Environmentally benign indole-catalyzed position-selective halogenation of thioarenes and other aromatics

Article abstract of DOI:10.1039/c8gc02415d

Halogenated aromatic compounds are the cores of many pharmaceutical, agricultural and chemical products but they are commonly prepared using electrophilic halogenation reactions in non-green chlorinated solvents under harsh conditions. A separate problem happens in the aromatic halogenation of thioarenes because they readily undergo oxidative side-reactions. Herein we report an environmentally benign electrophilic bromination of aromatics using an indole-catalytic protocol, which is suitable for a wide range of substrates including thioarenes.

Full text of DOI:10.1039/c8gc02415d

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Environmentally Benign Indole-Catalyzed Position-Selective
Halogenation of Thioarenes and Other Aromatics†‡
Yao Shi, a Zhihai Ke*a and Ying-Yeung Yeung*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Halogenated aromatic compounds are the cores of many halogenation of arenes in the environmentally friendly solvent
pharmaceutical, agricultural and chemical products but they are heptane. In particular, this newly developed catalytic protocol
commonly prepared using electrophilic halogenation reactions in was found to be highly efficient in suppressing the disulfide
non-green chlorinated solvents under harsh conditions. A separate formation in the halogenation of thioarenes. The scope was
problem happens in the aromatic halogenation of thioarenes found to be broad and the products could be isolated under
because they readily undergo oxidative side-reactions. Herein we column-free condition.
report an environmentally benign electrophilic bromination of
The investigation began with the evaluation of a sample
aromatics using an indole-catalytic protocol, which is suitable for a containing thioanisole (2a) and N-bromosuccinimide (NBS) in
wide range of substrates including thioarenes.
dichloromethane using GCMS (Scheme 1, path a). Strong
O
Me
O
Halogenated arenes are important to the pharmaceutical,
agricultural, chemical, and material sciences. In addition, they
are important synthetic intermediates for metal-mediated
aryl-coupling chemistry.1-6 Thus, development of new synthetic
methods to introduce halogens into arenes is of great
significance.1-9
O
Me
S
S
no reaction
n-heptane
NBS
H2O
no catalyst
path b
C
D
m/z 140.1
H2O
m/z 156.1
Me
S
Electrophilic halogenation is a common method to produce
halogen-containing arenes. N-haloamides are frequently
employed in the electrophilic halogenation processes because
they are easy to handle as compared with the toxic and highly
corrosive molecular halogens. However, in many cases
environmentally unfriendly solvents such as chlorinated
solvents are necessary for high efficiency (due to the poor
solubility of the polar N-haloamide reagents) and selectivity. In
addition, conventional aromatic electrophilic halogenations
frequently encounter difficulty in controlling regioselectivity.10-
Br
Me
Br
S
S
S
2a
S
CH2Cl2
2a
+
O
major reaction
A
B
path a
Br
N
m/z 203.1
205.2
m/z 188.0
190.0
diphenyl
disulfide
m/z 218.3
O
13
NBS
Furthermore, these reactions generally require harsh
reaction conditions such as highly acidic solutions,11 high
reaction temperatures, or high catalyst loadings.11-13
Halogenation of thioarenes with N-haloamides often
encounter a separated type of challenge since thioarenes
readily undergo oxidative reactions to give disulfide
compounds and sulfoxides.14-18 Herein, we are pleased to
disclose our recent success in using structurally re-engineered
super-lipophilic indoles for the position-selective mono-
COOMe
Me
Me
S
N
H
COOMe
Me
Br
(A-D were
1a (5 mol%)
n-heptane
2a
not detected)
N
major reaction
Br 3a
1a-Br
m/z 267.1
269.1
path c
m/z 201.9
203.9
Scheme 1. Reaction between thioanisole (2a) and NBS analysed by GCMS.
