Palladium-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp3)-H activation: Concise synthesis of indole derivatives

Article abstract of DOI:10.1021/ol302035j

Synthesis of the indole skeleton was achieved using a Pd-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp³)-H activation. It was found that slow addition of isocyanide is effective for reducing the amount of catalyst needed and Ad₂PⁿBu is a good ligand for C(sp³)-H activation. The construction of the tetracyclic carbazole skeleton was also achieved by a Pd-catalyzed domino reaction incorporating alkyne insertion.

Full text of DOI:10.1021/ol302035j

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4270–4273
Palladium-Catalyzed Cascade Process
Consisting of Isocyanide Insertion and
Benzylic C(sp3)ÀH Activation: Concise
Synthesis of Indole Derivatives
Takeshi Nanjo, Chihiro Tsukano, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received July 23, 2012
ABSTRACT
Synthesis of the indole skeleton was achieved using a Pd-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp3)ÀH
activation. It was found that slow addition of isocyanide is effective for reducing the amount of catalyst needed and Ad2PnBu is a good ligand for
C(sp3)ÀH activation. The construction of the tetracyclic carbazole skeleton was also achieved by a Pd-catalyzed domino reaction incorporating
alkyne insertion.
C(sp3)ÀH functionalization, the transformation with
cleavage of an sp3-CÀH bond, is one of the most direct
and effective approaches for the construction of mole-
cules.1 Much effort has been focused on the development
of C(sp3)ÀH activation, and methods using palladium
catalysts have been developed by many groups, includ-
ing ours.2À5 Generally, palladium-catalyzed C(sp3)ÀH
activation can be divided into three catalytic sys-
tems: Pd(0)/(II),2,3 Pd(II)/Pd(0),4 and Pd(II)/Pd(IV).5 The
Pd(0)/Pd(II) catalystsystem initiated byoxidative addition
to aryl halides is expected to be very useful because it
enables cascade processes. Cascade processes combining
many steps are powerful tools for the concise syntheses of
complicated frameworks.6 However, almost all reactions
in previous reports involving C(sp3)ÀH activation can be
categorized as simple C(sp3)ÀH functionalizations con-
sisting of oxidative addition, C(sp3)ÀH activation, and
reductive elimination (Scheme 1a). To the best of our
(2) For selected examples of C(sp3)ÀH activation using a Pd(0)/(II)
catalyst system, see: (a) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.;
Baudoin, O. Chem.;Eur. J. 2012, 18, 4480. (b) Saget, T.; Lemouzy, S. J.;
Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 2238. (c) Rousseaux, S.;
ꢀ
Liegault, B.; Fagnou, K. Chem. Sci. 2012, 3, 244. (d) Pan, J.; Su, M.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8647. (e) Nakanishi,
€
M.; Katayev, D.; Besnard, C.; Kundig, E. Angew. Chem., Int. Ed. 2011,
ꢀ
50, 7438. (f) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.; Kefalidis, C. E.;
Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261. (g)
Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis,
C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132,
10706. (h) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K .W.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 10692. (i) Wasa, M.; Engle, K. M.; Yu,
J.-Q. J. Am. Chem. Soc. 2009, 131, 9886. (j) Chaumontet, M.; Piccardi, R.;
Audic, N.; Hitce, J.; Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem.
Soc. 2008, 130, 15157. (k) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H.
Org. Lett. 2008, 10, 1759. (l) Campeau, L.-C.; Schipper, D. J.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 3266. (m) Lafrance, M.; Gorelsky, S. I.;
Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (n) Ren, H.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 3462. (o) Dong, C.-G.; Hu, Q.-S.
Angew. Chem., Int. Ed. 2006, 45, 2289. (p) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (q)
(1) For recent reviews on C(sp3)ÀH activation, see: (a) Baudoin, O.
Chem. Soc. Rev. 2011, 40, 4902. (b) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci.
Technol. 2011, 1, 191. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem.
Soc. Rev. 2011, 40, 1885. (d) Gutekunst, W. R.; Baran, P. S. Chem. Soc.
Rev. 2011, 40, 1976. (e) Ackermann, L. Chem. Rev. 2011, 111, 1315. (f)
Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem.;Eur. J. 2010, 16, 2654.
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Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003, 42,
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r
10.1021/ol302035j
Published on Web 07/31/2012
2012 American Chemical Society

