Efficient construction of fused indolines with a 2-quaternary center via an intramolecular heck reaction with a low catalyst loading

Article abstract of DOI:10.1021/ol300584m

An efficient construction of fused indolines with a 2-quaternary center through a palladium-catalyzed intramolecular Heck reaction of N-(2(2-halobenzoxyl)-2,3-disubstituted indoles is disclosed. This protocol provided a straightforward access to diverse fused indolines with good functional group tolerance.

Full text of DOI:10.1021/ol300584m

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2066–2069
Efficient Construction of Fused Indolines
with a 2-Quaternary Center via an
Intramolecular Heck Reaction with a Low
Catalyst Loading
Lei Zhao, Ziyuan Li, Lin Chang, Jinyi Xu, Hequan Yao,* and Xiaoming Wu*
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, P. R. China
hyao@cpu.edu.cn (H.Y.); xmwu@cpu.edu.cn (X.W.)
Received March 7, 2012
ABSTRACT
An efficient construction of fused indolines with a 2-quaternary center through a palladium-catalyzed intramolecular Heck reaction of N-(2(2-
halobenzoxyl)-2,3-disubstituted indoles is disclosed. This protocol provided a straightforward access to diverse fused indolines with good
functional group tolerance.
In the past few years, intramolecular direct arylation of
heteroaromatic compounds to synthesize fused hetero-
aromatic products, such as fused indoles, via a radical
pathway (Scheme 1a),1 transition-metal-catalyzed single
CÀH bond activation (Scheme 1a),2,3 or double CÀH
bond activation (Scheme 1b)4 has become a popular
method for building carbonÀcarbon (CÀC) bonds of
complex molecular skeletons. Although palladium-
catalyzed intramolecular arylation at the C2 position of
the C2-unsubstituted heteroaromatic substrates has been
extensively explored, no example using C2-substituted
heteroaromatic compounds as the substrate to build
CÀC bonds at the C2 position has been reported so far.
In 2006, Knochel and co-workers5 reported a novel
approach for the preparation of various condensed pyr-
roles from 2,5-dimethylpyrroles; however, this approach
underwent a chemoselective palladium-catalyzed intramo-
lecular arylation of the methyl group at the C2 position of
the pyrrole ring. Very recently, Rawal et al.6 developed a
palladium-catalyzed benzylation of 2,3-disubstituted in-
doles to furnish CÀC bonds at the C3 position for synthe-
sizing a diverse range of 3-benzylindolenines.7,8 Although
both methods used C2-substituted heteroaromatic com-
pounds as substrates, neither of them generated a CÀC
bond at the C2 position. In this letter, we wish to report a
(1) For radical pathway, see: (a) Antonio, Y.; De La Cruz, E. M.;
Galeazzi, E.; Guzman, A.; Bray, B. L.; Greenhouse, R.; Kurz, L. J.;
Lustig, D. A.; Maddox, M. L.; Muchowski, J. M. Can. J. Chem. 1994, 72,
15. (b) Caddick, S.; Aboutayab, K.; Jenkins, K.; West, R. I. J. Chem.
Soc., Perkin Trans. 1 1996, 7, 675. (c) Kraus, G. A.; Kima, H. Synth.
Commun. 1993, 23, 55.
(2) For excellent reviews, see: (a) Roger, J.; Gottumukkala, A. L.;
Doucet, H. ChemCatChem 2010, 2, 20. (b) Alberico, D.; Scott, N. E.;
Lauten, M. Chem. Rev. 2007, 107, 174. (c) Bellina, F.; Cauteruccio, S.;
Rossi, R. Curr. Org. Chem. 2008, 12, 774. (d) Li, B.-J.; Yang, S. D.; Shi,
Z. -J. Synlett 2008, 949. (e) Serigin, I. V.; Gervogyan, V. Chem. Soc. Rev.
2007, 36, 1173.
(3) For selected examples through single CÀH bond activation, see:
(a) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581. (b) Laha, J. K.; Cunny, G. D. J. Org. Chem. 2011, 76,
8477.
(4) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. Org. Lett. 2007, 9, 3137. (b) Pintori, D. G.; Greaney, M. F. J. Am.
