C2-selective direct alkynylation of indoles

Article abstract of DOI:10.1021/ol3031389

The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.

Full text of DOI:10.1021/ol3031389

ORGANIC
LETTERS
2013
Vol. 15, No. 1
112–115
C2-Selective Direct Alkynylation
of Indoles
†
Gergely L. Tolnai, Stephanie Ganss, Jonathan P. Brand, and Jerome Waser*
ꢀ ^
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and
ꢀ ꢀ
Engineering, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO,
BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received November 14, 2012
ABSTRACT
The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX)
with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high
C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used
silyl protecting group can be easily removed to give terminal acetylenes.
Since the first synthesis of indole by Baeyer almost 150
years ago,1 interest in the preparation and functionaliza-
tion of this privileged heterocycle has constantly grown.2
Indoles can indeed be found in numerous important mol-
ecules such as pharmaceuticals, dyes, and natural products.
Consequently, methods to synthesize and modify this het-
erocycle are of utmost importance in organic chemistry.
Metal-catalyzed cross-coupling reactions constitute an
efficient tool for the modification of aromatic rings,3 but
the need for prefunctionalization makes this method less
efficient. In comparison, CÀH functionalization con-
stitutes a more direct alternative for the introduction of
various valuable functional groups. Recently, the direct
functionalization of indoles has been intensively examined
using metal catalysts to complement traditional FriedelÀ
Crafts reactions. Efficient methods have been developed to
introduce vinyl,4 aryl,5 alkyl,6 and cyano7 groups among
others.8 In several cases, the C2/C3 regioselectivity of these
functionalizations could be controlled by the reaction
conditions or using directing groups.4,9
(4) Selected examples: (a) Grimster, N. P.; Gauntlett, C.; Godfrey,
C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (b) Garcia-
Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009,
48, 6511. (c) Ding, Z. H.; Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51,
4698. (d) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew.
Chem., Int. Ed. 2012, 51, 1265.
(5) Selected examples: (a) Lane, B. S.; Sames, D. Org. Lett. 2004, 6,
2897. (b) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996. (c) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (d) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972. (e) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172. (f) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008,
130, 2926. (g) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 8172. (h) Cornella, J.; Lu, P. F.; Larrosa, I. Org. Lett.
2009, 11, 5506. (i) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.;
LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676.
(6) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990.
† New address: Institut f€ur Organische Chemie and Biochemie, Albert-
€
Ludwigs-Universitat, Freiburg, Germany.
(1) Baeyer, A. Liebigs. Ann. Chem. 1866, 140, 295.
(2) (a) Sundberg, R. J. Indoles; Academic: New York, USA, 1996. (b)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (d) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9608. (e) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2011, 111, PR215–PR283.
(3) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd, Completely Revised and Enlarged Edition; Wiley-WCH:
Weinheim, Germany, 2004.
(7) (a) Yan, G. B.; Kuang, C. X.; Zhang, Y.; Wang, J. B. Org. Lett.
2010, 12, 1052. (b) Xu, S.; Huang, X.; Hong, X.; Xu, B. Org. Lett. 2012,
14, 4614.
r
10.1021/ol3031389
Published on Web 12/18/2012
2012 American Chemical Society

