Microwave irradiated synthesis of 2-bromo(chloro)indoles via intramolecular cyclization of 2-(gem-dibromo(chloro)vinyl)anilines in the presence of TBAF under metal-free conditions

Article abstract of DOI:10.1039/c4ra00603h

2-Bromo(chloro)indoles were readily and efficiently prepared through TBAF-promoted intramolecular cyclization of 2-(gem-dibromo(chloro)vinyl)anilines in excellent yields under metal-free and microwave irradiation conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00603h

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Microwave irradiated synthesis of 2-bromo(chloro)
indoles via intramolecular cyclization of 2-(gem-
dibromo(chloro)vinyl)anilines in the presence of
TBAF under metal-free conditions†
Cite this: RSC Adv., 2014, 4, 26918
Received 21st January 2014
Accepted 28th May 2014
a
ac
Min Wang,a Pinhua Li,ab Wei Chen and Lei Wang
*
DOI: 10.1039/c4ra00603h
www.rsc.org/advances
2-Bromo(chloro)indoles were readily and efficiently prepared through construction of various functionalized indole derivatives from
TBAF-promoted intramolecular cyclization of 2-(gem-dibromo- 2-(2,2-dibromovinyl)anilines and 2-(2,2-dibromovinyl)(N-
(chloro)vinyl)anilines in excellent yields under metal-free and micro- substituted)anilines through the transition-metal-catalyzed
wave irradiation conditions.
cross-coupling methodologies, such as carbon–nitrogen/
carbon–carbon,7 carbon–nitrogen/carbon–nitrogen,8 carbon–
nitrogen/carbon–phosphine,7a
carbon–nitrogen/carbon–
Introduction
hydrogen,9 carbon–nitrogen/carbonylation,10 and carbon–
nitrogen/carbonylation/carbon–carbon tandem reactions11 has
been reported. Recently, Lautens et al. developed an efficient
method for the synthesis of 2-bromoindoles via Pd/Pt-Bu3-
catalyzed intramolecular reactions of 2-(gem-dibromovinyl)-
anilines.12
The indole skeleton is one of the important structural motifs
widely found in dyes, natural products, materials, and phar-
maceutically active compounds, such as antibiotic, anticancer
and anti HIV agents.1 In addition, the indole derivatives are also
used as starting materials for the synthesis of a large number of
alkaloids. Many halogenated indole derivatives are also found
in nature, and several brominated indole natural products have
been isolated.2 They are also present in biologically active
compounds, such as Convolutindole A,2d and polybrominated
bisindoles.2e,f
Due to the electron-rich nature of indoles, the preparation of
brominated indoles is still a challenge. The most straightfor-
ward method is electrophilic bromination of indoles, and
3-bromoindoles are obtained, along with the by-products.3
While unprotected 2-bromoindoles are useful for numerous
applications,4 their preparation is oen difficult. Although the
synthesis of 2-bromoindole based on lithiation of unsubstituted
indole, followed by bromination was developed, the extension
of its derivatives was less investigated owing to the limitation of
regioselectivity and functional group tolerance on lithiation.5
gem-Dihaloolens, as one of the important synthetic inter-
mediates for their higher reactivity and easy availability have
been attracted much attention in recent years.6 Especially, the
Microwave heating is an attractive tool that has recently been
used in organic synthesis. And it presents a powerful and green
alternative to conventional synthesis, which helps the chemical
process more economic and so.13 In continuing our efforts on
the organic transformations of gem-dihaloolens under metal-
free conditions14a–c and the solid-phase construction of indole
derivatives based on a traceless, activating sulfonyl linker by
Zhang,14d herein we developed a tetra-butylammonium uoride
(TBAF)-promoted intramolecular cyclization of 2-(gem-dibro-
movinyl)-N-methylsulfonylanilines15 for the synthesis of 2-bro-
moindoles under microwave irradiation conditions. The
reactions generated unprotected 2-bromoindoles under metal-
free and mild reaction conditions in nearly quantitatively yields.