knowledge, palladium-catalyzed cascade reactions con-
taining a C(sp3)ÀH activation step have not been investi-
gated, despite its potential usefulness; there is only one
specific example using insertion into the olefin bond of
norbornene.2r
(Scheme 1b). o-Methylphenyl isocyanide and an aryl
halide in the presence of a palladium catalyst would be
transformed into a 2-arylindole via a cascade consisting of
oxidative addition to the aryl halide, isocyanide insertion,
C(sp3)ÀH activation at the benzylic position, and reduc-
tive elimination. Upon comparison with other synthetic
methods for the indole skeleton,9 which is an impor-
tant nitrogen-containing heterocycle in pharmaceutical
sciences, our strategy has several advantages: (1) the
divergent synthesis of 2-arylindoles can be achieved by
changing the coupling partners; (2) the synthetic method
involving formation of a CÀC bond between the 2- and
3-positions of the indole is unique,10 particularly in palla-
dium-catalyzed syntheses;11 (3) the starting materials are
simple. To realize our idea, it was essential to overcome the
problem of isocyanide coordination to palladium, which
would hamper the palladium-catalyzed cascade process,
including C(sp3)ÀH activation. Here we report the use of a
combination of palladium-catalyzed isocyanide insertion
and C(sp3)ÀH activation as an effective procedure for the
construction of the heterocycles including the indole ske-
leton, with multibond formation.
Scheme 1. Strategy for Single and Multiple CÀC Bond For-
mation via C(sp3)ÀH Activation
Our initial efforts focused on optimization of the reac-
tion conditions using 2,6-dimethylphenyl isocyanide 1a
and iodobenzene 2a as test substrates (Table 1). Treatment
of 1a and 2a with stoichiometric amounts of palladium
acetate, tricyclohexylphosphine, which is known to be
effective for C(sp3)ÀH activation,2 and Cs2CO3 in DMF
at 100 °C gave the desired product 3a in 66% yield (entry 1).
When the amount of catalyst was decreased to 20 mol %,
the reaction proceeded to give 3a in 46% yield (entry 2).
Next, several ligands, including the bidentate ligand
(DPPF), the biphenyl-type ligand (biphPCy2), and bulkier
ligands (PtBu3 and Ad2PnBu12), were screened, and it was
found that Ad2PnBu effectively increased the yield (entries
3À6).3 However, lowering the amount of catalyst had a
negative impact on the yield (entry 7). Some reports on the
use of isocyanides have shown that an excess of isocyanide
deactivates the catalyst by forming palladium clusters.13
We assumed that the low conversions in the reactions were
Recently, several groups reported the cascade process
containing palladium-catalyzed isocyanide insertion and
C(sp2)ÀH activation for consice syntheses of carbo- and
heterocycles.7 While Jones and co-workers described the
indole formation from 2,6-disubstituted isocyanide via
Ru-catalyzed C(sp3)ÀH activation,8 there is no synthesis
of heterocycles using a combination of palladium-catalyzed
isocyanide insertion and C(sp3)ÀH activation. We believed
that this combination would enable concise syntheses of
various nitrogen-containing heterocycles and initially de-
signed the following cascade process based on this concept
(3) For recent work in our laboratory, see: Tsukano, C.; Okuno, M.;
Takemoto, Y. Angew. Chem., Int. Ed. 2012, 51, 2763.
(4) For selected examples of C(sp3)ÀH activation using a Pd(II)/(0)
ꢀ
catalyst system, see: (a) Novak, P.; Correa, A.; Gallardo-Donaire, J.;
ꢀ
(9) For recent reviews on the syntheses of indoles, see: (a) Mei, T.-S.;
Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis 2012, 44, 1778. (b)
Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (c) Cacchi,
S.; Fabrizi, G. Chem. Rev. 2011, 111, DOI: 10.1021/cr100403z. (d) Song,
J. J.; Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. ARKIVOC 2010, 390. (e) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875.
(10) For selected examples on the syntheses of indoles with the
formation of CÀC bond between 2- and 3-position, see: (a) Seong,
C. M.; Park, C. M.; Choi, J.; Park, N. S. Tetrahedron Lett. 2009, 50,
1029. (b) Lee, S.; Lee, W.-M.; Sulikowski, G. A. J. Org. Chem. 1999, 64,
4224. (c) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Martin, R. Angew. Chem., Int. Ed. 2011, 50, 12236. (b) Liegault, B.;
Fagnou, K. Organometallics 2008, 27, 4841. (c) Wang, D.-H.; Wasa, M.;
Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (d) Delcamp, J. H.;
White, M. C. J. Am. Chem. Soc. 2006, 128, 15076.
(5) For selected examples of C(sp3)ÀH activation using a Pd(II)/(IV)
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ꢀ
ꢀ
~
catalyst system, see: (a) Iglesias, A.; Alvarez, R.; de Lera, A. R.; Muniz,
K. Angew. Chem., Int. Ed. 2012, 51, 2225. (b) He, G.; Zhao, Y.; Zhang,
S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (c) Ano, Y.; Tobisu,
M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (d) He, G.; Chen,
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Org. Lett., Vol. 14, No. 16, 2012
4271