Despite the important applications of acetylenes in syn-
thetic chemistry, biochemistry, and material sciences,10
there are only a few methods for the direct alkynylation
ofthe indole core.11 In 2009, Gu and Wang first introduced
the C3-selective alkynylation of indoles using bromoace-
tylenes and a Pd catalyst.11a C2-selective alkynylation is
especially challenging, and only two examples have been
reported so far. Li and co-workers described an oxidative
HeckÀCassarÀSonogashira type method for the alkynyla-
tion of 1,3-dimethylindole.11f This reaction could be applied
to a broad scope of acetylenes, but only 3-methylindoles
were reported. More recently, a method for the alkynylation
of lithiated indoles using ethynylsulfonates as reagents was
reported by Garcia Ruano and co-workers.11g,h Depend-
ing on the sterical hindrance of the substituent on the
indole nitrogen, C2 or C3 alkynylation could be obtained.
Nevertheless, the requirement for a strong base such as
butyl lithium limited the scope of this transformation.
Consequently, the most frequently used methods to access
2-alkynylated indoles are often based on the formation of
the heterocycles via cyclization reactions.12
In 2009, our group introduced the hypervalent iodine
compound triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-
one (TIPS-EBX, 2)13 as an efficient reagent for the gold-
catalyzed C3 alkynylation of indoles (Scheme 1). During
our first investigation, palladium catalysts gave only traces
of product, albeit with very high C2 selectivity.11b We later
demonstrated that efficient acetylene transfer with Pd
catalysts was possible for the amino- and oxy-alkynylation
of olefins.14 Building upon these results, we report herein
the first Pd-catalyzed C2-selective alkynylation of 3H-
indoles using TIPS-EBX (2), which proceeds at room
temperature under air in the presence of a broad range of
functional groups (Scheme 1). In contrast to Gu and
Wang’s work, exclusive C2-alkynylation was observed.
To the best of our knowledge, our work constitutes also
the first example of Pd-catalyzed direct alkynylation of a
heterocycle using a hypervalent iodine reagent.
Scheme 1. Regioselective Alkynylation of Indoles
During preliminary investigations on indole itself, a
broad screen of Pd catalysts, solvents, and reaction condi-
tions was not successful in improving the yield beyond
20%. More promising results were obtained in the case of
N-methyl indole (1a) using a dichloromethane/water mix-
ture as the solvent and 3 equiv of TIPS-EBX (2) (Table 1).15
In this case, the reaction did not proceed without a catalyst
(entry 1) or with the Pd(0) source Pd(PPh3)4 (entry 2), but
Pd(II) salts such as Pd(OAc)2 and PdCl2 gave promising
yields (entries 3 and 4). A further increase in yield was
observed with Pd(MeCN)4(BF4)2, which has a less coordi-
nating counteranion (entry 5). In this case, the importance
of water was confirmed, as a lower yield was obtained
under dry conditions (entry 6). The catalyst loading had a
strong influence on the yield, with 2% being the optimal
amount (entries 7À9). Further screening of catalysts did not
lead to better yields and confirmed that the reaction did not
proceed in the presence of phosphine ligands (entries 10À12).
Table 1. Optimization of the C2 Selective Alkynylation
(8) Reviews: (a) Beck, E. M.; Gaunt, M. J. Pd-Catalyzed CÀH Bond
Functionalization on the Indole and Pyrrole Nucleus. In CÀH Activa-
tion; Yu, J. Q., Shi, Z., Eds.; Springer-Verlag Berlin: Berlin, 2010; Vol. 292,
pp 85À121. (b) Lebrasseur, N.; Larrosa, I. Recent Advances in the C2
and C3 Regioselective Direct Arylation of Indoles. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier Academic Press
Inc.: San Diego, 2012; Vol. 105, pp 309À351.
catalyst
loading
yield
(%)a
(9) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew.
Chem., Int. Ed. 2011, 50, 1338.
(10) Diederich, F.; Stang, P. J.; Tykwinsky, R. R. Acetylene Chem-
entry
Pd source
1
À
0
istry; Wiley-WCH: Weinheim, Germany, 2004.
2
10%
10%
10%
10%
10%
25%
0.5%
2%
Pd(PPh3)4
0
(11) (a) Gu, Y. H.; Wang, X. M. Tetrahedron Lett. 2009, 50, 763. (b)
Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48,
9346. (c) Brand, J. P.; Chevalley, C.; Waser, J. Beilstein J. Org. Chem.
2011, 7, 565. (d) Brand, J. P.; Chevalley, C.; Scopelliti, R.; Waser, J.
Chem.;Eur. J. 2012, 18, 5655. (e) de Haro, T.; Nevado, C. J. Am. Chem.
Soc. 2010, 132, 1512. (f) Yang, L.; Zhao, L.; Li, C. J. Chem. Commun.
3
Pd(OAc)2
34
4
PdCl2
40
5
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
[Pd(allyl)Cl]2
Pd(PPh3)2Cl2
Pd2dba3
50
6
23b
19
7
ꢀ
2010, 46, 4184. (g) Garcı
Alvarado, C.; Tortosa, M.; Dı
Int. Ed. 2012, 51, 2712. (h) Garcı
Alvarado, C.; Tortosa, M.; Dıaz-Tendero, S.; Fraile, A. Chem.;Eur. J.
2012, 18, 8414.
´
a Ruano, J. L.; Aleman, J.; Marzo, L.;
8
37
´
az-Tendero, S.; Fraile, A. Angew. Chem.,
9
61
ꢀ
a Ruano, J. L.; Aleman, J.; Marzo, L.;
´
´
10
11
12
13
2%
60
2%
traces
57
66c
(12) Mothe, S. R.; Kothandaraman, P.; Lauw, S. J.; Chin, S. M.;
Chan, P. W. Chem.;Eur. J. 2012, 18, 6133 and references herein.
(13) TIPS-EBX is commercially available and easily prepared in a
two-step protocol from iodobenzoic acid in high yield on a 30 g scale:
Brand, J. P.; Waser, J. Synthesis 2012, 44, 1155.
(14) (a) Nicolai, S.; Erard, S.; Fernandez Gonzalez, D.; Waser, J.
Org. Lett. 2010, 12, 384. (b) Nicolai, S.; Piemontesi, C.; Waser, J. Angew.
Chem., Int. Ed. 2011, 50, 4680.
2%
2%
Pd(MeCN)4(BF4)2
a 0.2 mmol of 1a, 0.6 mmol of 2, 2 mL of CH2Cl2, 0.04 mL of water,
overnight; GC-MS yields, using dodecanitrile as standard. b In dry
CH2Cl2. c Isolated yield on a 0.5 mmol scale.
Org. Lett., Vol. 15, No. 1, 2013
113

