A facile approach to the synthesis of 5,7-disubstituted indoles via a highly selective lithium-bromine exchange of 5,7-dibromoindoles

Article abstract of DOI:10.1016/S0040-4039(02)02658-8

A general approach to the synthesis of 5,7-disubstituted indoles has been developed based upon a highly selective lithium-bromine exchange reaction at the 7-position when 1-alkyl-5,7-dibromoindoles were treated with t-BuLi in ether. The resulting 5-bromo-7-lithiated indoles could react with various electrophiles to afford 5-bromo-7-substituted indoles (6) upon work-up. Without isolation of 6, the intermediates thus obtained could be exposed to a second lithium-bromine exchange reaction in a one-pot procedure and further reacted with various electrophiles to afford 5,7-disubstituted indoles (1).

Full text of DOI:10.1016/S0040-4039(02)02658-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 689–692
A facile approach to the synthesis of 5,7-disubstituted indoles
via a highly selective lithium–bromine exchange of
5,7-dibromoindoles
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 7 November 2002; revised 20 November 2002; accepted 22 November 2002
Abstract—A general approach to the synthesis of 5,7-disubstituted indoles has been developed based upon a highly selective
lithium–bromine exchange reaction at the 7-position when 1-alkyl-5,7-dibromoindoles were treated with t-BuLi in ether. The
resulting 5-bromo-7-lithiated indoles could react with various electrophiles to afford 5-bromo-7-substituted indoles (6) upon
work-up. Without isolation of 6, the intermediates thus obtained could be exposed to a second lithium–bromine exchange reaction
in a one-pot procedure and further reacted with various electrophiles to afford 5,7-disubstituted indoles (1). © 2003 Published by
Elsevier Science Ltd.
In a recent medicinal chemistry study, we needed a
general approach to the synthesis of indoles bearing
various functionalized carbon substituents at the 5- and
7-positions with an alkyl substituent on nitrogen (1).1
Although numerous methods are available for indole
preparation,1,2 the synthesis of this type of indole still
remains a great challenge. To date, a general but indi-
rect approach to indoles with substituent(s) on its ben-
zenoid portion involves the annulation of a pyrrole
portion with a suitably functionalized benzene as start-
ing material.3 There are obvious disadvantages like
lengthy synthesis, low compatibility to labile functional
groups, and difficulty in synthesis of complicated start-
ing materials. A better approach to serve our purpose is
to directly introduce the desired substituents to indole’s
5- and 7-positions. Due to indole’s distinct electron
density distribution, introduction of substituents on its
benzenoid portion by reaction with an activating elec-
trophile, i.e. Friedel–Crafts reaction, usually suffers
from problems with regioselectivity.4–6 Our strategy to
solve this problem is illustrated in Scheme 1. We used
the easily prepared 5,7-dibromoindoles 27 as scaffold, in
which the bromine substituents would act as activating
and directing groups if a selective lithium–bromine
exchange could be achieved.8–11
The 5,7-dibromoindoles (2) used in this study are pre-
sented in Table 1. To study the selectivity of lithium–
bromine exchange, 2b was used as substrate to screen
the alkyllithium and solvent. 2b was treated either with
1.1 equiv. of n-BuLi or with 2.2 equiv. of t-BuLi either
in THF or in ether at −78°C for 10 min, and was then
quenched by water. The composition of the crude
1
product was determined by H NMR. We found that
the exchange could be achieved selectively at 7-bromine
and t-BuLi in ether gave the best results (Table 1, entry
1).12 An attempt with a non-coordinating solvent tolu-
ene with t-BuLi resulted in no reaction (Table 1, entry
2). Optimized conditions were established by reducing
the amount of t-BuLi from 2.2 equiv. to 2.1 equiv. This
afforded 4b and 5b as a mixture of ratio 94:6 (Table 1,
entry 3). Satisfied with the conditions, we applied them
to indoles 2c, 2f, 2h, and 2k (entries 3–7). The results
showed that the selective lithium–bromine exchange
was a common reaction for indoles with various sub-
stituents at their 1-, 2-, 3-positions. No influence of
* Corresponding author. Fax: 1-514-4284900; e-mail: lianhai li@
–
Scheme 1.
merck.com
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02658-8

690
L. Li, A. Martins / Tetrahedron Letters 44 (2003) 689–692
Table 1. The selectivity of lithium–bromine exchange of 5,7-dibromoindoles
Entry
Indole 2
RLi (equiv.)
