Synthesis of substituted indoles via a highly selective 7-lithiation of 4,7-dibromoindoles and the effect of indole-nitrogen on regioselectivity

Article abstract of DOI:10.1016/S0040-4039(03)01482-5

We have developed an efficient synthetic pathway to rapidly access 4-bromoindoles, 4-substituted indoles, 4-bromo-7-substituted indoles, and 4,7-disubstituted indoles using a highly selective lithiation at the 7-position of 1-alkyl-4,7-dibromoindoles when treated with t-BuLi in ether. Based upon the selectivity obtained with 5,7-dibromoindoles in our previous study and with 4,7-dibromoindoles in the current study, we conclude that the alkylated indole nitrogen plays an important role in controlling selectivity.

Full text of DOI:10.1016/S0040-4039(03)01482-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5987–5990
Synthesis of substituted indoles via a highly selective 7-lithiation
of 4,7-dibromoindoles and the effect of indole-nitrogen
on regioselectivity
Lianhai Li* and Andrew Martins
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval,
Quebec, Canada H9R 4P8
Received 29 May 2003; revised 9 June 2003; accepted 15 June 2003
Abstract—We have developed an efficient synthetic pathway to rapidly access 4-bromoindoles, 4-substituted indoles, 4-bromo-7-
substituted indoles, and 4,7-disubstituted indoles using a highly selective lithiation at the 7-position of 1-alkyl-4,7-dibromoindoles
when treated with t-BuLi in ether. Based upon the selectivity obtained with 5,7-dibromoindoles in our previous study and with
4,7-dibromoindoles in the current study, we conclude that the alkylated indole nitrogen plays an important role in controlling
selectivity.
© 2003 Elsevier Ltd. All rights reserved.
The indole nucleus is a common substructure of many
biologically active compounds,1 and indoles with sub-
stituent(s) on the benzenoid portion are widely used in
medicinal chemistry studies.2 Although numerous meth-
ods are available for indole preparation,3 we still lack
ready access to indoles of certain substituted patterns
on the benzenoid portion—especially when substituents
are labile. Recently, we reported a general approach to
the synthesis of 5,7-disubstituted indoles based upon a
selective lithiation at 7-bromine of 5,7-dibromoindoles.4
This approach is very attractive in terms of efficiency
and applicability, and prompted us to extend it to the
synthesis of substituted indoles of other substituted
patterns on the benzenoid portion.
with slight selectivity (3:2) for the 7-position. The major
selectivity difference between an N-alkyl-substituted
indole (1a or 1b) and an N-potassio-substituted indole
(1c) could be caused by the dramatic electronic nature
change of the indole aromatic system when the sub-
stituent R was changed from the N-alkyl to the N-
potassio. The highly selective reaction at the 7-position
of N-alkylated 5,7-dibromoindoles could involve either
a mechanism-based process5 aided by the alkylated
indole-nitrogen or a halogen dance process6 following
an initially non-selective exchange reaction to form the
thermodynamic favored 7-lithiated product. Either
way, if true, a highly selective exchange reaction could
be expected at the 7-position of other types of 7-bromo-
indoles that have 1–3 bromine substituent(s) on the
benzenoid portion. Among all such indoles, 4,7-dibromo-
indole aroused our interest because of their potential
use in the synthesis of 4,7-disubstituted indoles and
4-substituted indoles (Scheme 1)—two types of substi-
tuted indoles found in many natural products and
bioactive compounds that have proven difficult to syn-
thesize.7,8 They can also serve as key intermediates for
natural product synthesis.9 We also expected that a
study of the lithium–bromine exchange reaction of 4,7-
dibromoindoles would provide more insight into the
main factor controlling selective lithiation.
Furthermore, we are interested in understanding what
causes the highly selective lithium–bromine exchange of
5,7-dibromoindoles. In our previous study, we obtained
some useful information about the reaction: steric hin-
drance of 1-alkyl substituent has no influence on selec-
tivity, both 1a and 1b are lithiated at the 7-position;
lithiation of 1-potassio-5,7-dibromoindole (1c) proceeds
The 4,7-dibromoindoles used in this study were pre-
pared by Fisher indole synthesis10 (for 2a, Table 1) or
by Bartoli indole synthesis11 (for indole 2b). Both 2a
* Corresponding author. E-mail: lianhai li@merck.com
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01482-5

