-bromoindoles in good to excellent
yields (2l–2n). Apart from various indoles, 7-azaindole also per-
formed well in this transformation, and provided 3-bromo-7-aza-
indole (2o) in 85% yield.
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