Solvent
Products
2
3
4
5
1
2
3
4
5
6
7
8
2b
2b
2b
2c
2f
2h
2k
2a
2d
2d
2i
t-BuLi (2.2)
t-BuLi (2.2)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (2.1)
t-BuLi (1.8)
t-BuLi (1.8)
Et2O
PhCH3
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
–
100
–
–
–
–
–
–
–
–
–
–
–
–
–
–
40
–
–
–
88
–
12
–
6
12
6
8
10
–
22
8
94
88
94
92
90
60
78
92
89
9
10
11
–
–
11
steric hindrance of the 1-substituent on selectivity was
observed, as shown by the results from indole 2c (Table
1, entry 4).
Apparently, various reactions15 could be used to replace
the 5-bromo group of indoles 6 with other substituents.
Among them, another sequence of lithium–bromine
exchange followed by reaction with electrophiles in
one-pot seemed convenient and promising.16 The idea
was tested by using indole 2b. After the first lithium–
bromine exchange and reaction with benzaldehyde, the
reaction mixture was treated with t-BuLi again and
further reacted with CO2 to afford the corresponding
5,7-disubstituted indole 1a after esterification of the
acid in 86% yield (Table 3, entry 1).17 Then we applied
similar reaction conditions to various combinations of
electrophiles to afford valuable products 1b–e in good
yields (Table 3, entries 2–5). Using the same method,
we also examined indole 2d, which afforded the corre-
sponding indoles 1f–j in good yields (Table 3, entries
6–10). Examinations of other indoles 2f, 2h, 2k, and 2i
with an electrophile combination of PhCHO-CO2 were
further performed and afforded products in good yields
(Table 3, entries 11–15).
To extend our study to the synthesis of indoles without
a substituent at 1-position, we applied the best condi-
tions to indole 2a after treatment with 1 equiv. of base
(EtMgCl, MeLi, or KH). Only the use of KH gave a
clean reaction to afford a 2:3 ratio of 3a and 4a, while
the other cases afforded complicated mixtures of prod-
ucts.13 Hence, indole 2d bearing a removable alkyl
substituent SEM (2-(trimethylsilyl)ethoxymethyl)14 was
examined, and more bis-exchange product 5d formed
(Table 1, entry 9). But satisfactory results could be
obtained with both indoles 2d and 2i when 1.8 equiv. of
t-BuLi was used in ether (Table 1, entries 10–11).
Having the selectivity of the exchange reaction deter-
mined and the reaction conditions optimized, we set out
to examine the reaction of the resulting 7-lithiated
indoles with various electrophiles (see Table 2). We first
treated the lithiated intermediates from indoles 2b and
2d with various electrophiles like aromatic and aliphatic
aldehydes, acetone, DMF, and CO2. All yielded the
corresponding products in good to excellent yield with-
out modifying reaction conditions (Table 2, entries 1–5
and 10–14). The reaction of the lithiated species from
indoles 2c, 2f, 2h, 2k, and 2i with benzaldehyde as
electrophile also gave the corresponding alcohols in
good yields (Table 2, entries 6–9 and 15).
In summary, we have developed a general approach to
the synthesis of 5,7-disubstituted indoles based upon a
highly selective lithium–bromine exchange reaction at
the 7-position when 1-alkyl-5,7-dibromoindoles were
treated with t-BuLi in ether. The resulting 5-bromo-7-
lithiated indoles could react with various electrophiles
to afford 5-bromo-7-substituted indoles (6) upon work-
up. Without isolation of 6, the intermediates thus
obtained could be exposed to a second lithium–bromine

L. Li, A. Martins / Tetrahedron Letters 44 (2003) 689–692
Table 2. The synthesis of 5-bromo-7-substituted indoles
691
Entry
Indole 2
E+
Producta
E
Isolated yield
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2c
2f
2h
2k
2d
2d
2d
2d
2d
2i
PhCHO
CH3CHO
MeC(ꢀO)Me
DMF
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
PhCH(OH)
CH3CH(OH)
(CH3)2C(OH)
HC(ꢀO)
MeOC(ꢀO)
PhCH(OH)
PhCH(OH)
PhCH(OH)
PhCH(OH)
PhCH(OH)
CH3CH(OH)
(CH3)2C(OH)
HC(ꢀO)
88
65
75
78
79
49
82
67
48
83
71
74
79
76
74
CO2
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
CH3CHO
MeC(ꢀO)Me
DMF
9
10
11
12
13
14
15
CO2
PhCHO
MeOC(ꢀO)
PhCH(OH)
a The yielded carboxylic acid was treated with CH2N2, and methyl ester was isolated.
exchange reaction in a one-pot procedure and further
reacted with various electrophiles to afford 5,7-disubsti-
tuted indoles (1).
Acknowledgements
We thank NSERC for an Undergraduate Student
Research Award (USRA) for Andrew Martins.