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signals that correspond to the sulfonium bromide species
A
Table 1 Bromination of thioanisole (2a) with NBS
(m/z 203.1, 205.2), the S-Br species B (m/z 188.0, 190.0), and
diphenyl disulfide (m/z 218.3) were detected (Scheme 1, path
a). However, minor aromatic halogenation product was
observed. We believe that the putative sulfonium bromide
Me
S
Me
Me
S
S
catalyst (5 mol%)
NBS, n-heptane
23 oC, 48 h
S
Br
+
+
S
species A could be formed through the nucleophilic attack of
the Lewis basic sulfide in 2a to NBS.14,19-23 A possible pathway
Br
3a
to the formation diphenyl disulfide could undergo through the
3a'
2a
nucleophilic attack of the sulfide in species
2a followed by demethylation.14,15 At the same time, two weak
signals that correspond to sulfone (m/z 140.1) and sulfoxide
(m/z 156.1) were observed and these compounds could be
B by a molecule of
diphenyl
disulfide
C
catalysts
D
COOMe
R
1a (R = Me)
formed through the nucleophilic attack of species
moisture.16-18
A by
1b (R = n-C9H19
)
1c (R = n-C5H11
)
Recently, we have introduced a new concept of using
lipophilic indole 1a as an organocatalyst in electrophilic
halogenation in non-polar green solvents through a solid-liquid
phase transfer mechanism and have demonstrated that the
catalytic protocol is suitable for a range of electrophilic
halocyclization reactions.24 Since the charged sulfonium
N
H
1d (R = CH(C2H5)2)
Entrya Catalyst Unreacted 2a (%)b 3a (%)b
3a’ (%)b
(PhS)2 (%)b
1
2
-
1a
100
60
0
0
0
2
0
0
bromide species
A could be the active species for the
38
98
99
83
50
46
64
formation of the undesired oxidative products, we
hypothesized that conducting the reaction in lipophilic media
could shut down the channel towards the oxidized products
3
1b
2
0
4
1c
0
1
0
through suppressing the formation of species A.
5
1d
15
18
10
6
2
0
To test the hypothesis, the aromatic bromination of
thioanisole (2a) was performed in n-heptane. No reaction was
observed in the absence of catalyst (Scheme 1, path b and
Table 1, entry 1). On the other hand, we were delighted to
realize that 3a was the exclusive product when the reaction
was conducted in n-heptane in the presence of 5 mol % of
indole catalyst 1a in the GCMS analysis (Scheme 1, path c).
Although the yield of 3a was moderate (38%), the reaction
returned with a high para-selectivity and no oxidized products
were detected (Table 1, entry 2). The reaction efficiency was
not satisfactory, potentially due to the moderate solubility of
the indole catalyst. We then decided to incorporate a lipophilic
side chain to the indole catalyst system aiming at improving
the reaction efficiency through the increase in solubility.
6c
7c
8c
Ph3PS
HCl
FeCl3
5
27
31
5d
13
5
a
Reactions were conducted using thioanisole (2a) (1 mmol), NBS (1.05 mmol) in
n-heptane (2 mL) at 23 °C for 48 h in the absence of light. NBS was purified via
recrystallization. b Determined by GC–MS. c CH2Cl2 was used as the solvent. d c.a.
20% of sulfoxide products was detected.
COOMe
3
Me
2
N
H
Thus, a series of indole catalysts
1 with various alkyl
substituents were prepared according to a modified literature
procedure.25 As illustrated in Figure 1, the solubility of 1a was
moderate in n-heptane (Figure 1a and 1b). In contrast, indole
1b that has a n-nonanyl side chain at the C(2) position
appeared as a pale yellow oil and it was found to be miscible
1a (0.05 mmol)
(a) pure 1a
(b) 1a in n-heptane
at 23 o
C
o
with n-heptane even the temperature was reduced to –28 C
(Figure 1c and 1d).
COOMe
3
Next, the performance of the newly prepared indoles 1 was
evaluated. To our delight, catalyst 1b exhibited superior
performance in driving the reaction to completion to give the
desired product 3a in 87% isolated yield (Table 1, entry 3).
More importantly, excellent para/ortho-selectivity was
obtained and no diphenyl disulfide side product was detected.
Indole catalyst 1c that has a relatively shorter hydrocarbon
also gave comparable performance (entry 4). On the other
8
2
N
H
Me
1b (0.05 mmol)
(c) pure 1b
(d) 1b in n-heptane
at -28 o
Fig 1 Comparison of the solubility of indole catalysts 1a and 1b.
C
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hand, the reaction efficiency was slightly reduced when indole
Other arenes were also examined using the catalytic
catalyst 1d was used, attributable to the relatively bulkier protocol (Scheme 3). A broad range of aromatic substrates was
branching hydrocarbon substituent (entry 5). We have also
H
Br
investigated the reaction using some common catalysts for
halogenation including Lewis base (Ph3PS), Lewis acid (FeCl3),
and Brønsted acid (HCl) in dichloromethane. Although the
reactions proceeded with moderate efficiency, poor
para/ortho-selectivity together with significant amount of
diphenyl disulfide side product were observed (entries 6–8).
Indole catalyst 1c was then used in the substrate scope study.
