Generation and reactivity of 1,2-dilithioindole

Article abstract of DOI:10.1081/SCC-100103332

The generation of a 1,2-dianion (1) from 2-iodoindole is described. This dianion reacts at the carbanionic center with a range of electrophiles to give 2-substituted indoles in good yields.

Full text of DOI:10.1081/SCC-100103332

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GENERATION AND REACTIVITY
OF 1,2-DILITHIOINDOLE
a
John M. Herbert & Maria Maggiani
a
Isotope Chemistry and Metabolite Synthesis
Laboratories , Sanofi-Synthélabo, Willowburn
Ave., Alnwick, Northumberland, NE66 2JH, UK
Published online: 09 Nov 2006.
To cite this article: John M. Herbert & Maria Maggiani (2001) GENERATION AND
REACTIVITY OF 1,2-DILITHIOINDOLE, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:6, 947-951,
DOI: 10.1081/SCC-100103332
To link to this article: http://dx.doi.org/10.1081/SCC-100103332
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SYNTHETIC COMMUNICATIONS, 31(6), 947–951 (2001)
GENERATION AND REACTIVITY OF
1
,2-DILITHIOINDOLE
John M. Herbert* and Maria Maggiani
Isotope Chemistry and Metabolite Synthesis Laboratories,
Sanofi-Synthelabo, Willowburn Ave., Alnwick,
´
Northumberland NE66 2JH, UK
ABSTRACT
The generation of a 1,2-dianion (1) from 2-iodoindole is
described. This dianion reacts at the carbanionic center with a
range of electrophiles to give 2-substituted indoles in good
yields.
Recently, we described a process for the direct formation of indole-
-carboxamides from 2-iodoindoles by palladium-catalyzed carbonylation
2
1
in the presence of an amine. As part of our investigations in this area, it was
of interest also to examine the formation of indole-2-carboxylic acids and
amides from 2-halo or 2-unsubstituted precursors. Lithiation at the 2-posi-
2
tion of 1-protected indoles is a well-known process, but 1,2-bis-metalation
3
of indoles has been reported only very rarely. We report the formation
of 1,2-dilithioindole (1) from 2-iodoindole (2a); this intermediate reacts
with a range of electrophiles to give 2-substituted indoles in respectable
yields.
*
Corresponding author.
9
47
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

9
48
HERBERT AND MAGGIANI
Our examination of the formation and reactions of 1,2-dilithioindole
was prompted by the consistent failure, in our hands, of the dianion (3)
formed by deprotonation of lithium indole-1-carboxylate to react with
4
carbon dioxide, although the formation of the anion was demonstrated
by incorporation of deuterium at the 2-position of the product 4 (Scheme
1), and the corresponding reaction of dianion 3 with phenyl isocyanate
resulted in the formation of N-phenylindole-2-carboxamide (2h) in 43%
yield.
2
Scheme 1. Formation of [2- H]-Indole-1-carboxylic acid, 4.
5
Upon treatment with excess butyllithium, 2-iodoindole (2a) under-
goes both deprotonation at nitrogen and lithium-halogen exchange to give
dianion 1. The process requires three moles of alkyllithium for optimum
results: with a smaller excess of base, 1 is sufficiently basic to eliminate the
elements of hydrogen iodide from 1-iodobutane, and indole (2b) is the major
product (Scheme 2). At the same time, where less than three equivalents of
base were used, lithium-halogen exchange remained incomplete and small
amounts of 2a were recovered. Even when three molar equivalents of n- or
t-butyllithium were used, the degree of deuterium incorporation did not
greatly exceed 70% after quenching with methanol-d. Beyond this level,
there was no improvement in the degree of metalation and some indole
was always formed.

1
,2-DILITHIOINDOLE
949
Scheme 2. Course of reaction of 1 with electrophiles.
Table 1. Summary of the Reactions of 1,2-Dilithioindole with Electrophiles
þ
BuLi
equiv.) Solvent
E
(equiv.)
Product 2
(R; yield, %)
Side-Products 2a Yield
(yield,%)
(
(%)
2.4
3.0
3.0
4.0
3.0
3.3
3.0
3.0
3.0
3.3
2.0
3.0
DME
DME
CD
CD
3
OD(excess) 2c (D; 60)
OD(excess) 2c (D; 73)
—
—
—
—
—
—
—
40
27
37
3
Toluene C Cl (1.5)
6
2d (Cl; 62)
2
a
THF
THF
Toluene EtOCOOEt (1.2) 2f (COOH; 60)
Toluene PhNCO (1.1)
Toluene BuNCO (1.2)
Toluene DMF (5)
Toluene MeI (1.5)
Toluene MeI (3.0)
CO
2
(excess)
(excess)
2e (COOH; 56)
2e (COOH; 61)
n.i.
n.i.
a
CO
2
36
41
b
b
2g (CONHPh; 55)
2h (CONHBu; 17)
b
b
7a (10)
63
50
65
24
b
b
2i (CHO; 50)
b
2j (Me; 30)
—
—
b
b
b
b
2j (Me; 54)
2k (0)
8 (21)
7b (6), 2m (5)
b
b
Toluene BrCH
2
COOEt
89
a
Indole was formed but not isolated.
b
Product were not separated: yields based on yield of crude mixture, adjusted for GC
ratio of products, and identification was made based on MS data and agreement with
a standard of known structure.