caused by such catalyst deactivation, so slow addition of
isocyanide was adopted as a standard procedure (entries
8À12). Asa result, catalystloadings aslow as5 mol % were
sufficient for complete conversion (entry 10). Further
screening revealed that toluene was the best solvent
(entry 12).
a substrate with no substituent at one side of the ortho
position of the isocyanide (i.e., 2,4-dimethylphenyl iso-
cyanide) resulted in no reaction, probably because of the
instability of less hindered isocyanides7a,14 and the flexible
conformation of the reaction intermediate (3r).
Scheme 2. Substrate Scopea,b
Table 1. Investigation of Reaction Conditions
entry
x
ligand (mol %)
solvent
DMF
yielda
1
100
20
20
20
20
20
10
20
10
5
PCy3•HBF4(200)
PCy3•HBF4(40)
DPPF(20)
66%
2b
3
DMF
(46%)
N.D.
N.D.
trace
(54%)
trace
(65%)
(62%)
54%
DMF
4
biphPCy2(40)
PtBu3•HBF4(40)
Ad2PnBu(40)
Ad2PnBu(20)
Ad2PnBu(40)
Ad2PnBu(20)
Ad2PnBu(10)
Ad2PnBu(10)
Ad2PnBu(10)
DMF
5b
6
DMF
DMF
7
DMF
8c
9c
10c
11c
12c
DMF
DMF
DMF
5
1,4-dioxane
toluene
54%
5
81%
a Isolated yield (GC yield in parentheses). b 1.6 equiv of Cs2CO3 was
used. c Isocyanide 1a was added dropwise to the solution of PhI,
Pd(OAc)2, Ad2PnBu, and Cs2CO3 by using syringe pump. biph =
2-biphenyl, Ad = 1-adamantyl, N.D. = Not detected.
a Isolated yield. bIsocyanides were added dropwise to the solution of
ArX, Pd(OAc)2, Ad2PnBu, and Cs2CO3 by using syringe pump. c5 mol %
of Pd(OAc)2 and 10 mol % of Ad2PnBu were used. Ad = 1-adamantyl,
N.D. = Not detected.
Weinvestigatedthesubstrate scopeofthereactionunder
the optimal conditions (Scheme 2). Initially, various aryl
halides were used as the coupling partner. The reactions of
aryl iodides bearing a variety of electron-withdrawing and
-donating groups at the para position gave the desired
products 3bÀh in moderate to good yields. Introducing a
methyl group at the meta position maintained a high yield,
but methyl substitution at the ortho position decreased the
yield (3i and 3j). Bromobenzene was also successfully
transformed to the indole 3a in 73% yield, but chloroben-
zene did not react. Not only a benzene ring but also
heteroaromatic rings, such as thiophenes and pyrroles,
could be introduced at the 2-position of indoles 3k and
3l. Then the reaction was performed using various aryl
isocyanides. The reactions of isocyanides bearing nitro and
methoxy groups gave 3m and 3n in 77% and 85% yields,
respectively. When one methyl group at the ortho position
of the isocyanide was replaced by other groups such as
chloro and ethyl groups, a CÀH bond of the methyl group
selectively reacted to give the desired products 3o and 3p as
single products. In contrast, diethylphenyl isocyanide did
not give indole 3q via CÀH activation of methylene. Use of
Scheme 3. Domino Reaction Using o-Alkynylphenyl Isocyanide
To extend the synthetic scope of the cascade process via
palladium-catalyzed isocyanide insertion and C(sp3)ÀH
activation, we attempted the following domino reaction
(Scheme 3). o-Alkynylphenyl isocyanide and iodo-2,6-
dimethylbenzene in the presence of a palladium catalyst
would couple to give a tetracyclic carbazole via a cascade
process consisting of oxidative addition to iodobenzene,
sequential insertions of isocyanide and alkyne, C(sp3)ÀH
activation at the benzylic position, and reductive elimina-
tion. Under the optimal conditions, using Pd(OAc)2,
Ad2PnBu, and Cs2CO3 in toluene at 100 °C, this reaction
gave the desired product 4a but the conversion was low
ꢀꢁ
(14) (a) Baelen, G. V.; Kuijer, S.; Rycek, L.; Sergeyev, S.; Janssen, E.;
de Kanter, F. J. J.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Chem.;
Eur. J. 2011, 17, 15039. (b) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.;
de Kanter, F. J. J.; Maes, B. U. W.; Orru, R. V. A. Org. Lett. 2011, 13,
6496.
4272
Org. Lett., Vol. 14, No. 16, 2012