In addition, this methodology can also be extended to synthesis
of 2-chloroindoles (Scheme 1).
In our initial attempt to obtain 2-bromoindole from the
corresponding 2-(gem-dibromovinyl)aniline in the presence of
TBAF in THF at 80 ꢀC for 8 h, a complicated mixture of
aDepartment of Chemistry, Huaibei Normal University, Huaibei, Anhui, 235000, P.R.
China. E-mail: leiwang@chnu.edu.cn; Fax: +86 561-309-0518; Tel: +86 561-380-2069
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.R. China
cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P.R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra00603h
Scheme 1 Microwave irradiated synthesis of 2-bromo(chloro)indoles.
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Table 1 Screening of base and solvent for the intramolecular cycli-
zation of 1aa
compounds was obtained, but no desired 2-bromoindole was
observed. When N-substituted derivatives of 2-(gem-dibromo-
vinyl)aniline, such as N-benzyl, N-acetyl, and N-triuoroacetyl
were used as substrates, however, no desired 2-bromoindole
was detected and a complicated mixture of compounds
was generated. While 2-(gem-dibromovinyl)-N-tert-butoxy-
carbonylaniline was used, 2-(bromoethynyl)-N-tert-butoxy-
carbonylaniline was isolated in 91% yield. To our delight, 94%
yield of 2-bromoindole was obtained when 2-(gem-dibromo-
vinyl)-N-methylsulfonylaniline was used as substrate. However,
2-(gem-dibromovinyl)-N-(p-tolylsulfonyl)aniline was inferior and
generated 2-bromoindole in 76% yield. The results indicated
that this cyclization depends on the nitrogen substituents of
substrates. When the amine is activated by a strong electron-
withdrawing group such as sulfonyl, the tandem reaction can
occur efficiently in one pot. The N-sulfonyl linker serves as a
dual-activating group to undergo 2-bromoindoles formation.
Aer rst-step cyclization, the sulfonamide linkage proceeds
nitrogen–sulfur bond cleavage to remove sulfonyl group.
To further optimize the reaction conditions for the synthesis
of 2-bromoindole (2a) from 2-(gem-dibromovinyl)-N-methyl-
sulfonylaniline (1a) through a base-promoted intramolecular
cyclization, a variety of bases were examined. The results were
summarized in Table 1. As the analogues of TBAF, TBAC (tetra-
butylammonium chloride), TBAB (tetra-butylammonium
bromide), TBAI (tetra-butylammonium iodide), or TBA$HSO4
(tetra-butylammonium hydrogen sulfate) was used instead of
TBAF, no product was detected and starting material was
unchanged and recovered (Table 1, entries 2ꢁ5). Meanwhile,
TBA$OH (tetra-butylammonium hydroxide) and TBA$OAc (tetra-
butylammonium acetate) generated 2-bromo-N-methyl-
sulfonylindole (3a) in 35 and 72% yields, and no 2a was
obtained (Table 1, entries 6 and 7). Other bases, KF, CsF, Et3N,
and DABCO were ineffective promoters to the reaction (Table 1,
entries 8ꢁ11). However, K2CO3, K3PO4, and tBuOK gave 3a or a
mixture of 2a and 3a in inferior yields (Table 1, entries 12ꢁ14).
