PhI(OAc)2/NaX-mediated halogenation providing access to valuable synthons 3-haloindole derivatives

Article abstract of DOI:10.1039/c8nj03822h

This paper describes a mild phenyliodine diacetate mediated method for selective chlorination, bromination, and iodination of indole C-H bonds using sodium halide as a source for analogous halogenations. The combination of NaX and phenyliodine diacetate provides an invincible system for halogenation of indoles. This protocol was compatible with a wide array of indole substrates and provides straight forward access to potential halogenated arenes.

Full text of DOI:10.1039/c8nj03822h

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PhI(OAc)2/NaX-mediated halogenation providing
access to valuable synthons 3-haloindole
derivatives†
Cite this: New J. Chem., 2018,
42, 18889
Vittam Himabindu,ab Sai Prathima Parvathaneni *a and
ab
Vaidya Jayathirtha Rao
*
This paper describes
a mild phenyliodine diacetate mediated method for selective chlorination,
Received 31st July 2018,
Accepted 17th October 2018
bromination, and iodination of indole C–H bonds using sodium halide as a source for analogous halo-
genations. The combination of NaX and phenyliodine diacetate provides an invincible system for halo-
genation of indoles. This protocol was compatible with a wide array of indole substrates and provides
straight forward access to potential halogenated arenes.
DOI: 10.1039/c8nj03822h
rsc.li/njc
Indoles are ubiquitous in marketed drugs and stand as a privileged on the basis of the availability and ease of handling of hypervalent
scaffold in biologically active natural products.1 Functionalized iodine(III) compounds.8 Chlorination of arenes has been reported
indoles are of paramount importance in chemical synthesis; in using the hypervalent iodine(III) reagent 1-chloro-1,2-benziodoxol-3-
particular, 3-haloindoles are widely recognized as valuable inter- one as a chloro source (Scheme 1A).9 The combination of hyperva-
mediates/prefunctionalized starting materials in cross-coupling lent iodine reagents with metal halides as the halide source has
reactions.2 The most appropriate strategy for the synthesis of the been less explored for halogenations.10 More recently Rh(III)-
functionalized indole framework is through halogenations and catalyzed halogenations of arylpyridines with PhI(OAc)2/NaX have
subsequent cross-coupling methodologies or through direct C–H been reported.11 Therefore, it is appealing to develop simple
activation.3 Recently 3-chloroindoles in conjunction with methyl reagents/systems without using metal catalysts.
coumalate have been demonstrated to generate carbazoles and
Our previous study revealed that chlorination of MBH adducts
3-haloindoles to 3-(azol-1-yl)indoles, providing simple access to could be easily achieved in high yields with the NaCl/oxone system
heterocycles under metal-free conditions.4 Despite the utility of in water.12 This suggested that NaCl could be a better halo source
these compounds, installing halogen atoms, especially bromine as it is more economic, and readily activated to allow the halogena-
and iodine, due to their high reactivity relative to chlorine on tion of arenes under mild, atom economical, metal-free and
aromatic structures, is highly desirable.5
environmentally benign conditions. We undertook a study of
The most common approach to halogenated arenes is
electrophilic aromatic substitution (EAS) using reagents such
as N-halosuccinimides, X2 and peroxides with HX/MX.6 Due to
the clear limitations of the current methods, the development
of an efficient, safe, simple and selective protocol for the
formation of C–Cl, C–Br and C–I bonds is challenging but at
the same time very attractive. In recent times, the oxidative
halogenation by metal halides has emerged as an important
alternative for the synthesis of halo compounds.7 In this
context phenyliodine diacetate was chosen as the best oxidant
a Fluoro AgroChemicals Laboratory, Organic Chemistry Division II, CSIR-Indian
Institute of Chemical Technology (IICT), Tarnaka,
Hyderabad-500 607, India. E-mail: saiprathimaiict@gmail.com
b AcSIR, CSIR-Indian Institute of Chemical Technology (IICT), Tarnaka,
Hyderabad-500 607, India. E-mail: vaidya.opv@gmail.com;
Fax: +91-40-27160921; Tel: +91-40-27193181
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8nj03822h
Scheme 1 Halogenation reaction of indoles.
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Table 1 Optimization of reaction conditionsa
bromination, and iodination) of various indoles under mild
conditions (Scheme 1B).
Results and discussion
We commenced our studies by examining the reaction of indole
as the model substrate with NaCl as a halogenating agent to
investigate the optimal reaction conditions (Table 1). Treatment
of indole (1 mmol) with oxone (1 mmol) and NaCl (1 mmol) in
the presence of water as a solvent starting material was observed
(entry 1). However, stoichiometric peroxy oxidants like TBHP, aq.
H2O2, K2S2O8 and hypervalent iodine(III) oxidant DIB were used
in combination with NaCl in an aqueous system resulting in no
reaction (entries 2–5). Furthermore, 1,4-dioxane, CH3CN and
DCE were used as solvents and the desired product was observed
in a 50% yield in the acetonitrile system with PIDA (entries 6–8).
Entry
Oxidant
Salt