Table 3. The synthesis of 5,7-disubstituted indoles
References
1. The indole nucleus is a common substructure of many
biologically active compounds. For examples see: Sund-
berg, R. J. Indoles; Academic Press: London, 1996.
2. For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045–1075; (b) Robinson, B. The Fischer
Indole Synthesis; John Wiley and Sons: Chichester, 1982;
(c) Sundberg, R. J. In Comprehensive Heterocyclic Chem-
istry; Clive, W. B.; Cheeseman, G. W. H., Eds.; Perga-
mon: Oxford, 1984; Vol. 4, pp. 313–368; (d) Pindur, U.;
Adam, R. J. Heterocycl. Chem. 1988, 25, 1–8.
3. For synthesis of indoles with substituent(s) on the ben-
zenoid portion, see: (a) Ezquerra, J.; Pedregal, C.; Lamas,
C. J. Org. Chem. 1996, 61, 5804–5812 and references
cited therein; (b) Dobbs, A. J. Org. Chem. 2001, 66,
638–641 and references cited therein; (c) Aoki, K.; Peat,
A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
3068–3073.
4. For example, Friedel–Crafts acylation of indole without
EW group on the pyrrole portion takes place preferen-
tially at the 3-position. See: (a) Ottoni, O.; Neder, A. D.
V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org.
Lett. 2001, 3, 1005–1007 and references cited therein. For
examples of acylation on the benzenoid portion, see: (b)
Ref. 1, chapter 14, and references cited therein.
5. Bromination on indole’s benzenoid portion, see: (a) Liu,
Y.; Gribble, G. W. J. Nat. Prod. 2002, 65, 748–749; (b)
Settimo, A. D.; Nannipieri, E. N. J. Org. Chem. 1970, 35,
2546–2550 and references cited therein.
Entry
Indole 2
Producta E1, E2
Yield
86
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2d
2d
2d
2d
2d
2f
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
PhCH(OH), MeOC(ꢀO)b
CH3CH(OH), MeOC(ꢀO)c 49
MeOC(ꢀO), PhCH(OH)d
PhCH(OH), HC(ꢀO)e
MeOC(ꢀO), PhC(ꢀO)f
PhCH(OH), MeOC(ꢀO)b
PhCH(OH), HC(ꢀO)e
PhCH(OH), PhC(ꢀO)g
58
73
50
52
78
61
9
CH3CH(OH), MeOC(ꢀO)c 53
10
11
12
13
14
15
Me2C(OH), MeOC(ꢀO)h
PhCH(OH), MeOC(ꢀO)b
PhCH(OH), MeOC(ꢀO)b
PhCH(OH), MeOC(ꢀO)b
PhCH(OH), MeOC(ꢀO)b
MeOC(ꢀO), PhCH(OH)d
72
48
57
42
82
52
2h
2k
2i
2i
a The yielded carboxylic acid was treated with CH2N2, and methyl
ester was isolated.
b E1+, E2+=PhCHO, CO2.
c E1+, E2+=MeCHO, CO2.
d E1+, E2+=CO2, PhCHO.
e E1+, E2+=PhCHO, DMF.
f E1+, E2+=CO2, PhCONMe(OMe).
g E1+, E2+=PhCHO, PhCONMe(OMe).
h E1+, E2+=acetone, CO2.

692
L. Li, A. Martins / Tetrahedron Letters 44 (2003) 689–692
6. Nitration, see: (a) Leclerc, V.; Yous, S.; Delagrange, P.;
Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832–838; (b)
Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org.
Chem. 1995, 60, 1486–1487. Still coupling, see: (c) Pearce,
B. C. Synth. Commun. 1992, 22, 1627–1643. Suzuki cou-
pling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett
1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert,
D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.;
Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med.
Chem. 1994, 37, 4423–4429.
Boutin, J. A.; Renard, P.; Lesieur, D. J. Med. Chem.
2002, 45, 1853–1859; (b) Noland, W. E.; Rush, K. R. J.
Org. Chem. 1966, 31, 70–77 and references cited therein.
7. For example, the indole used in this study can be easily
prepared by: (a) Fisher indole preparation from 2.4-
dibromophenyl hydrazine with corresponding cyclohex-
anone or cyclopentanone (refluxing for 20 min in AcOH)
in 70–80% yield, followed by alkylation; (b) by Swern
oxidation of the 5,7-dibromoindoline or 5,7-dibromo-2-
methylindoline to afforded indole in more than 90%
yield, see: Kiers, D.; Overton, K. J. Chem. Soc., Chem.
Commun. 1987, 21, 1660.
16. Lithium–bromine exchange reaction was well tolerated by
substrates bearing electrophilic functionals, see: review:
Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982,
15, 300–305.