5988
L. Li, A. Martins / Tetrahedron Letters 44 (2003) 5987–5990
Given the results from the first two entries in Table 1,
we found that the selectivity of the lithium–bromine
exchange reaction of 4,7-dibromoindoles followed the
same trend as of 5,7-dibromoindoles. The exchange of
N-methyl indole proceeded exclusively at the 7-position
while the N-potassio analog gave much lower selectiv-
ity. This provides further support for our previous
claim that it is the electronic nature change of the
indole aromatic system that caused this dramatic differ-
ence in selectivity. Based on these results, we also
concluded that the alkylated indole-nitrogen played a
key role in controlling regioselectivity, but the complex-
ity associated with the lithium-bromine exchange reac-
tion in nature and the uncertainty of the reaction
mechanism still prevent us from proposing a detailed
mechanism. However, the possibility of directed metal-
lation by the indole nitrogen can most probably be
ruled out, as supported by the following facts: indole-
nitrogen uses two electrons to participate in the aro-
matic system, and loses coordinating ability completely
after being blocked by an alkyl substituent; and the
experimental results showing that N-potassio indoles
afford lower selectivity than do N-alkyl analogs.
Scheme 1.
Table 1. The determination of regioselectivity of the Li–Br
exchange reaction of 4,7-dibromoindoles
Having determined the regioselectivity of the lithiation,
we set out to apply the 7-lithiated intermediates to the
preparation of 4-bromo-7-substituted indoles. When
the 7-lithiated intermediate from indole 2d was treated
with benzaldehyde, the corresponding alcohol 6a was
obtained in 90% yield (Table 2, entry 1). Using acetal-
dehyde or acetone to replace benzaldehyde as an elec-
trophile, the reaction gave more modest yields (Table 2,
entries 2 and 3). When DMF was used as an elec-
trophile, the corresponding aldehyde 6d was obtained
in 82% yield (Table 2, entry 4). By reacting with CO2
Entry
Indole 2
t-BuLi (equiv.)
Products
2
3
4
5
1
2
3
4
2aa
2c
2d
2e
2.1
2.1
1.8
1.8
–
10
–
28 72
–
–
8
–
–
–
90
92
89 11
Table 2. The synthesis of 4-bromo-7-substituted indoles
–
a Indole 2a was treated with 1 equiv. of KH before Li–Br exchange
reaction.
and 2b could be alkylated at the 1-position to afford
indoles 2c, 2d, and 2e by using methyl iodide or
SEMCl12 as an alkylating reagent. With the desired
4,7-dibromoindoles in hand, we started to investigate
the regioselectivity of their lithium–bromine exchange
reaction. This was done by treating a certain indole
with a required amount of t-BuLi in ether at −78°C for
15 min followed by a water-quench (Table 1). The
1
crude mixture thus obtained was analyzed by using H
Entry
Indole 2
E+
Product 3, E (isolated yield)
NMR. We found that when 1-potassio indole,13 formed
in situ by the reaction of indole 2a with KH, was
treated with 2.1 equiv. of t-BuLi, the corresponding
7-lithiated and 4-lithiated products were afforded in 72
and 28% yields, respectively (Table 1, entry 1). Under
the same conditions, N-methyl indole 2c only afforded
7-lithiated product in 90% yield (Table 1, entry 2).
When SEM was used as a substituent on nitrogen, 1.8
equiv. of t-BuLi was enough to complete the highly
selective mono-lithiation at the 7-position for both
indoles 2d and 2e (Table 1, entries 3 and 4).
1
2
3
4
5
6
7
8
9
2d
2d
2d
2d
2d
2c
2c
2e
2e
PhCHO
MeCHO
Acetone
DMF
CO2
PhCHO
CO2
6a, PhCH(OH) (90%)
6b, MeCH(OH) (66%)
6c, Me2C(OH) (68%)
6d, HC(ꢀO) (82%)
6e, MeOC(ꢀO)a (79%)
6f, PhCH(OH) (85%)
6g, MeOC(ꢀO)a (69%)
6d, PhCH(OH) (74%)
6e, MeOC(ꢀO)a (74%)
PhCHO
CO2
a Treated with CH2N2 after work-up.