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Oxone
TBHP
H2O2
K2S2O8
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
Oxone
PIDA
PIDA
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaBr
NaI
H2O
H2O
H2O
H2O
H2O
1,4-Dioxane
CH3CN
—
—
—
—
—
30
50
20
72
40
30
25
78
91
DCE
9
CH3CN : H2O
1,4-Dioxane : H2O
DCE : H2O
CH3CN : H2O
CH3CN : H2O
CH3CN : H2O
10
11
12
13
14
1
Indole C-3 substitution was identified by its H NMR spectrum
as the sole product/major product. Encouraged by this result,
it was of interest to develop a green version of this useful
halogenation process for which we used a combination of water
with organic solvents in 1 : 1 ratios. To our surprise, 3-chloro
indole was obtained in a high yield (72%) in the CH3CN: H2O
a
Reaction conditions: substrate 1a (1.0 mmol), oxidant (1.0 mmol),
sodium salt (1.0 mmol) and solvent (2.0 mL) at room temperature for
1–2 h. Isolated yields.
b
the combination of NaX with phenyliodine diacetate for regio- system compared to other mixtures (entries 9–11). Hence, entry 9
selective construction of C–X bonds at the C-3 position of was chosen as the perfect optimized conditions for C-3 chlorina-
indoles. This combination indeed acts as a very effective tion with a 72% yield in the presence of hypervalent iodine(III)
halogenating system for the C–H halogenations (chlorination, and diacetoxyiodobenzene PhI(OAc)2 with 1.0 equiv. of NaCl in
a
Table 2 Halogenation of indoles with NaX/PhI(OAc)2
Yieldb (%)
Entry
1
Substrate 1
Product (2a–2j)
Product (3a–3l)
Product (4a–4m)
2
3
4
72
78
91
2
3
4
5
6
7
8
62
67
64
74
65
79
78
61
69
65
79
59
82
81
75
82
85
89
68
94
92
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Table 2 (continued)
Yieldb (%)
Entry
9
Substrate 1
Product (2a–2j)
Product (3a–3l)
Product (4a–4m)
2
3
4
58
64
62
71
10
11
12
74
71
90
82
—
—
—
—
—
—
94
—
94
94
13
—
a
Reaction conditions: substrate 1a (117 mg, 1.0 mmol), PhI(OAc)2 (322 mg, 1.0 mmol), NaCl (58 mg, 1.0 mmol)/NaBr (103 mg, 1.0 mmol)/NaI
b
(150 mg, 1.0 mmol) and CH3CN : H2O (1 : 1) (2.0 mL) at room temperature for 1–2 h. Isolated yields were provided.
CH3CN: H2O (1: 1) as a solvent. However, the reaction was very substrates showed a high selectivity, affording mono iodinated
slow with a 25% yield in the presence of oxone in the CH3CN: compounds 4a–m in high yields (68–94%). Thus we found that
H2O system (entry 12). Interestingly NaBr and NaI also afforded the method is widely applicable to construct C–Cl, C–Br and C–I
C-3 bromination and iodination of indoles with 78% and 91% bonds of indoles with high regioselectivity.
yields successively in the presence of PhI(OAc)2 (entries 13 and 14).
Furthermore, we extended our study with heterocycles such
To confirm the scope of the chlorination reaction, we as pyrrole, furan, thiophene and imidazole. Among them only
attempted to apply the reaction to a variety of indoles under imidazole gave the desired chloro and bromo products under
the optimized conditions. As a result, the present reaction is the optimized reaction conditions and the results have been
applicable to a wide range of substituted indoles, and these included in Table 3.
results are summarized in Table 2. The effect of substituents of
both electron-donating and electron-withdrawing groups at the
5-position of the indole ring was considered. The results proved
a,b
Table 3 Halogenation of heterocycles with NaX/PhI(OAc)2
Yieldb (%)
—
that the electronic characteristics of substituents on the aromatic
ring have no considerable influence on the reaction yields. The
chlorination reaction of indoles, having withdrawing substituents
at their 5-position, smoothly proceeded and afforded the corres-
ponding 3-chlorinated products (entries 2–6).
Entry
1
Compound
Product
—
The results showed that C-5 substituted with an electron
donating group afforded the corresponding monohalogenated
products with very good yields (entries 7 and 8). However, in the
case of N-phenyl substituted indoles, chlorination also proceeds
regioselectively at the C-3 position with a low yield (entry 10).
In addition, bromination of the indole derivatives was
studied, employing NaBr as a halogen source (Table 2). The
substituted indole substrates with Me, OMe and F, Cl, Br, I, or
NO2 at the 5-position reacted to give the corresponding C-3
brominated products 3a–i in 59–82% yields. The same results
were obtained via phenyl, benzyl and methyl substitution at the
N-1 position of indoles (entries 10–12).
2
3
—
—
—
—
4
88
90
5
a
Reaction conditions: imidazole (68 mg, 1.0 mmol), PhI(OAc)2 (322 mg,
1.0 mmol), NaCl (58 mg, 1.0 mmol)/NaBr (103 mg, 1.0 mmol) and
Finally, iodination of indole derivatives was investigated in
the presence of NaI as a halogen source (Table 2). The studied
b
CH3CN : H2O (1 : 1) (2.0 mL) at room temperature for 1–2 h. Isolated
yields were provided.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are grateful for the financial assistance provided by
the CSIR-Senior Research Associateship, New Delhi and the
Inspire Junior Research Fellowship, Govt. of India. VJR acknowl-
edges CSIR-New Delhi for the Emeritus Scientist Honour. We
also acknowledge Director, IICT for providing infrastructural
facilities.
Scheme 2 Chlorination of indoles with benziodoxole 6.
Scheme 3 Possible mechanism.
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