1c (5 mol%)
NBS or DBDMH (1.05 equiv)
Z
Z
n-heptane, 23 o
C
Ar
Ar
Z = alkyl, OR, NR2
4
5
OMe
OMe
OMe
OMe
OMe
Me
Br
Br
OMe
Other aryl thioethers
are shown in Scheme 2. In general, excellent selectivity and
chemical yield of the desired products were observed. Again,
2 were then examined and the results
Me
Br
5a (95%)
Br
Me
5c (97%)
Et
Br
5e (90%)
5b (99%)
5d (92%)
3
(NBS, 24 h) (DBDMH, 16 h) (NBS, 24 h)
(NBS, 24 h) (DBDMH, 12 h)
no disulfide by-product was detected in all these cases. Other
than S-methyl substrates, 2d and 2e that have different S-alkyl
substituents were also found to be compatible with this
catalytic protocol. Naphthalene thioether 2f also gave the
corresponding C(1) brominated product 3f in excellent yield.
We were also delighted to realize that the sulfides were not
oxidized in all these cases. Since the halogen carrier
succinimide is insoluble in n-heptane, we intended to purify
the product under column-free condition. Thus, the reaction of
2a was conducted using 1 mol % of indole 1c (Scheme 2). Upon
completion, the reaction was filtered and the succinimide
residue was washed with n-heptane to yield the desired
product 3a in 92% yield with purities of up to 99% (as
OMe
OMe
OBn
OiPr
O
O
OMe Me
Me
Br
Br
Br
Br
Br
5f (92%)
5g (97%)
5h (89%)
5i (93%)
5j (90%)
(NBS, 24 h) (DBDMH, 12 h)
OMe
(DBDMH, 14 h) (NBS, 24 h) (NBS, 24 h)
NMe2
MeO
HO
Br
Br
Br
Br
5k (90%)
5l (98%)
5m (93%)
5n (90%)
(NBS, 24 h)
NMe2
1
determined by H NMR) together with the recovery of 95% of
(NBS, 24 h)
NEt2
(NBS, 24 h)
(NBS, 24 h)
succinimide. It is worth-mentioning that the reaction was
performed at 10 mmol scale and the reaction performance
was satisfactory.
NH2
NMe2
CHO
NHAc
Br
Br
N
H
Br
Br
iPr
Br
Br
R1
R1
1c (5 mol%)
NBS, n-heptane
23 oC, 48 h
5o (90%)
5p (90%)
5q (95%)
5r (87%)
5s (91%)
S
S
Ar
Ar
(NBS, 24 h)
(NBS, 24 h)
(NBS, 24 h)
(NBS, 24 h) (NBS, 24 h)
2
3
NMe2
Me
Me
Me
Et
S
Br
Br
Me
S
S
S
S
Me
Me
Br
N
Br
5u (96%)
Me
5t (90%)
5v (81%)
5w (92%)
Br
Br
3b (97%)
Br
Br
(NBS, 24 h)
(NBS, 24 h)
(NBS, 24 h)
(NBS, 24 h)
3a (92%)
3c (93%)
3d (94%)
NMe2
NMe2
Br
1b (5 mol%)
S
S
NIS (1.05 equiv)
n-heptane, 23 oC, 24 h
Me
Br
3e (92%)
3f (99%)
H
I
6 (91%)
4n
Me
S
Me
S
O
Scheme 3. Indole-catalyzed bromination of aromatics.
1c (1 mol%)
NBS (1.05 equiv)
n-heptane, 23 oC, 5 d
(column-free)
NH
O
+
found to be compatible and clean conversion was observed in
all these cases. In general, anisole-type substrates with
substituents at the ortho-, meta-, or para-position reacted
4
H
2a
Br
3a (92%)
succinimide
(95%)
smoothly, giving the brominated products
5
in good yields and
(10 mmol)
excellent position-selectivity (Scheme 3, 5a
–
5h). Anisoles, such
Scheme 2. Indole-catalyzed bromination of thioethers 2 in n-heptane.
as 3-methylanisole (4b) and 1,3-dimethoxybenzene (4g), were
brominated with excellent regioselectivities and good yields
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using 5 mol% of 1c as the catalyst and 1.05 equivalent of 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) as the bromine
source. para-Substituted anisoles 4c and 4d produced ortho-
brominated anisoles 5c and 5d, respectively, in excellent
O
H
COOMe
Br
NH
4
Z
Ar
N
yields. Benzyl phenyl ether (4i) and isopropyl phenyl ether (4j
)
O
2 or 4
1c-Br (detected by
were converted into the corresponding mono-bromides 5i and
5j in excellent para-selectivity (> 99:1 p/o ratio). Naphthenyl
methyl ethers 4k and 4l worked equally well as the anisole-
type substrates. The unprotected 2-naphthol (4m) could be
brominated to give 5m in 93% isolated yield.
succinimide
NMR and HRMS)
O
COOMe
Br
NBr
4
Z
Ar
Substituted anilines were also examined and the
corresponding mono-brominated compounds could be
N
H
O
3 or 5
1c (5 mol%)
furnished in high efficiency and selectivity (Scheme 3, 5n–5r).
