Communications
DOI: 10.1002/anie.200905419
Direct Alkynylation
Direct Alkynylation of Indole and Pyrrole Heterocycles**
Jonathan P. Brand, Julie Charpentier, and Jꢀrꢁme Waser*
Indoles and pyrroles occupy a privileged position in pharma-
ceuticals, material sciences, and natural products.[1] Conse-
quently, methods to synthesize and functionalize these
heterocycles are of utmost importance in organic chemistry.[2]
Metal-catalyzed cross-coupling is the method most often used
for the introduction of (hetero)aryl, vinyl, or acetylene groups
to indoles and pyrroles, but it requires premodification of the
heterocycle.[3] Recently, the direct C H functionalization of
À
indoles and pyrroles has emerged as a more efficient
Scheme 1.
alternative for the introduction of vinyl and aryl groups.[4] In
contrast, examples of the direct alkynylation of aromatic
compounds are scarce.[5] Recently reported methods include
the gallium-catalyzed acetylenation of phenols and aniline-
s;[5a,b] the palladium-catalyzed alkynylation of N-fused heter-
ocycles,[5c] anilines,[5d] and indoles;[5e] the nickel-catalyzed
alkynylation of azoles;[5f] the reaction of pyrroles with
bromoacetylene ketone derivatives;[5g,h] and the oxidative N-
alkynylation of indoles.[5i] The single example of alkynylation
of indoles[5e] was limited to the use of aryl and alkenylbro-
moacetylenes in large excess (3 equiv). These substrates
cannot be converted into free acetylenes and the large
excess of reagent needed limited the practicability of the
reaction. Furthermore, the reaction was limited to indoles
with only methyl, methoxy, or ester functional groups. Indoles
substituted at position 2 resulted in a low yield, and 3-
substituted indoles could not be used. In view of the limited
scope in the case of indoles and pyrroles, there is an urgent
need for new alkynylation methods, especially when consid-
ering the importance of acetylenes in organic synthesis.[6]
Herein, we report a functional group tolerant gold-catalyzed
alkynylation of indoles and pyrroles. The reaction proceeds in
high yield at room temperature in air by using benziodox-
olone-derived hypervalent iodine reagent 1d, and gives easily
deprotected silylacetylene products (Scheme 1).
although other hypervalent iodine reagents have been highly
successful in arylation and heteroatom-transfer reac-
tions.[4g,h,9] However, no product could be isolated when the
reaction conditions reported for the direct arylation of indole
2a using copper[4g] and palladium[4h] catalysts were examined
with alkynyliodonium salts 1a and 1b[8b,d–f] and neutral
[8h,i]
benziodoxolone-derived reagents 1c and 1d
(Table 1,
Table 1: Optimization of alkynylation of indole (2a).
Entry
Catalyst
Solvent
Yield[a]
1
2
3
4
5
6
7
8
Pd(OAc)2
Cu(OTf)2
AuCl
AcOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
THF
CH3CN
DMF
<5%
<5%
65%
56%
17%
42%
84%
85%
82%
62%
81%
51%
AuCl3
[Au(NHC)Cl][b]
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
9
The limited results obtained with halogenated acetylene
derivatives[5a–h] prompted us to consider using more-reactive
hypervalent iodine reagents.[7,8] In particular, the use of
alkynyliodonium salts as electrophilic/oxidative reagents for
acetylene transfer are well-established.[8a–g] Surprisingly, their
10
11
12
iPrOH
MeOH
[a] Reaction conditions: 0.20 mmol 2a, 5–10% mol catalyst, 1.2 equiv
reagent, 4 mL solvent. Yield was determined by GC-MS. [b] NHC=1,3-
di(2,6-diisopropylphenyl)imidazol-2-ylidene.
À
use for C H functionalization has not yet been reported,
[*] J. P. Brand, J. Charpentier, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9700
entries 1 and 2); the same result was also obtained with
several other metal catalysts.[10] We then turned our attention
to gold catalysts.[11] Their capacity to activate multiple
p bonds[12] is well-established and they have also been used
À
in the formation of C C bonds with an accompanying change
E-mail: jerome.waser@epfl.ch
in the oxidation state of the gold center.[13] The functionaliza-
À
tion of C H bonds using gold catalysts has been realized in
[**] Dr. Tom Woods (LSYNC) is acknowledged for proofreading this
manuscript.
classical hydroarylation reactions.[14] Other reports remained
limited to stoichiometric methods[15] or the introduction of
heteroatoms.[16] Hydroarylation reactions were shown to be
Supporting information for this article is available on the WWW
9346
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Angew. Chem. Int. Ed. 2009, 48, 9346 –9349