Novel palladium-catalyzed acyloxylation/cyclization of 2-(3′-alkenyl) indoles

Article abstract of DOI:10.1021/ol9007348

A new and mild palladium(II)-catalyzed reaction for the intramolecular acyloxylation/cyclization of 2-(3′-alkenyl)indoles was developed. The newly formed cycles involve oxygen-containing functionalized groups, which might be transferred further to provide other indole derivatives.

Full text of DOI:10.1021/ol9007348

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2381-2384
Novel Palladium-Catalyzed
Acyloxylation/Cyclization of
2-(3′-Alkenyl)indoles
Xiuling Han and Xiyan Lu*
College of Chemistry, Chemical Engineering and Materials Science,
Soochow UniVersity, Suzhou 215123, People’s Republic of China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai, 200032, People’s Republic of China
xylu@mail.sioc.ac.cn
Received February 5, 2009
ABSTRACT
A new and mild palladium(II)-catalyzed reaction for the intramolecular acyloxylation/cyclization of 2-(3′-alkenyl)indoles was developed. The
newly formed cycles involve oxygen-containing functionalized groups, which might be transferred further to provide other indole derivatives.
Owing to the potent and diverse biological activity
exhibited by various indole derivatives, this heterocyclic
system has attracted considerable attention in chemistry
and medicinal chemistry.1 There are some reports related
to the synthesis of indole derivatives, including fused
polycyclic indoles and carbazoles catalyzed by platinu-
m(II)2 or palladium(II)3 using the substituted indoles with
an unactivated olefin as the substrate. In these reactions,2,3
one of the possible pathways involves nucleophilic attack
of the indole on a metal-coordinated olefin followed by
protonolysis, alkoxycarbonylation, or ꢀ-hydride elimination
(initiated by carbometalation). Another possible pathway is
functionization of the C-H bond of indole followed by olefin
insertion and ꢀ-hydride elimination (initiated by C-H bond
functionization). The reason for the success of all these
reactions lies in the fact that indole rings are electron-rich,
and thus they can easily act as nucleophiles. In most of these
reactions catalyzed by Pd(II) species, ꢀ-hydride elimination
is usually the last step, and no other nucleophiles participate.
Herein, we report a mild, novel, Pd(II)-catalyzed cyclization
of 2-(3′-alkenyl)indoles, in which some nucleophiles, includ-
ing organic acids or pentafluorophenol, can be introduced.
(1) (a) Sundberg, R. J. Chemistry of Indoles; Academic Press: New York,
1970. (b) Houlihan, W. J., Ed. Indoles; Wiley-Interscience: New York, 1972;
Part 1. (c) Saxton, J. E., Ed. Indoles; Wiley-Interscience: New York, 1983;
Part IV. (d) Saxton, J. E. Nat. Prod. Rep. 1997, 559. (e) Sundberg, R. J.
Indoles; Academic Press: San Diego, CA, 1996.
We have recently reported the Pd(II)-catalyzed oxidative
cyclization of 3-(3′-alkenyl)indoles to form carbazoles
(Scheme 1).3j The reactions of indoles with substitution at
the C-3 position proceeded smoothly and had good results.
However, when we conducted the reaction using a C-2
-substituted substrate, 2-(3′-alkenyl)indole (1a), under the
same conditions, the reaction was more complex to give
carbazole 4aa and another product, 3aa4 (Scheme 2).
(2) (a) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2004, 126, 3700. (b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8,
3801.
(3) (a) Trost, B. M.; Godleski, S. A.; Geneˆt, J. P. J. Am. Chem. Soc.
1978, 100, 3930. (b) Trost, B. M.; Fortunak, J. M. D. Organometallics
1982, 1, 7. (c) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am.
Chem. Soc. 1993, 115, 9323. (d) Baran, P. S.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 7904. (e) Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am.
Chem. Soc. 2003, 125, 5628. (f) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem.
Soc. 2003, 125, 9578. (g) Beccalli, E. M.; Broggini, G. Tetrahedron Lett.
2003, 44, 1919. (h) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2004, 126, 10250. (i) Liu, C.; Widenhoefer, R. A. Chem. Eur.
J. 2006, 12, 2371. (j) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339.
From the structure of 3aa, it was not difficult to determine
that acetic acid, which served as cosolvent, participated in
the reaction and acted as a nucleophile. In previous literature
10.1021/ol9007348 CCC: $40.75
Published on Web 05/06/2009
 2009 American Chemical Society

