One-pot multicomponent synthesis of indoles from 2-iodobenzoic acid

Article abstract of DOI:10.1002/anie.200703671

(Chemical Equation Presented) A synergism: The multicomponent assembly of an alkyne, a nucleophile, and a carboxylic acid gave indole derivatives in good yield and high regioselectivity by a one-pot Curtius rearrangement/palladium- catalyzed indolization process (see scheme). A synergistic effect was observed; the by-product of the first reaction served as a reagent for the second step. The first synthesis of indole N-carboxamide derivatives by heteroannulation is also described.

Full text of DOI:10.1002/anie.200703671

Communications
DOI: 10.1002/anie.200703671
Multicomponent Reactions
One-Pot Multicomponent Synthesis of Indoles from 2-Iodobenzoic
Acid**
Olivier Leogane and HØl›ne Lebel*
Considerable attention has been devoted to the synthesis of
indole scaffolds because of their prominence as a motif in a
wide variety of bioactive natural products and pharmaceutical
compounds.[1] The seminal work of Fischer and Jourdan[2] has
been followed by numerous other approaches to prepare this
useful framework.[3] Recently, the palladium-catalyzed annu-
lation of 2-iodoanilines or anilides with internal alkynes or
carbonyl compounds has emerged as one of the most power-
ful synthetic methods to access the indole skeleton.[4] How-
ever, drawbacks such as the high cost and the low stability of
2-iodoanilines are still associated with this process.[5] To
overcome this problem, a one-pot strategy could be envi-
sioned.[6] Not only would such a process eliminate the need for
isolation of the potentially unstable 2-iodoanilines, but also it
would decrease the amount of chemical waste generated.[7]
Furthermore, it has been shown that the overall yields for
one-pot procedures are higher than those of step-by-step
processes.[8] Synergistic effects between reactions are also
likely, and it is possible that a by-product from a reaction
could become a reagent in a subsequent reaction. Herein we
report a novel multicomponent process that allows the
transformation of readily available 2-iodobenzoic acid into
indole derivatives by a one-pot Curtius rearrangement/
palladium-catalyzed indolization process (Scheme 1). In this
strategy the 2-iodoaniline intermediate is not isolated, and
moreover one of the by-products of the Curtius rearrange-
ment becomes an essential reagent for the next step of the
transformation.
There are few reported examples of an intermolecular
palladium-catalyzed indolization with alkynes in which a
carbamate substrate is used.[9] Initially the annulation reac-
tion of benzyl 2-iodophenylcarbamate (1) and 4-octyne was
investigated. By using the optimized reaction conditions of
palladium acetate, one equivalent of lithium chloride, and
sodium carbonate, the carbobenzoxy (CBz) protected indole
2 was isolated in 48% yield after three hours [Eq. (1)].[10] This
moderate yield was a consequence of cleavage of the CBz-
protecting group and indeed, a longer reaction time of 16
hours and an excess of base led to the exclusive formation of
the unprotected indole 3 in an excellent yield [Eq. (2)].[11] No
indolization reaction occurred in the absence of lithium
chloride, however an excess of the salt led to low yields.[10]
We then investigated the formation of indole 3 using a
one-pot Curtius-indolization process starting from 2-iodo-
benzoic acid (Table 1). This substrate was treated under the
standard Curtius reaction conditions recently reported by our
research group which allows the direct conversion of aromatic
carboxylic acids into carbamates and ureas.[12] The CBz-
protected aniline intermediate 1 was not isolated, but directly
subjected to the palladium-catalyzed indolization reaction
Scheme 1. One-pot multicomponent synthesis of indoles from 2-iodo-
benzoic acid. Nuc=nucleophile.
[*] O. Leogane, Prof. H. Lebel
DØpartement de Chimie
Table 1: One-pot Curtius rearrangement/palladium-catalyzed indoliza-
tion starting from 2-iodobenzoic acid and 4-octyne.
UniversitØ de MontrØal
PO Box 6128, Station Downtown, MontrØal
QuØbec, H3C 3J7 (Canada)
Fax: (+1)514-343-2177
E-mail: helene.lebel@umontreal.ca
[**] This research was supported by the NSERC (Canada), AstraZeneca
Canada Inc., Boehringer Ingelheim (Canada) Ltd, Merck Frosst
Canada Ltd, the CFI (Canada), the Canada Research Chair Program,
and the UniversitØ de MontrØal. O.L. thanks the Conseil gØnØral de
la Guadeloupe for a graduate scholarship. We thank Prof. Dean
Toste for helpful discussions.
Entry
LiCl
Base [equiv]
Alkyne [equiv]
Yield [%]
1
2
3
4
5
6
yes
no
no
no
no
no
K2CO3 (5.0)
Na2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5)
Na2CO3 (3.0)
K2CO3 (3.0)
5.0
1.5
1.5
1.5
3.0
3.0
29
71
73
40
84
73
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
350
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Angew. Chem. Int. Ed. 2008, 47, 350 –352

