Rapid, robust, clean, catalyst-free synthesis of 2-halo-3-carboxyindoles

Article abstract of DOI:10.1016/j.tetlet.2011.02.037

A novel synthesis of 2-halo-3-carboxyindoles from 2-(2,2-dihalovinyl) anilines was discovered. Reaction conditions and substrate applicability were studied. Optimally, the reaction takes only minutes when these substrates are heated in DMSO at 120 °C in t

Full text of DOI:10.1016/j.tetlet.2011.02.037

Tetrahedron Letters 52 (2011) 1815–1818
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Tetrahedron Letters
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Rapid, robust, clean, catalyst-free synthesis of 2-halo-3-carboxyindoles
⇑
Aaron R. Kunzer , Michael D. Wendt
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of 2-halo-3-carboxyindoles from 2-(2,2-dihalovinyl)anilines was discovered. Reaction
conditions and substrate applicability were studied. Optimally, the reaction takes only minutes when
these substrates are heated in DMSO at 120 °C in the presence of cesium carbonate. However, the reac-
tion is robust and takes place at a wide range of temperatures, is tolerant of aqueous reaction conditions,
and can be performed in a variety of polar solvent/carbonate base combinations—where the limiting fac-
tor is base solubility. A wide range of substituents is tolerated on the 2-(2,2-dihalovinyl)anilines, and
yields are generally high, requiring only acidic aqueous work-up to obtain pure products. No catalyst
is required for the transformation. The mechanism is believed to involve initial formation of an alkynyl
bromide intermediate followed by ring closure and carbon dioxide trapping, leading to product
formation.
Received 28 January 2011
Revised 3 February 2011
Accepted 8 February 2011
Available online 13 February 2011
Keywords:
2-Bromoindole
2,2-Dibromo-vinyl
Carbon dioxide trapping
Non-catalyzed
Ó 2011 Elsevier Ltd. All rights reserved.
In the course of our drug discovery work, we were exploring po-
tential routes to oxindoles under mild conditions. We were curious
if the known conversion of (2,2-dibromovinyl)benzenes to pheny-
lacetylamides1 shown in Scheme 1 might provide such a route if
applied intramolecularly. We were, however, skeptical due to the
fact that the alkynamine intermediate, 2-3-indolyne, is unlikely
to form in this case (Scheme 1).2
Upon running an initial test reaction with 1a (synthesized via
Corey–Fuchs olefination of 2-nitrobenzaldehyde followed by
reduction of the nitro group), the 2-bromo-3-carboxyindole 2a
was cleanly isolated in high yield via aqueous acidic work-up only
(Scheme 2). Production of this disubstituted indole derivative
seemed to be a very interesting and promising result.
2-Chloro and 2-bromoindoles can undergo nucleophilic
substitution reactions at the 2-position3 as well as a variety of
typical cross-coupling reactions including Suzuki,4 Heck,5 Stille,6
Sonogashira,7 carboxylation,8 and C–H activation coupling.9
Further, 2-halo-3-carboxyindoles have historically been synthe-
sized by subjecting oxindoles to Vilsmeier–Haack reaction
conditions followed by oxidation of the resulting 2-halo-3-carbox-
aldehydes with strong oxidants such as KMNO4 or NaClO2.3b,10 This
methodology obviously limits the functional groups that can be
present in the substrate. Additionally, attempts to synthesize
2-bromo-3-carboxyindoles via bromination have had limited
success. First, the brominations were performed on esters rather
than directly on the acids, and second, there are no examples of
clean, selective bromination at the 2-position of N-unsubstituted
indoles in the literature.11
We immediately undertook a study to examine the effects of
various solvent systems and temperatures on the transformation
(Table 1). It should be noted that in all cases, pure product was iso-
lated by aqueous acidic work-up alone. The results demonstrated
that more polar solvents generally performed well, with the excep-
tion of NMP (entry 2). DMSO (entry 1) appeared to be the most
effective solvent tested, likely due to increased base solubility,
and 1,4-dioxane (entry 5) proved ineffective. Reaction temperature
(entries 8 and 9) did not affect yields. Most interesting was the
anhydrous run included in the study (Table 1, entry 10). Cs2CO3
in DMSO was used to maximize base solubility and the reaction
time was significantly shortened to 45 min compared to 6 h for
the analogous aqueous condition (entry 1). Thus, it appears that
while the reaction can tolerate the presence of water with no del-
eterious effects on product purity or yield, the reaction rate in-
creases in the absence of water.
With the discovery of the improved anhydrous reaction condi-
tions, we sought to investigate various aspects of the base in the
reaction as well as revisiting the effects of temperature (Table 2).
Reducing the equivalents of base in the reaction (entries 4 and 5)
slows the rate, but appears to have no effect on yield, further estab-
lishing the robustness of the reaction. The use of K2CO3 as base (en-
try 6) also slowed the reaction rate, but the addition of 18-crown-6
to improve base solubility under the same conditions (entry 7) re-
stored the rate to equivalence with the use of Cs2CO3. In both cases,
the use of K2CO3 did not adversely affect the high yields of the
reaction. In general, conditions increasing the rate of reaction
(higher temperature, better base solubility) also seem to improve
yields.
Given the ease of indole formation under the reaction
conditions, we sought to determine if the analogous 2-bromo-3-
carboxybenzofuran and benzothiophene could be formed in the
⇑
Corresponding author. Tel.: +1 847 935 2363; fax: +1 847 938 1004.
E-mail address: aaron.kunzer@abbott.com (A.R. Kunzer).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.037