NBS
The aldehyde-containing substrate 4q, which is sensitive
towards oxidation condition, was found to be compatible with
the catalytic protocol and the product 5q was obtained in 95%
yield. Amino-pyridines 4s and 4t could readily be converted
into 5s and 5t under the optimized reaction conditions.
Polycyclic compounds were studied as well. The cyclopropane-
containing bicyclic system 7,7a-dihydro-6bH-cyclopropa[a]
acenaphthylene (4u) could be mono-brominated to give 5u
in heptane
favored
R
Br
R
S
S
Ar
Ar
2
2
with the cyclopropane remained intact. Anthracene (4v
)
oxidation
side-products
polar sulfonium
intermediate
underwent mono-bromination smoothly to give 5v in good
yield and excellent regioselectivity. We were also delighted to
realize that the heterocyclic compound 5-Bromo-2-
in heptane
disfavored
methylthiophene
(5w) was obtained in good yield and
Scheme 4. Proposed catalytic cycle.
regioselectivity from 2-methylthiophene (4w). The catalytic
protocol was found to be applicable to the preparation of
iodinated arene. For instance, reaction of dimethylaniline (4n
)
Conclusions
with N-iodosuccinimide (NIS, 1.05 equiv) catalyzed by indole
1b smoothly achieved p-iodo-N,N-dimethylaniline (
yield in n-heptane at 23°C.
6) in 91%
In summary, good yields and excellent regioselectivities
were achieved in the bromination of aromatics using indole-
based organocatalysts in the lipophilic media heptane.
Mechanistic studies revealed that the putative active species
3-bromoindole could be formed through a solid-liquid phase-
transfer mechanism. The catalytic protocol is compatible with
a wide range of arenes. In particular, the formation of
oxidative side products in the halogenation of thioarenes can
effectively be suppressed in the lipophilic reaction media. The
bromination scheme introduced in this report does not require
the use of hazardous substances, such as halogenated
solvents, which conforms with the principles of green
chemistry. Moreover, easy purification of the halogenated
products could be realized without the need for column
The proposed catalytic cycle for the aromatic bromination
is shown in Scheme 4. We suspect that the reaction might
begin with the halogen exchange between the soluble indole
catalyst 1c and the insoluble N-bromoamide to give the
corresponding lipophilic 3-bromoindole species 1c-Br through
a
solid-liquid phase-transfer mechanism,24 which was
evidenced by physical analysis using NMR and ESI high-
resolution mass spectrometry (HRMS).26 We believe that the
Br in species 1c-Br is highly active towards electrophilic
bromination as a result of the loss of aromaticity in the
conversion of 1c to 1c-Br. Species 1c-Br could then deliver the
Br to the arenes
2
or
4
3
in the lipophilic media, giving in the
or in high efficiency. A possible
brominated products
5
chromatography.
These
make
this
approach
an
explanation for the driving force of the reaction could be due
to the resuming of the aromaticity of indole 1c after delivering
the Br to the substrates. Unlike many other halogenation
protocols that rely on the polarized or charged halogen
species,27-29 the current reaction system involves the neutral
brominating species 1c-Br in non-polar media, which could
execute the halogenation under mild and virtually neutral
conditions, and could avoid the formation of side products
through supressing the formation of the polar sulfonium
intermediate (Scheme 4).
environmentally friendly and sustainable pathway for the
synthesis of valuable bromoarenes. Efforts are now underway
to apply green solid-liquid phase-transfer organocatalysts to
other classes of reactions.
Conflicts of interest
There are no conflicts to declare.
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Notes and references
‡ We thank the financial support from RGC General Research
Fund of HKSAR (CUHK 14306916) and The Chinese University of
Hong Kong Direct Grant (project code: 4053193). Equipment was
partially supported by the Faculty Strategic Fund for Research
from the Faculty of Science of the Chinese University of Hong
Kong.
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Position-selective halogenation of thioarenes and a wide range of aromatics using highly lipophilic indole
organocatalyst has been developed.