With respect to TBAF loading, 2 equiv. of TBAF was found to be
optimal. On the other hand, the inuence of solvent on the
reaction was also examined, and the results indicated that THF
was the best one among the solvents tested. Other solvents,
DMF, CH3CN, H2O, DMSO, dioxane, toluene, and C2H5OH were
inferior (Table 1, entries 15ꢁ21). However, only 43% yield of 2a
was obtained in the absence of solvent (Table 1, entry 22). The
further investigation indicated that the reaction was completed
Yieldb [%]
Entry
Base
Solvent
2a
3a
1
2
3
4
TBAF
TBAC
TBAB
TBAI
THF
THF
THF
THF
94
0
0
0
0
0
0
0
5
6
7
8
TBA$HSO4
TBA$OH
TBA$OAc
KF
THF
THF
THF
THF
0
0
0
0
0
35
72
0
9
CsF
THF
0
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
26f
27g
28h
29i
Et3N
THF
THF
THF
THF
0
0
0
0
0
DABCO
K2CO3
K3PO4
tBuOK
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
—
18
27
51
Trace
Trace
Trace
Trace
16
0
23
Trace
10
0
22
36
91
78
67
52
27
25
19
43
57
99
99
72
<5
<5
<5
THF
DMF
CH3CN
H2O
DMSO
Dioxane
Toluene
C2H5OH
—
THF
THF
THF
THF
0
0
—
—
—
THF
THF
THF
—
—
a
Reaction conditions: 2-(gem-dibromovinyl)-N-methylsulfonylaniline
(1a, 0.50 mmol), base (1.0 mmol), solvent (2.0 mL) at 80 ꢀC for 8 h.
b
c
Isolated yields. The reaction was irradiated at 100 W and 80 ꢀC for
20 min. d The reaction was irradiated at 100 W and 100 ꢀC for 20 min.
e
f
The reaction was irradiated at 100 W and 100 ꢀC for 5 min. The
g
reaction was irradiated at 100 W and 100 ꢀC for 2 min. Pd(OAc) (5.0
h
ppm in THF) was added. Pd(OAc) (10.0 ppm in THF) was added.
i
CuI (50.0 ppm in THF) was added.
at 80 ꢀC in 8 h. Gratifyingly, the reaction was completed under trace amount of Pd (5.0–10.0 ppm) or Cu (50.0 ppm) was added
microwave irradiation conditions at 100 W and 100 ꢀC in 5 min to the reaction of 1a in THF under microwave irradiation
and 99% yield of 2a was obtained (Table 1, entries 23ꢁ26).
condition without TBAF, providing less than 5% yield of 2a
Organic reactions performed in the absence of transition (Table 1, entries 27ꢁ29).14c,17e,f This result indicated that TBAF
metal have received much attention, because they can overcome plays an important role in the intramolecular cyclization reac-
the drawbacks of the expensive, poisonous, and air-sensitive tion of 1a.
properties of metals or organometallics, and metal-free reaction
On the basis of the optimized reaction conditions (in the
is one of the best choices in the pharmaceutical industry due to presence of TBAF under microwave irradiation at 100 W and
the avoidance of metal contamination.16 However, some reac- 100 C for 5 min), the scope of this transformation was inves-
ꢀ
tions turned out to be actually catalyzed by a trace amount of Pd tigated and the results were summarized in Table 2. A variety
or Cu contamination, not really “transition-metal-free”.17 In of 2-(gem-dibromovinyl)-N-methylsulfonylanilines bearing
order to gure out whether the model reaction completed in the substituents on the benzene rings were examined. The results
presence of trace amount of transition metal or not, additional showed that
a
number of functional groups, including
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Table 2 Microwave irradiated synthesis of 2-bromo(chloro)indoles
through TBAF-promoted intramolecular cyclization of 1a
proceed the reaction to generate 2-chloroindole (2v) with high
yield in DMF at 110 C under microwave irradiation (Table 2,
ꢀ
entry 22). It is important to note that the reaction scale was
increased up to 10 mmol under TBAF/THF conditions for 10
min, 94% isolated yield of 2a was obtained from 1a (Scheme 2).
2-Arylindoles exhibit high biological activities, such as anti-
estrogen, h5-HT2A antagonism, anti-inammatory, and cyto-
toxicity.18 Palladium-catalyzed cross-coupling of 2-haloindoles
with an arylmetal species is one of the useful strategies for the
synthesis of 2-arylindoles,19 but this application has been
limited by the inaccessibility of the 2-haloindoles.20 With the
prepared 2-bromoindoles in our hands, transformation of them
into the corresponding 2-arylindoles was investigated via
palladium-catalyzed cross-coupling with arylboronic acids
(Scheme 3). The results indicated that the corresponding
products were obtained in high yields under the Suzuki reaction
conditions (Scheme 3, eqn (1) and (2)). In the analogy studies, a
special ligand such as dppf, S-Phos, or P(t-Bu)3 is essential.7a,b,e
Futhermore, only 4c, 4d or 5d was obtained in high yield during
the reaction of 2d with 4-MeOC6H4B(OH)2 or PhB(OH)2 by
controlling Suzuki coupling conditions (Scheme 3, eqn (3)–(5)).