1816
A. R. Kunzer, M. D. Wendt / Tetrahedron Letters 52 (2011) 1815–1818
HNR1R2
base
Br
NR1R2
NR1R2
Br
polar solvent
heating
O
Br
Br
Br
?
O
Br
NH2
N
N
polar solvent
heating
H
NH2
H
1a
3a
Scheme 1. Known conversion of (2,2-dibromovinyl)benzene to amides and analogous intramolecular reaction mechanism.
2-Bromobenzofurans can also be synthesized from corresponding
(2,2-dibromovinyl)benzenes by treatment with base alone.13 How-
ever, this transformation appears to be specific to indoles. No de-
sired products were observed in either case, with the reaction
conditions leading to decomposition of the 2,2-dibromovinyl
substrates.
O
OH
Br
Na2CO3
Br
DMSO / water
100 °C, 6 h
Br
NH2
N
H
In order to establish the scope of the reaction, we evaluated
numerous substrates (Table 3). In general yields were high with
the exception of 1c, which unsurprisingly, rapidly oxidized. Both
electron-donating (1b–d) and electron-withdrawing groups (1g–
j) were tolerated at various ring positions. In addition, some degree
of steric hindrance (1d–e) was not detrimental to the transforma-
tion. 2,2-Dichlorovinyl substrates also cleanly underwent the
transformation to yield the corresponding 2-chloro-3-carboxyin-
doles (1k–l). Interestingly, N-substituted substrates (1m–n) did
not produce the expected 1-substituted indole products. Instead,
the cyclic carbamate, 4-[1-Bromo-meth-(Z)-ylidene]-1,4-dihydro-
benzo[d][1,3]oxazin-2-one, products 2m and 2n were produced
in low yield. As these reactions were much less clean, products
had to be isolated by flash column chromatography. However, this
was another interesting result as examples of this chemotype in
the literature are limited to a few references, and have historically
been synthesized by either subjecting isatoic anhydrides to
Wittig14/Horner–Wadsworth–Emmons15 chemistry or via enolate
formation of amino acetophenones.16 In fact, there are no exam-
ples of alkenyl halides such as these in the literature that would
allow for further cross-coupling chemistry and derivative
generation.
To elucidate the mechanism of the indole formation, we started
with the observation that at reaction temperatures lower than
120 °C, the slower reaction rate of 1a allowed an intermediate to
be observed by LC/MS. The mass of this intermediate corresponded
to the mass of the alkynyl bromide 3a that would be formed by
first abstracting the benzylic proton (Scheme 1). Since it is known
that under basic conditions these alkynyl bromides and chlorides
form from their corresponding 2,2-dihalovinyl compounds,17 it
would be logical to propose that the first step of the reaction is
alkynyl halide formation. To prove this, we used the anhydrous
reaction conditions, but ran the reaction at 80 °C. This allowed us
to observe the formation of a large amount of intermediate by
LC/MS, stop the reaction before completion, and isolate this inter-
mediate. NMR and LC/MS comparison of a sample of 3a generated
by treatment of 1a with DBU confirmed that the intermediate was,
in fact, 3a. Further, we subjected 3a to the standard reaction con-
ditions, and 2a was obtained in 77% yield. At this point, we could
confidently propose a mechanism for indole formation ( Fig. 1).
The mechanism begins with alkynyl halide generation followed
by ring closure and trapping of CO2 present in solution due to
the carbonate base. This mechanism has support in the literature
as base-catalyzed alkyne cyclizations are a well established indole
synthesis technique.18 Alkyne cyclizations to indoles with
1a
2a (79%)
Scheme 2. Initial test reaction.
Table 1
Solvent/temperature studya
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMSO
NMP
DMF
Ethylene glycol
1,4-Dioxane
DMSOe
DMSOf
100
100
100
100
100
100
100
80
6
79
25
71
65
0d
85
86
85
91
73
23c
12
4
48
5
6
24
2
DMSO
DMSO
120
100
10
DMSOg
45 min
a
Standard conditions: dibromoalkene 0.5 mmol, 3 equiv Na2CO3 (3 M solution,
0.5 mL), solvent 1.5 mL (solvent/water = 3:1).
b
Isolated yields.
Reaction not complete, but stopped and isolated product.
Trace by LC/MS.
DMSO/water, 2:1 (2 mL total solvent volume maintained).
DMSO/water, 4:1 (2 mL total solvent volume maintained).
Anhydrous conditions: 3 equiv Cs2CO3, 2 mL DMSO.
c
d
e
f
g
Table 2
Anhydrous temperature/base studya
Entry
Base
Equiv Base
Temp (°C)
Time (min)b
Yieldc (%)
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
3
3
3
2
1
3
3
100
80
45
6 h
8d
10
60
45
5
73
70
87
81
83
85
93
120
120
120
120
120
e
K2CO3
a
b
c
Standard conditions: dibromoalkene 0.5 mmol, 3 equiv base, DMSO 2.0 mL
Times minimized.
Isolated yields.
Only trace of SM at 5 min by LC/MS.
Added 6 equiv 18-crown-6.
d
e
same manner. It is known that 2-bromobenzofurans and 2-bro-
mobenzothiophenes can be synthesized from their respective
(2,2-dibromovinyl)benzenes via intramolecular cross-coupling.12