17. General procedure: To a 0.03 M solution of indole 2 in
dry Et2O under N2 at −78°C, t-BuLi (1.7 M/pentane, 2.1
equiv. for 2b, 2c, 2f, 2h, and 2k; 1.8 equiv. for 2d and 2i)
was added dropwise and the resulting mixture was stirred
for 15 min at −78°C after the addition. Electrophile (1.2
equiv.) was then added (bubbled through when CO2(g)
used), and the resulting mixture was stirred for 1 h at
−78°C. t-BuLi (2.4 equiv.) was added, followed by stir-
ring at −78°C for 15 min. For reaction that CO2(g) was
used as electrophile, the reaction mixture was subjected
to vacuum for about 5 minutes before the addition of
t-BuLi. Electrophile (1.2 equiv.) was then added (bubbled
through when CO2(g) used), and the resulting mixture was
stirred for 1 h after the addition at −78°C. The reaction
mixture was then quenched by the addition of 5% of
aqueous NaH2PO4. The organic phase was separated and
the aqueous phase was further extracted with EtOAc.
The organic phase was combined and dried over Na2SO4,
filtered and concentrated (after treatment with CH2N2
prior to concentration when carboxylic acid was afforded
as product). The crude obtained thus was purified by
flash chromatography. By using this procedure, methyl
5 - [hydroxy(phenyl)methyl] - 4 - methyl - 1,2,3,4 - tetrahydro-
cyclopenta[b]indole-7-carboxylate (1a) was prepared from
2b (329 mg, 1.0 mmol), flash chromatography (10–20%
EtOAc/hexane) to afford 246 mg (86% yield) of 1a as a
white solid. 1H NMR (500 MHz, acetone-d6) l 8.04 (d,
1H, J=1.4 Hz), 7.72 (s, 1H), 7.41–7.34 (m, 4H), 7.29 (t,
1H, J=6.9 Hz), 6.55 (d, 1H, J=5.7 Hz), 5.17 (d, 1H,
J=5.0 Hz), 3.83 (s, 6H), 2.90–2.83 (m, 4H), 2.54–2.48 (m,
2H); 13C NMR (125 MHz, DMSO-d6) l 167.2, 149.5,
144.5, 140.8, 128.5, 128.1, 126.9 (2C), 125.0, 121.4, 119.9,
119.5, 117.9, 70.5, 51.6, 34.6, 27.4, 24.8, 24.4. Anal. calcd
for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
75.21; H, 6.40; N, 4.17%.
8. Applications to the synthesis of substituted benzenes and
naphathalenes, see: (a) Baldwin, J. E.; Jesudason, C. D.;
Moloney, M. G.; Morgan, D. R.; Pratt, A. J. Tetrahedron
1991, 47, 5603–5614; (b) Asami, T.; Kim, B.-T.; Yoshida,
S. Tetrahedron Lett. 1994, 35, 6117–6118; (c) Duerr, B.
F.; Chung, Y. S.; Czarnik, A. W. J. Org. Chem. 1988, 53,
2120–2122 and references cited therein; (d) Parham, W.
E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257–260.
9. Applications to the synthesis of substituted pyridines, see:
(a) Peterson, M. A.; Mitchell, J. R. J. Org. Chem. 1997,
62, 8237–8239 and references cited therein; (b) Gu, Y. G.;
Bayburt, E. K. Tetrahedron Lett. 1996, 37, 2537–2540
and references cited therein.
10. Applications to the synthesis of substituted quinolines,
see: Mongin, F.; Fourquez, J.-M.; Rault, S.; Levacher,
V.; Godard, A.; Trecourt, F.; Queguiner, G. Tetrahedron
Lett. 1995, 36, 8415–8418.
11. For previous example to introduce substituents to
indole’s pyrrole portion by using selective lithium–
bromine exchange, see: Liu, Y; Gribble, G. W. Tetra-
hedron Lett. 2002, 43, 7135–7137.
12. In THF, both n-BuLi and t-BuLi afforded 4b and 5b as
a mixture of ratio 79:21. In ether, n-BuLi afforded 4b in
50% yield with 50% of 2b intact.
13. Previous example of lithium–bromine exchange per-
formed on 1-potassio indoles, see: (a) Moyer, M. P.;
Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51,
5106–5110; (b) Yang, Y.; Martin, A. R.; Nelson, D. L.;
Regan, J. Heterocycles 1976, 34, 1169–1175.
14. Muchowski, J. M.; Solas, D. R. J. Org. Chem. 1984, 49,
203–205.
15. For example, palladium-catalyzed coupling reaction has
been widely used for such purpose. Heck coupling, see:
(a) Yokoyama, Y.; Takahashi, M.; Takashima, M.;
Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.;