When the reaction was scaled up to 0.5 mmol, the alkynyl-
ation product was obtained in 66% isolated yield with
Pd(MeCN)4(BF4)2 (entry 13). In contrast to the work of
Gu and Wang,11a only the C2-alkynylated product was
isolated from the reaction mixture. This transformation
consequently was the first C2-selective direct alkynylation
of 3-unsubstituted indoles.
The reaction worked well with different halogens on
various positions on the benzene ring (Table 2, entries
2À7), which has two main advantages. First, halogen sub-
stituents can be used to adjust the polarity, lipophilicity,
and metabolic stability of dyes or pharmaceuticals. Second,
halogens allow further modification using cross-coupling
reactions for the elaboration of molecule libraries. These
results also indicated that the reaction most likely did not
proceed via a Pd(0) intermediate, as oxidative addition on
the carbonÀhalogen bond would have been expected in this
case. This is an important advantage when compared with
previously published methods involving Pd(0) catalysis.11a
Furthermore, both electron-withdrawing (entries 8À9) and
electron-donating (entry 10) groups were tolerated on the
benzene ring.
In general, N-alkylated indoles are very important build-
ing blocks for the synthesis of bioactive compounds, in
particular for natural indole alkaloids. We consequently
decided to further examine the scope of alkyl groups on the
nitrogen (Table 3).16 Propylphenyl substituted indole 1k
gave a 58% yield, demonstrating that the reaction was not
limited to the small methyl group (entry 1). Allyl or benzyl
groups on nitrogen could present a serious issue in the
presence of a palladium catalyst. Nevertheless, the alky-
nylationproductscouldstill be obtainedinmoderateyields
in this case (entries 2À4). Conversely, a TIPSO-ethyl and a
sensitive bromo ethyl group gave good yields, opening the
door for a wide range of further synthetic modifications
(entries 5À6). Finally, indole 1q, bearing an acetal pro-
tected aldehyde, could also be alkynylated in 66% yield
(entry 7).
Table 2. Scope of Substituents on the Benzene Ring
Based on precedence from other Pd-mediated trans-
formations, in particular arylation,5 a speculative mecha-
nism may possibly involve a Pd(II)/(IV) cycle (Scheme 2).
Table 3. Scope of Substituents on the Nitrogen
a Isolated yields with 0.5 mmol of indole 1, 1.5 mmol of (2), 5 mL of
CH2Cl2, 0.1 mL of water, 10 μmol of Pd(MeCN)4(BF4)2.
a Isolated yields, 0.5 mmol of indole 1, 1.5 mmol of 2, 5 mL of
CH2Cl2, 0.1 mL of water, 10 μmol of Pd(MeCN)4(BF4)2.
114
Org. Lett., Vol. 15, No. 1, 2013