A. R. Kunzer, M. D. Wendt / Tetrahedron Letters 52 (2011) 1815–1818
1817
Table 3
Substrate study under standard anhydrous conditionsa
Substrate
Product
Yieldb (%)
87
Substrate
Product
Yieldb (%)
Br
CO2H
Br
MeO2C
Br
CO2H
Br
MeO2C
Br
NH2
Br
NH2
81
85
65
1h
1a
N
N
H
H
2a
CO2H
2h
Br
Br
Br
Br
CO2H
Br
NH2
Br
NH2
Br
Br
79
40
MeO
MeO
1b
1c
N
N
N
N
MeO
MeO
1i
H
H
N
N
2b
2c
2i
CO2H
CO2H
Br
Br
Br
Br
NH2
NH2
N
H
N
H
1j
2j
Br
CO2H
Cl
CO2H
Cl
NH2
Br
NH2
Cl
Br
67
74
95c
80
1k
N
N
H
H
OMe
2k
1d
OMe
Cl
2d
2e
2f
Cl
Cl
CO2H
CO2H
Br
Br
Br
Cl
Cl
Br
NH2
1l
Br
NH2
N
Br
N
H
H
2l
1e
1f
F
F
Br
Br
CO2H
Br
Br
O
NH
84
73
22c
Br
NH2
N
H
1m
1n
N
N
O
O
2m
2n
Br
CO2H
Br
Br
O
Br
NH2
Br
Br
MeO2C
NH
18
1g
N
MeO2C
H
2g
a
b
c
Standard conditions: dibromoalkene 0.5 mmol, 3 equiv Cs2CO3, DMSO 2.0 mL, 120 °C, 10 min. unless otherwise noted.
Isolated yields.
Reaction time 20 min.
:Base
Br
Br
Br
Br
H
O
Br
C
H
R
R
H
O
Br
NH2
N
N
H
:Base
N
H
H
1a
3a
:Base
:Base
:Base = Cs2CO3, CsHCO3
H-A = HBr, CsHCO3
:Base = Cs2CO3, CsHCO3
O
O
C
OH
O
H
A
H
Br
O
-
Br
Br
Br
-
N
H
O
N
H
2a
N
R
O
N
O
R
Figure 1. Proposed mechanism for indole formation.
Figure 2. Proposed mechanism for cyclic carbamate formation.
accompanying carboxylation at the 3-position are also known, al-
beit using transition metal catalysts with trapping of CO in the
presence of an alcohol.19 Base-catalyzed alkyne cyclization with
subsequent CO2 trapping has, however, been demonstrated in the
synthesis of benzofurans,20 and recently carboxylation of aromatic
heterocycles has been achieved using a combination of CO2 and
Cs2CO3 in hot DMF.21
The proposed mechanism of cyclic carbamate formation, as
shown in Figure 2, starts similarly, as 3a is also readily formed in