Angewandte
Chemie
conditions. A disappointing 29% yield of the desired indole 3
was observed when the standard reaction conditions for
indolization (including one equivalent of lithium chloride)
were used (Table 1, entry 1). It has been shown previously
that an excess of a chloride salt is detrimental for palladium-
catalyzed heteroannulations.[4f] An equivalent of sodium
chloride is generated in situ as a by-product after the Curtius
rearrangement, thus remained in the reaction mixture and led
to a low yield.
Significantly lower yields (67%) were observed for the
indolization reaction in the presence of one equivalent of
lithium chloride or one equivalent of sodium chloride, which
are considerably less soluble than the in situ generated
species.[10] Conversely, when no lithium chloride was added,
the reaction with 1.5 equivalents of both potassium carbonate
and alkyne resulted in the yield of 3 improving to 73%
(Table 1, entry 3). A real synergy was observed between the
two reactions (namely the Curtius rearrangement and the
indolization processes), as one by-product of the first step
became a reagent in the second step. To our knowledge this is
one of the few examples of such a synergistic effect in a one-
pot strategy. After optimization, three equivalents of sodium
carbonate proved to be the best base and gave 3 in 84% yield
(compare Table 1, entry 5 to entries 2–4 and 6). This yield is
comparable to that obtained for the individual indolization
step [see Eq. (2)], which clearly illustrates that one-pot
processes lead to higher yields than step-by-step procedures.
The above one-pot process is also compatible with aryl-
substituted alkynes (Table 2, entry 1) and affords the corre-
sponding indoles in good yield. Unsymmetrical alkynes gave
the corresponding indole 5 and 6 with complete regiocontrol
in 56% and 82% yields, respectively (Table 2, entries 2 and
3). Aldehydes and ketones could also be used as coupling
partners by using 1,4-diazabicyclo[2.2.2]octane (DABCO)
instead of the carbonate base.[4l] Under these modified
reaction conditions, 2-iodobenzoic acid was converted into
3-benzylindole (7) in 50% yield using hydrocinnamaldehyde
(Table 2, entry 4). A benzyl ether was also tolerated, produc-
ing indole 8 in 53% yield (Table 2, entry 6), and when
cyclohexanone was employed, the tetrahydrocarbazole 9 was
recovered in 56% yield.[13]
The preparation of indole N-carboxamide derivatives,[1,14]
which are important pharmacophores, typically proceeds
through the acylation of indoles.[15] No intermolecular hetero-
annulation has so far been reported with aromatic ureas.[7]
Thus, we investigated a novel one-pot urea synthesis by using
palladium-catalyzed heteroannulation with internal alkynes,
to produce 2,3-disubstituted indole-carboxamide derivatives
(Table 3). Treatment of 2-iodobenzoic acid with phenyl
chloroformate and sodium azide, followed by addition of an
amine led to the formation of the corresponding urea
Table 3: Synthesis of indole N-carboxamides from 2-iodobenzoic acid by
a one-pot Curtius rearrangement/palladium-catalyzed indolization
process.
Entry
1
Product
Yield [%][a]
64
Table 2: Synthesis of indoles from 2-iodobenzoic acid by a one-pot
Curtius rearrangement/palladium-catalyzed indolization process.
Entry
1
Coupling agent Base
Product
Yield [%][a]
77
2
3
4
68
54
62
2
3
56
82
4
5
6
50
53
56
5
6
59
39
[a] Yields of isolated products. TMS=trimethylsilyl, Bn=benzyl.
[a] Yields of isolated products. NMP=N-methyl-2-pyrrolidinone.
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Communications
45, 2938 – 2942; g) T. Sakamoto, T. Nagano, Y. Kondo, H.
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intermediate. Without isolation, the intermediate was directly
engaged in palladium-catalyzed indolization with diphenyl-
propyne or 4-octyne to give indole-carboxamides. The cyclic
amines morpholine, piperidine, and pyrrolidine produced
indoles 10–13 in 54–68% yield (Table 3, entries 1–4), whereas
a substituted acyclic amine produced indole 14 in 59% yield
(Table 3, entry 5). A moderate yield of indole 15 was obtained
with phenylethylamine (Table 3, entry 6).
In conclusion, we have developed a novel one-pot Curtius
rearrangement/palladium-catalyzed indolization process that
allows the direct synthesis of 2,3-disubstituted and 3-substi-
tuted indoles starting from readily available 2-iodobenzoic
acid. A synergistic effect between the two reactions of the
process was observed, with a by-product of the first reaction
serving as a reagent in the second synthetic step. In addition,
the use of a one-pot procedure leads to higher yields while
generating less by-products and chemical residues. This
multicomponent process was also used to synthesize the
first indole N-carboxamide derivatives through a hetero-
annulation procedure.
[5] It is possible to use the cheaper 2-chloro or 2-bromo derivatives
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Experimental Section
Typical procedure: Benzyl chloroformate (150 mL, 1.10 mmol) was
added to a solution of sodium azide (0.110 g, 1.70 mmol), sodium tert-
butoxide (14.4 g, 0.15 mmol), and 2-iodobenzoic acid (0.248 g,
1.0 mmol) in N,N-dimethylformamide (DMF, 5.0 mL) at 258C. The
resulting mixture was then stirred at 758C for 5 h and then cooled to
room temperature. Pd(OAc)2 (11.2 mg, 0.05 mmol), the base
(Na2CO3 for alkynes or DABCO for carbonyl compounds
(3 mmol)), and the alkyne (3 mmol) or the carbonyl compound
(3 mmol for ketones and 0.90 mmol for aldehydes) were then added
and the mixture was heated at 1208C for 16 h. The reaction mixture
was then cooled to room temperature and then filtered through celite,
which was washed with EtOAc (100 mL). The resulting organic layer
was washed with saturated NH4Cl (2 ” 40 mL) and brine (40 mL). The
organic layer was dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography on silica gel.
[7] A. Bruggink, R. Schoevaart, T. Kieboom, Org. Process Res. Dev.
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[10] See the Supporting information for the optimization details.
[11] Similar cleavage has been previously observed with trifluoroa-
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[13] It should be noted that in this case the use of a chloride salt is not
required.
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Received: August 10, 2007
Published online: November 23, 2007
Keywords: heteroannulation · indole · one-pot process ·
.
palladium · rearrangement
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