9
50
HERBERT AND MAGGIANI
Once formed, the dianion reacts with electrophiles at position 2 in
preference to position 1, as expected. The results of the reaction of 1 with
a range of electrophiles are summarized in Scheme 2 and Table 1. Yields
of 2-substituted indoles were generally in the 50–60% range, based on 2a
(
corresponding to 70–85% based on 1). The best results were obtained
with electrophiles of moderate reactivity (where reaction of a second
mole equivalent of electrophile with the N-anion was not a major process).
The low-yielding reaction of 1 with butyl isocyanate also gave a quantity
of the urea 7a formed by attack of the isocyanate upon the indole nitro-
gen. Given that the reaction with phenyl isocyanate is very much
more efficient, one may speculate that this is a result of 1 acting as a
base, and eliminating the elements of cyanic acid from the reagent in
preference to attacking as a nucleophile. Certainly, treatment of 1 with
4
(
-chloro-1-bromobutane returns only indole, with the elimination product
4-chloro-1-butene) being a major component of the crude reaction
product. More predictably, the reaction of 1 with methyl iodide gave
either a low yield of 2-methylindole (2j) or a mixture of 2j with
1
(
,2-dimethylindole (8). Unexpectedly, small quantities of 2-bromoindole
2m) and 1-acetylindole (7b) were formed from the reaction of 1 with
ethyl bromoacetate; nevertheless, indole was the major product. If the
major process occurring in this instance is proton abstraction from the
electrophile, 2m can be rationalized as the product of metal-halogen
exchange, and the ethyl acetate thereby formed might react with the
N-anion to form 7b.
In conclusion, we have demonstrated that the formation of 1 is a
comparatively facile process. The dianion, 1, will react predictably with an
electrophile, provided that the latter cannot undergo elimination or suffer
proton abstraction. The majority of products are 2-substituted only,
although treatment of 1 with more reactive electrophiles, such as methyl
iodide, results in the formation of 1,2-disubstituted species, even where the
electrophile is not used in excess.
EXPERIMENTAL
Gas chromatography was performed using a Hewlett-Packard
chromatograph (HP 5890) fitted with a mass-selective detector (HP 5970
MSD) on a capillary column (HP-1, 23 m  0.2 mm  0.33 mm); the oven
ꢀ
ꢀ
ꢀ
temperature was increased from an initial 100 C to 240 C at 10 C per
minute.

1
,2-DILITHIOINDOLE
N-Phenylindole-2-carboxamide (2h)
951
5
To a solution of 2a (122 mg, 0.5 mmol) in THF (5 mL) under nitrogen
ꢀ
at À70 C was added butyllithium (1.6 M in hexanes; 0.94 mL, 1.5 mmol). The
mixture was stirred for 15 m, following which phenyl isocyanate (61 mL,
0
.6 mmol) was added. The mixture was stirred for a further 3 h, while warm-
ing to room temperature, and finally quenched by addition of aqueous
ammonium chloride. The mixture was extracted twice with ethyl acetate,
and the combined extracts were dried over magnesium sulfate and concen-
trated to dryness. Preparative t.l.c. of the residue on silica in 1:9 ethyl acetate-
hexane gave 2b (24 mg, 41%), followed by 2h (65 mg, 55%), which was
1
identical to material obtained previously. Butyllithium (1.6 M in hexanes;
4
.4 mL, 7.1 mmol) was added to a solution of indole (0.752 g, 6.4 mmol) in
ꢀ
THF (10 mL) under nitrogen at À70 C. After 15 m carbon dioxide gas was
passed through the mixture for 5 m, following which the mixture was stirred
for 5 m, degassed under vacuum, and allowed to warm to room temperature
under vacuum, forming a white solid. The apparatus was flushed with nitro-
ꢀ
gen, fresh THF (15 mL) was added, and the mixture was cooled to À70 C, at
which temperature t-butyllithium was added and the resulting bright yellow
solution stirred for a further 15 m. Phenyl isocyanate (0.810 mL, 8 mmol) was
ꢀ
added, and the mixture was stirred for 5 m at À78 C, then allowed to warm
to room temperature. Deuterium oxide (3 mL) was added, followed after 5 m
by saturated aqueous sodium hydrogen carbonate. The mixture was
extracted twice with ethyl acetate and the combined extracts were dried
(MgSO ) and evaporated. Column chromatography of the residue on silica
4
gel in 1:9 ethyl acetate-hexane gave 2h (0.657 g, 43%).
ACKNOWLEDGMENTS
The authors thank Dr. S. J. Byard for NMR spectra and Dr. D. I. Smith
for helpful discussions.
REFERENCES
1
2
3
4
5
. Herbert, J.; McNeill, A. Tetrahedron Lett. 1998, 39, 2421.
. Sundberg, R.J. Indoles; Academic Press: London, 1996.
. Eberle, M.K. J. Org. Chem. 1976, 41, 633.
. Katritzky, A.R.; Kutagawa, K. Tetrahedron Lett. 1985, 26, 5935.
. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495.
Received in the U.K. March 27, 2000