1818
A. R. Kunzer, M. D. Wendt / Tetrahedron Letters 52 (2011) 1815–1818
2. (a) Gribble, G. W.; Conway, S. C. Synth. Commun. 1992, 22, 2129–2141; (b)
Gribble, G. W.; Conway, S. C. Heterocycles 1992, 34, 2095–2108.
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the reaction. In the case of 1m, a LC/MS sample taken at 10 min
showed a significant amount of alkynylbromide present in the
reaction mixture. The presence of the methyl group in 1m and
the ring constraints of 1n may slow attack of the anilino N on
the alkynyl bromide, allowing the well-established base-catalyzed
CO2 trapping by the anilino N to become significant.22 This forms
an intermediate that can be quickly trapped by attacking the alky-
nyl bromide group at the benzylic position. Nucleophilic attack at
this position has been demonstrated previously.23 Further, the
geometry of this attack explains why only the Z-isomer products
are observed.
5. Recent examples: (a) Priebbenow, D. L.; Henderson, L. C.; Pfeffer, F. M.; Stewart,
S. G. J. Org. Chem. 2010, 75, 1787–1790; (b) Hussain, M.; Tùng, D. T.; Langer, P.
Synlett 2009, 1822–1826.
In summary, we have developed a novel synthesis for 2-halo-3-
carboxyindoles by heating (2,2-dihalovinyl)arenes in DMSO in the
presence of carbonate base. The reaction is fast and robust to a
wide range of reaction conditions and substrates. The broad func-
tional group tolerance of this transformation is a significant
improvement over the historical Vilsmeier–Haack/oxidation meth-
odology and produces clean products in high yields that can be
easily isolated by simple aqueous work-up. This reaction offers a
novel way to make synthetically important fluorinated indoles, dif-
ferentiated bis-carboxy indoles, and mixed halogen indoles, which
can serve as an entry for both selective and successive cross-cou-
pling chemistries. Recently, the palladium-catalyzed synthesis of
2-bromoindoles, including mixed halogen indoles, was reported.24
Our synthesis eliminates the need for palladium and the added
presence of the 3-carboxy group allows the products described
here to be employed as stable synthons for their corresponding
3-H analogs. Thus, potentially unstable 2-haloindoles are stabilized
and can be readily decarboxylated if desired.25 In addition, we have
discovered a stereospecific synthetic route to the novel 4-[1-bro-
mo-meth-(Z)-ylidene]-1,4-dihydro-benzo[d][1,3]oxazin-2-ones,
and an investigation of optimized reaction conditions for this
underexplored chemotype is ongoing. Given the substantial impor-
tance of indoles in both organic and medicinal chemistry, we be-
lieve this novel transformation will find broad use in the
synthesis of functionalized indoles.
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We are grateful to Jan Waters and Jeffery Cross for NMR confir-
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Supplementary data
Supplementary data (representative procedures and NMR spec-
tra of products) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.02.037.
References and notes
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