obtained in 66% yield. The structure of carbazole 4a was
determined using X-ray crystallography.15
Scheme 4. Investigation of Domino Reaction
In this reaction, bromo-2,6-dimethylbenzene (X = Br),
instead of iodo-2,6-dimethylbenzene (X = I), can be used
as the substrate; the electronic state of the alkyne did
not significantly influence the yields of carbazoles 4aÀc
(R = Ph, NO2C6H4, MeOC6H4) (Scheme 4, eq 1).
Furthermore, this strategy can be applied to the synthesis
of indolo[2,3-a]carbazole derivatives, which have interest-
ing biological effects.16 Using 1-Boc-2-bromoskatole as
the substrate, the desired carbazole 5 was obtained in 36%
yield (eq 2). These results were the first example of
a palladium-catalyzed domino reaction containing a
C(sp3)ÀH activation step.
In summary, we have developed a palladium-catalyzed
cascade process involving C(sp3)ÀH activation and iso-
cyanide insertion for the construction of 2-arylindoles and
polycyclic nitrogen-containing compounds such as benzo-
and indolo-carbazoles. Inthe reaction, formation of two or
three CÀC bonds was achieved byavoiding deactivation of
the Pd catalyst. We are currently extending this strategy to
give a comprehensive approach to the synthesis of nitro-
gen-containing polycycles.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on the Innovation
Area “Molecular Activation Directed toward Straightfor-
ward Synthesis” from The Ministry of Education, Culture,
Sports, Science and Technology, Japan (C.T.), and JSPS
Research Fellowships for Young Scientists (T.N.).
(Scheme 4, eq 1). This is probably because the reaction
proceeded via a seven-membered palladacycle, which is
less favored than five- or six-membered palladacycles.
In contrast, the addition of catalytic amounts of PivOH
and PivNHOH, which have been reported to promote
C(sp3)ÀH activation,2m,3 effectively accelerated the reaction,
and when PivOH was used, tetracyclic carbazole 4a was
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) See Supporting Information.
(16) For recent reviews on the indolocarbazole derivatives, see: (a)
€
Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012, 112,
€
3193. (b) Janosik, T.; Wahlstrom, N.; Bergman, J. Tetrahedron 2008, 64,
9159.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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