A reaction mechanism for the generation of 2-bromoindole
(2a) was proposed in Scheme 4. Initially, an elimination of HBr
from 1a to intermediate 6a proceeded smoothly in the presence
of TBAF,14a,b followed by an intramolecular nucleophilic addi-
tion of nitrogen to carbon–carbon triple bond of 6a to afford a
cyclization product 3a with the assistance of uoride anion.
Entry
1, R
X
2
Yieldb [%]
1
2
3
4
5
6
7
8
1a, H
1b, 4-F
1c, 4-Cl
1d, 4-Br
1e, 4-I
1f, 5-F
1g, 5-Cl
1h, 5-Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
99
97
96
97
94
91
93
91
92
91
95
93
92
94
96
91
90
96
91
93
90
91c
9
1i, 3-F
1j, 3-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
1k, 4-CH3
1l, 4-CH3O
1m, 4-C6H4CH2O
1n, 4-CH3SO2O
1o, 4-(p-CH3O)C6H4
1p, 4,5-(OCH2O)
1q, 6-CH3
1r, 5,6-benzo
1s, 4-CH3OCO
1t, 5-CH3OCO
1u, 5-CH3CO
1v, H
2s
2t
2u
2v
Finally, the obtained 3a underwent
a cleavage of the
a
Reaction conditions: 1 (0.50 mmol), TBAF (1.0 mmol), THF (2.0 mL)
and the reaction mixture was irradiated at 100 W and 100 ꢀC for 5
min. Isolated yields. DMF (2.0 mL), the reaction mixture was
irradiated at 100 W and 110 ꢀC for 10 min.
b
c
Scheme 2 Synthesis of 2-bromoindole in 10 mmol scale.
electron-withdrawing and electron-donating ones were toler-
ated, and the corresponding 2-bromoindoles were generated in
excellent yields (Table 2, entries 1ꢁ21). Halogen substituents,
such as F, Cl, Br and I, on the 4-, 5-, or 3-position of substrates
(1b–j) underwent the intramolecular cyclization very smoothly
and afforded the excellent yields of the corresponding di-halo-
genated indoles 2b–j (Table 2, entries 2ꢁ10), which could
provide the further transformation via transition-metal-cataly-
zed cross-coupling reactions. 2-(gem-Dibromovinyl)-N-methyl-
sulfonylanilines with an electron-donating functionality, such
as CH3, CH3O, C6H5CH2O, CH3SO2O, p-CH3OC6H4 or OCH2O
on the anilines also underwent the cyclization very well to
generate the corresponding products 2k–q in 90–96% yields
(Table 2, entries 11ꢁ17). It should be noted that the reaction
could tolerate ortho-substituted group (2q). Under the present
reaction conditions, 1-(gem-dibromovinyl)-2-naphthylamine
(1r) also underwent the reaction very well to generate the
desired product 2r in 96% yield. Substrates (1s–u) with electron-
withdrawing groups, CH3OCO, and CH3CO on the 4-, and
3-position of anilines also gave the corresponding products 2s–
u in 90–93% yields. More remarkable observation was that 2-
(gem-dichlorovinyl)-N-methylsulfonylaniline (1v) also could Scheme 3 The Suzuki coupling of 2a and 2d with arylboronic acids.
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intramolecular cyclization reactions of gem-dibromoolens
were carried out under microwave irradiation conditions and
1
air atmosphere. H NMR and 13C NMR spectra were measured
on a Bruker Avance NMR spectrometer (400 MHz or 100 MHz,
respectively) with CDCl3 as solvent and recorded in ppm relative
to internal tetramethylsilane standard. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; m, multi-
plet; q, quartet. The coupling constants, J, are reported in Hertz
(Hz). High resolution mass spectroscopy data of the product
were collected on a Waters Micromass GCT instrument. All MW
reactions were carried out in a Discover SP (CEM) microwave
reactor.