Chem. Soc. 2010, 133, 1209.
(5) (a) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462.
(b) Ren, H.; Li, Z.; Knochel, P. Chem.;Asian J. 2007, 2, 416.
(6) Zhu, Y.; Rawal, V. H. J. Am. Chem. Soc. 2011, 134, 111.
(7) For selected examples of Pd-catalyzed allylation reactions of
3-unsubstituted indoles, see: (a) Bandini, M.; Melloni, A.; Umani-
Ronchi, A. Org. Lett. 2004, 6, 3199. (b) Kimura, M.; Futamata, M.;
Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592. (c) Bandini,
M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi,
A. J. Am. Chem. Soc. 2006, 128, 1424.
r
10.1021/ol300584m
Published on Web 03/30/2012
2012 American Chemical Society

C2-arylation of 2,3-disubstituted indoles through an in-
tramolecular Heck type reaction,9 leading to the formation
of fused indolines with a 2-quarternary center (Scheme 1c),
which are similar to the structural skeleton10 of bioactive
natural products, such as Isatisine A and (À)-Isatisine A.11
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Construction of Fused Indoles or Indolines
catalyst
(mol %)
additive
(equiv)
temp yield
(°C) (%)b
entry
base
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PPh3 (0.2) Cs2CO3
none Cs2CO3
AgOAc (1) Cs2CO3
Ag2O (1) Cs2CO3
120 20
120
7
120 45
120 12
120 32
120 52
120 42
120 99
Ag2CO3 (1) Cs2CO3
AgOAc (1) KOAc
AgOAc (1) K2CO3
AgOAc (1) Na2HPO4
12H2O
3
3
3
3
3
3
3
3
3
3
3
9
PdCl2 (10)
AgOAc (1) Na2HPO4
12H2O
120 76
120 90
100 99
10
11
12
13
14
15
16
Pd(MeCN)2Cl2 (10) AgOAc (1) Na2HPO4
12H2O
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (2)
Pd(OAc)2 (1)
none
AgOAc (1) Na2HPO4
12H2O
AgOAc (1) Na2HPO4
12H2O
80
60
80
80
99
AgOAc (1) Na2HPO4
12H2O
90c
We began our investigation by using N-(2-iodobenzoxyl)-
2,3-dimethylindole 4aa12 as a model substrate. When 4aa
was treated with 10 mol % of Pd(OAc)2, 20 mol % of PPh3,
and 2 equiv of Cs2CO3 in DMF at 120 °C for 12 h, we were
delighted to find that the corresponding product 5a was
afforded in about 20% yield (Table 1, entry 1). The relative
configuration of 5a was determined by an X-ray structural
analysis, showing that the CÀC bond at the C2 postion
and the 3-exo double bond were formed (Figure 1).13
AgOAc (1) Na2HPO4
12H2O
99
(99d)
87c
AgOAc (1) Na2HPO4
12H2O
AgOAc (1) Na2HPO4
12H2O
120 0c
17e Pd(OAc)2 (2)
18f Pd(OAc)2 (10)
AgOAc (1) Na2HPO4
12H2O
80
80d
AgOAc (1) Na2HPO4
12H2O
120 trace
a Reaction conditions: 4aa (0.5 mmol), Pd catalyst, additive, and
base (1 mmol) in DMF (2.0 mL) for 12 h. b 1H NMR yield using
dibromomethane as an internal standard. c 24 h. d Isolated yield. e 4ab
was used as a substrate. f 4ac was used as a substrate.
(8) For reactions of 3-substituted indoles, see: (a) Trost, B. M.;
Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (b) Kagawa, N.;
Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381. (c) Repka,
L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418.
(d) Kieffer, M. E.; Repka, L. M.; Reisman, S. E. J. Am. Chem. Soc. 2012,
134, 5131.
(9) (a) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(b) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
For recent reviews on the Heck reaction, see: (d) Coeffard, V.; Guiry,
P. J. Curr. Org. Chem. 2010, 14, 212. (e) Le Bras, J.; Muzart, J. Chem.
Rev. 2011, 111, 1170. (f) Oestreich, M. The MizorokiÀHeck Reaction;
Wiley: Chichester, U.K., 2009.