L. Li, A. Martins / Tetrahedron Letters 44 (2003) 5987–5990
Table 3. The synthesis of 4,7-disubstituted indoles
5989
Entry
Indole 2
E1+
E2+
Product 7, [E1,E2] (isolated yield)
1
2
3
4
5
6
7
2d
2d
2d
2d
2d
2c
2e
PhCHO
PhCHO
PhCHO
MeCHO
Acetone
PhCHO
PhCHO
CO2
DMF
PhCONMe(OMe)
CO2
CO2
CO2
CO2
7a, [PhCH(OH), MeOC(ꢀO)]a (59%)
7b, [PhCH(OH), HC(ꢀO)] (54%)
7c, [PhCH(OH), PhC(ꢀO)] (62%)
7d, [MeCH(OH), MeOC(ꢀO)]a (66%)
7e, [Me2C(OH), MeOC(ꢀO)]a (67%)
7f, [PhCH(OH), MeOC(ꢀO)]a (80%)
7g, [PhCH(OH), MeOC(ꢀO)]a (65%)
a Treated with CH2N2 after work-up.
gas followed by treatment with CH2N2 after work-up,
the methyl ester was obtained in 79% yield (Table 2,
entry 5). Indoles 2c and 2e were also tested with
benzaldehyde and CO2 as electrophiles; all afforded the
desired 7-substituted-4-bromoindoles in good yields
(Table 2, entries 6–9).
as a deprotection process. By using a limited amount of
proton source, a one-pot process is possible. After the
7-lithiated indole from indole 2d (Table 1, entry 3) was
treated with 1.2 equiv. of MeOH for 5 min at −78°C,
the resulting mixture was treated with 2.5 equiv. of
t-BuLi, followed by the addition of electrophiles. Benz-
aldehyde, acetaldehyde, acetone, DMF, and CO2 were
chosen as representative electrophiles, all of which gave
the corresponding desired products in good yields rang-
ing from 62 to 77% (Table 4, entries 1–5). When
PhCHO was used as electrophile, 4-substituted indoles
8f and 8g were obtained from indoles 2c and 2e (Table
4, entries 6 and 7) in 60 and 70% yields, respectively.
After our success with the preparation of 4-bromo-7-
substituted indoles, we started to look at the possibility
of applying the sequential lithium–bromine exchange
strategy to the synthesis of 4,7-disubstituted indoles by
using 4,7-dibromoindoles as scaffolds. Without the
work-up of the reaction mixture, which contained the
intermediate leading to 4-bromo-7-substituted indole 6a
(Table 2, entry 1), a second lithium–bromine exchange
reaction was performed by treatment with t-BuLi. The
lithium reagent thus obtained could react with another
electrophile like CO2, DMF, or N-methoxy-N-methyl-
benzamide to afford 4,7-disubstituted indoles 7a, 7b,
and 7c, respectively, in good yields (Table 3, entries
1–3). Using the same conditions, the intermediates that
lead to indoles 6b (Table 2, entry 2) and 6c (Table 2,
entry 3) were also subjected to a second lithium–
bromine exchange. After reacting with CO2 and treat-
ment with CH2N2, the corresponding acid esters 7d and
7e were obtained in good yields (Table 3, entries 4 and
5). By using a combination of PhCHO-CO2 as the first
and second electrophiles, both indoles 2c and 2e could
be efficiently transformed into the corresponding esters
7f and 7g (Table 3, entries 6 and 7), respectively, in
good yields.
In summary, we have developed an efficient synthetic
pathway to rapidly access 4-bromoindoles, 4-substi-
Table 4. The synthesis of 4-substituted indoles
The 4-bromoindoles obtained in Table 1 could serve as
valuable intermediates for preparing 4-substituted
indoles.14 In considering the origin of the 4,7-dibro-
moindoles (2), the 7-bromine can be viewed as a protec-
tive group of the 7-carbon that helps avoid the
regioselectivity problem during the Fisher and Bartoli
indole synthesis. In the Bartoli method, the 7-bromine
also plays an important role in improving the reaction
yield.15 The sequence of a selective lithiation at 7-posi-
tion followed by quenching with a proton source serves
Entry
Indole 2
E+
Product 8, E (isolated yield)
1
2
3
4
5
6
7
2d
2d
2d
2d
2d
2c
2d
PhCHO
MeCHO
Acetone
DMF
CO2
PhCHO
PhCHO
8a, PhCH(OH) (70%)
8b, MeCH(OH) (62%)
8c, Me2C(OH) (72%)
8d, HC(ꢀO) (77%)
8e, MeOC(ꢀO)a (74%)
8f, PhCH(OH) (70%)
8g, PhCH(OH) (74%)
a Treated with CH2N2 after work-up.

5990
L. Li, A. Martins / Tetrahedron Letters 44 (2003) 5987–5990
tuted indoles, 4-bromo-7-substituted indoles, and 4,7-
disubstituted indoles based upon a highly selective lithia-
tion at the 7-position of 1-alkyl-4,7-dibromoindoles
when treated with t-BuLi in ether. Given the selectivity
obtained with 5,7-dibromoindoles in our previous study
and with 4,7-dibromoindole in current study, we con-
clude that the indole nitrogen bearing an alkyl group
plays an important role in controlling selectivity. A
detailed mechanism study is in progress.
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B. M. J. Am. Chem. Soc. 2002, 124, 13179–13184; (b)
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Acknowledgements
We would like to thank NSERC for an Undergraduate
Student Research Award (USRA) for Andrew Martins,
and Dr. Cameron Black for proofreading this paper.
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