Scheme
4 Possible reaction mechanism and the controlled
experiments.
Typical procedure for the synthesis of 2-bromoindole (2a) via
microwave irradiated intramolecular cyclization of 2-(gem-
dibromovinyl)-N-methylsulfonylaniline (1a) in the presence of
TBAF
sulfonamide linkage to afford the desired product 2a under
TBAF conditions.14d,21
In a 10 mL of sealable reaction tube with a Teon-coated screw
cap equipped with a magnetic stir bar was charged with 2-(gem-
dibromovinyl)-N-methylsulfonylaniline (1a, 0.50 mmol), TBAF
(THF solution, 1.0 mol Lꢁ1, 1.0 mL, 1.0 mmol) and THF (2.0
mL). The reaction vessel was placed in a Discover SP (CEM)
microwave reactor, and the reaction mixture was irradiated at
100 W and 100 ꢀC for 5 min. Then it was cooled to room
temperature, extracted twice with Et2O. The organic layers were
combined, dried over Na2SO4, and concentrated under reduced
pressure to yield the crude product, which was further puried
by ash chromatography on silica gel (eluant: hexane/ethyl
acetate) to give the desired product 2-bromoindole (2a).
To verify the formation of intermediates 6a and 3a in the
reaction, control experiments of 1a and its isotope investigation
were conducted. When 1a was carried out in the presence of
TBAF (1.0 equiv.) under microwave irradiation at 100 W and 100
ꢀC for 5 min, 3a was isolated in 61% yield, and 2a was obtained
in 15% yield. On the other hand, when deuterium-labeled 1a-D
was carried out under the present reaction conditions, 2a was
obtained in 98% yield, and no 2-bromo-3-D-indole was detected
(Scheme 4, eqn (1)). It also supports that the reaction
was through an alkynyl bromide intermediate 6a. We also tried
the reaction of 2-(10-methyl-20,20-dichlorovinyl)-N-methyl-
sulfonylaniline (1w) in the presence of TBAF in DMF under
present reaction conditions, however, no product was isolated
and 1w was recovered in 98% yield (Scheme 4, eqn (2)). In
addition, ICP analysis indicated that Cu and Pd in the reaction
mixture were 0.27 and 0.03 ppm, respectively.22
In summary, we have developed an efficient and facile TBAF-
promoted intramolecular cyclization of 2-(gem-dibromo(chloro)-
vinyl)anilines for the synthesis of 2-bromo(chloro)indoles under
microwave irradiation conditions. The reactions were carried
out in THF in the absence of metal, and generated the corre-
sponding products in excellent yields. It is important to note
that when the amine is activated by a strong electron-with-
drawing group such as sulfonyl, the tandem reaction can occur
efficiently in one pot. The reaction mechanism investigation
indicated that the sulfonyl linker serves as a dual-activating
group to undergo indole cyclization. And aer indole forma-
tion, it is activated and subsequently proceeds nitrogen–sulfur
bond cleavage to remove sulfonyl group promoted by TBAF.
Moreover, further transformation of 2-bromoindoles via palla-
dium-catalyzed cross-coupling can be carried out.
Acknowledgements
We gratefully acknowledge nancial support by the National
Natural Science Foundation of China (no. 20372095, 21172092,
and 21002039), the Project of Science and Technology of
the Department of Education, Anhui (no. KJ2010ZD09,
KJ2012A253).
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General remarks
All reagents were purchased from commercial suppliers and
used without further purication. 2-(gem-Dibromovinyl)-N-
methylsulfonylanilines were prepared according to the liter-
ature.7b All TBAF (tetra-n-butylammonium uoride)-promoted
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22 The reaction solution was analysis by ICP-MS, and the
determination data indicated that Cu and Fe are less than
0.27 ppm, and Pd, Sn, Ni, Co, Ru and Rh are less than 0.03
ppm.
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