(10) For constructing similar indole skeletons by intramolecular
carbopalladation of allenes followed by nucleophilic substitution, see:
Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.; Kato, F.; Hiroi, M.
Synlett 2001, 263.
(11) For the isolation of isatisines, see: (a) Liu, J. F.; Jiang, Z. Y.;
Wang, R. R.; Zheng, Y. T.; Chen, J. J.; Zhang, X. M.; Ma, Y. B. Org.
Lett. 2007, 9, 4127. For the recent total synthesis of isatisines, see: (b)
Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2010, 49, 1133. (c)
Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830. (d) Lee, J.;
Panek, J. S. Org. Lett. 2011, 13, 502. (e) Zhang, X.; Mu, T.; Zhan, F. X.;
Ma, L. J.; Liang, G. X. Angew. Chem., Int. Ed. 2011, 50, 6164. (f) Wu,
W.; Xiao, M.; Wang, J.; Li, Y.; Xie, Z. Org. Lett. 2012, 14, 1642.
(12) See the Supporting Information for the preparation of the
substrates.
Very interestingly, the reaction could take place even with-
out a phosphine ligand (entry 2). Encouraged by these
results, a variety of additives, catalysts, and reaction tem-
peratures were then evaluated to optimize the reaction
conditions as shown in Table 1. First, we found that the
addition of silver salt, such as Ag2CO3, Ag2O, and AgOAc
(entries 3À5), could enhance the yield of 5a.14 Next screen-
ing of bases revealed that the yield of 5a was increased to
(13) The crystallographic data for 5a have been deposited at the
Cambridge Crystallographic Data Centre with deposition No. CCDC
861219.
(14) Silver salts were proved to enhance the cross-coupling efficiency;
see: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(b) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
(c) Xu, D.; Lu, C.; Chen, W. Tetrahedron 2012, 68, 1466.
Org. Lett., Vol. 14, No. 8, 2012
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99% when Na2HPO4 12H2O was employed (entries 6À8).
3
Further trials using other palladium catalysts such as PdCl2
and Pd(MeCN)2Cl2 led to no improvement in the reaction
performance (entries 9, 10). A survey of reaction tempera-
ture showed that this reaction proceeded efficiently at 100
and 80 °C, while a longer reaction time was needed at 60 °C
(entries 11À13). Gratifyingly, this reaction was also
quite effective with a low catalyst loading (entries 14, 15).
A control experiment confirmed that a palladium catalyst
was necessary to promote this reaction (entry16). This
reaction using N-(2-bromobenzoxyl)-2,3-dimethylindole
4ab as a substrate also proceeded smoothly to give 5a
in good yield, while it failed for N-(2-chlorobenzoxyl)-
2,3-dimethylindole 4ac (entries 17, 18).
Scheme 2. Substrate Scopea,b
Figure 1. X-ray crystal structure of fused indoline 5a.
With the optimized conditions established, we then
investigated the substrate scope and generality of this
method. We first examined the substituent effect on the
benzene ring in the indole part of N-(2-iodobenzoxyl)-2,3-
dimethylindoles. As shown in Scheme 2, a variety of
functional groups, such as hydrogen, electron-donating
and -withdrawing groups, and halogen were compatible
with this intramolecular cross-coupling reaction. The sub-
strates (4aaÀ5ga) bearing hydrogen or electron-donating
groups such as methyl, ethyl, i-propyl, n-butyl, or methox-
yl could afford the desired products in excellent yields.