The reaction could be initiated by a C2-palladation to give
intermediate II, either via direct concerted metalationÀ
deprotonation (CMD, path a)5i,17 or via electrophilic
palladation at the C3 position to give I, followed by Pd
migration (path b).5c,18 Water or water clusters could play
a key role in promoting this metalationÀdeprotonation
step. The indole Pd complex II can then be oxidatively
alkynylated by TIPS-EBX (2), to give Pd(IV) intermediate
III,19 which undergoes reductive elimination to give the
product 4a and regenerate the Pd(II) catalyst.
Scheme 2. Speculative Mechanism for the Alkynylation
Reaction
In conclusion, we have described the first Pd-catalyzed
alkynylation of indoles proceeding with high C2 regio-
selectivity. The reaction is orthogonal to classical cross-
coupling reactions and has a broad functional group
tolerance on both the indole core and the alkyl substituent
(15) A broad range of other solvents and additives were examined,
but without a positive effect on the reaction outcome. A steady im-
provement in the yield was observed with increasing amounts of TIPS-
EBX (2) up to 3 equiv. Other silyl substituted alkynes gave lower yields,
and no product was observed with aryl or alkyl substituted acetylenes.
See Supporting Information for details.
(16) The required substrates were synthesized using known proce-
dures: (a) Guida, W. C.; Mathre, D. J. J. Org. Chem. 1980, 45, 3172. (b)
Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915. (c) Bode,
J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410. (d) Bressy, C.;
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (e)
Jorapur, Y. R.; Jeong, J. M.; Chi, D. Y. Tetrahedron Lett. 2006, 47, 2435.
See Supporting Information for further details.
on the nitrogen. The mild and neutral reaction conditions
and the tolerance of the process toward air and moisture
lead to a convenient method for the direct C2 alkynylation
of indoles.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(18) Li, Y.; Wang, W.-H.; He, K.-H.; Shi, Z. J. Organometallics 2012,
31, 4397.
Acknowledgment. We thank the EPFL for funding and
F. Hoffmann-La Roche Ltd. for an unrestricted research
grant. The work of G.L.T. was supported by a Sciex-NMSch
fellowship of the Swiss confederation. We thank Dr. Reto
Frei (LCSO, EPFL) for proofreading the manuscript.
(19) (a) Canty, A. J.; Rodemann, T.; Skelton, B. W.; White, A. H.
Organometallics 2006, 25, 3996. For a recent review on high valent metal
catalysis, see: (b) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
The involvement of Pd(IV) or Pd(III) dimers in catalytic cycles is
currently a topic of intensive discussion; see for example: (c) Powers,
D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (d) Powers, D. C.; Lee, E.;
Ariafard, A.; Sanford, M. S.; Yates, B. F.; Canty, A. J.; Ritter, T. J. Am.
Chem. Soc. 2012, 134, 12002.
The authors declare no competing financial interest.
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