In addition, the halogen substituted substrates (4haÀ5ja)
could also be converted into the desired products in
satisfactory yields. It is noteworthy that the chloro and
bromo substituted substrates could survive under the
optimized conditions. The reaction on the substrate with
an electron-withdrawing subsituent, such as CF3 (4ka) on
the benzene ring, proceeded smoothly to provide the
coupling product in 90% yield, although an increased
catalyst loading was needed. Furthermore, the intramole-
cular cross-couping reactions on N-(2-bromobenzoxyl)-2,
3-dimethylindoles (4abÀ4jb) were also very effective to
afford the desired products in excellent yields.
a Reaction conditions: 4 (0.5 mmol), Pd(OAc)2 (2 mol %), AgOAc
(0.5 mmol), and Na2HPO4 12H2O (1 mmol) in DMF (2.0 mL) at 80 °C
3
for 12 h. bIsolated yield. c120 °C. dPd(OAc)2 (10 mol %) was used.
ePd(OAc)2 (5 mol %) was used.
resulted in lower yields of the correspoding products
(7a, 7b), steric hindrance at the C3 position exhibited little
influence on the reaction yield (7c). It should be noted that
all 2-phenyl substrates reacted very smoothly to furnish the
desired fused indolines (7dÀ7i) in excellent yields, despite
different types of substituents being introduced on this
phenyl ring.
According to the fact that the combination of Pd(OAc)2
and the phosphine ligand worked well for this palladium-
catalyzed intramolecular cross-coupling reaction, we pro-
posed that our protocol might be initiated by Pd(0) species
as outlined in Scheme 4.14c,16 First, oxidative addition of
Next, we investigated the substituent effect at the 2- or
3-position of indole as illustrated in Scheme 3. We were
pleased to find that all substrates in Scheme 3 could under-
go the cross-coupling reaction under the optimized condi-
tions, resulting in the corresponding products in moderate
to excellent yields (6aÀ7i). Although steric hindrance at the
C2 position of the 2-alkyl substituted indoles 6a and 6b
(15) See the Supporting Information.
(16) For selected review, see: (a) Beletskaya, I. P.; Cheprakov, A. V.
Chem. Rev. 2000, 100, 3009. For selected examples, see: (b) Magill,
A. M.; McGuinness, D. S.; Cacell, K, J; Britovsek, G. J. P; Gibson, V. C.;
White, A. J. P.; William, D. J.; White, A. H.; Skelton, B. W.
J. Organomet. Chem. 2001, 617À618, 546. (c) Liu, H.; Chen, C.; Wang,
L.; Tong, X. Org. Lett. 2011, 13, 5072.
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Org. Lett., Vol. 14, No. 8, 2012

Scheme 3. Substrate Scopea,b
Scheme 4. Plausible Mechanism
loading. This transformation is effective for 2,3-disub-
stituted indoles with good functional group tolerance.
We anticipate that this methodology would find many
applications in the synthesis of complex natural prod-
ucts. Research on the detailed reaction mechanism,
extension to other heteroaromatic substrates, and enan-
tioselective synthesis of this protocol are currently under-
way in our laboratory.
a Reaction conditions: 6 (0.5 mmol), Pd(OAc)2 (2 mol %), AgOAc
(0.5 mmol) and Na2HPO4 12H2O (1 mmol) in DMF (2.0 mL) at 80 °C
3
for 12 h. bIsolated yield. cInseperable mixture, E/Z = 10:1 (determined
by 1H NMR and NOE).15
the Pd(0) species to substrate 4aa forms Pd(II) intermedi-
ate A (ArÀPdI), followed by a silver-mediated anion
exchange to generate Pd(II) intermediate B (Ar-PdOAc).
Next, intramolecular coordination of the olefin of the
indole part to the palladium center and transmetallation
provide intermediate C. Finally, C undergoes a reductive
elimination to afford the desired product 5a and HPdOAc,
which is neutralized with base to give Pd(0) to complete the
catalytic cycle.
In conclusion, we have demonstrated a highly efficient
approach to construct fused indolines with a newly
formed C2-quaternary center and 3-exo double bond
via an intramolecular Heck reaction with a low catalyst
Acknowledgment. This research was supported by the
State Key Laboratory of Natural Medicines (JKGZ201110
for HY), NCET-2008, PCSIRT-IRT1193 and Fundamental
Research Funds for the Central Universities (JKZ2009002
for H.Y.). We thank Youla Su in this group for reproducing
the reactions of 4ba and 4ha in Scheme 2.
Supporting Information Available. Experimental pro-
cedures and characterization of all title compounds
(5aÀ5k, 7aÀ7i). This material is available free of charge
via Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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