to 1a) (Table 1, entry 4). Almost the same result was obtained
when using 10 equiv of acetic acid instead of using 20 equiv
(Table 1, entry 5). Further decreasing the amount of the acid
to 2 equiv slowed down the reaction dramatically (Table 1,
entry 6). In this reaction, the oxidant used was very
important; benzoquinone (BQ) showed a good effect here.
When the amount of benzoquinone was decreased to 1.2
equiv, the yield of 3aa was only 40% (Table 1, entry 8).
Thus, the use of 1.8 equiv of BQ was selected in our
reactions. No product was detected in the presence of other
oxidants such as CuCl2 or Cu(OAc)2. When the benzo-
quinone/MnO2 system was used to decrease the amount of
benzoquinone,5 product 3aa could not be successfully
obtained at room temperature, but the reaction did occur
when the temperature was raised to 50 °C (Table 1, entries
11-14). In the absence of Pd(OAc)2, no reaction occurred.
Most of the polar solvents such as THF, DMF, and CH3CN
were ineffective in the reaction. Reaction in 1,2-dichloroet-
hane gave a yield of 3aa (68%) similar to that in toluene.
Finally, the following reaction conditions were chosen as
our optimal conditions: 0.3 mmol of 2-(3′-alkenyl)indole,
10 equiv of nucleophile, 5 mol % of Pd(OAc)2, and 1.8 equiv
of BQ in 3 mL of toluene at room temperature for 8 h.
Next, other nucleophiles were examined in this reaction.
There was a large variation in yields with respect to the
different nucleophiles. While acetic acid, pentafluorophenol,
and o-nitrobenzoic acid afforded the corresponding products
in good yields (Table 2, entries 1, 7, and 8), halo-substituted
acetic acid, n-butyric acid, acrylic acid, and benzoic acid
gave moderate yields (Table 2, entries 2-6). Phenol and
benzyl alcohol were unsuccessful as nucleophiles under the
reaction conditions. From these results, it was obvious that
the pKa value of the nucleophiles seems to be an important
factor, and acids with pKa values close to that of acetic acid
were the best. In addition, some N-containing compounds
such as p-toluenesulfonamide, phthalimide, and dipheny-
lamine were also investigated, but they were all unreactive.
Then the influence of the substituents R on the nitrogen atom
of indole was studied. Indoles with electron-donating groups
on nitrogen such as benzyl and methyl groups gave similar
results (Table 2, entries 1 and 12), but the electron-
withdrawing benzoyl group on nitrogen hindered the cy-
clization reaction (Table 2, entry 13), showing the influence
on the electronic density of carbon atoms of indoles through
the electron transfer from the nitrogen atom. Indole with
unprotected N-H (1b) did not inhibit the reaction and gave
the desired compound in good yield as well (Table 2, entry
11). In all of the experiments shown in Table 2, byproducts
such as 4aa (less than 10%) were also produced, which
cannot be inhibited completely at the present time.
Scheme 1
.
Pd(II)-Catalyzed Oxidative Cyclization of
3-(3′-Alkenyl)indoles
for the intramolecular cyclization of alkenylindoles, such
phenomena have never been reported. This intrigued us to
focus our attention on improving the formation of 3aa.
Scheme 2
.
Pd(II)-Catalyzed Oxidative Cyclization of
2-(3′-Alkenyl)indoles
To our delight, when the reaction was carried out at room
temperature, the yield of 3aa was raised from 33% to 56%,
Table 1. Palladium-Catalyzed Reaction of 1a and Acetic Acid
in Toluene with Different Conditionsa
yield (%)b
amt of HOAc
(equiv)
oxidant
temp (°C)/
entry
(amt (equiv))
time (h)
3aa 4aa
1
2
3
4
33
33
33
20
10
2
BQ (2.1)
BQ (1.8)
BQ (1.8)
80/2
room temp/8
10/30
33 42
56 33
trace
BQ (1.8)
BQ (1.8)
BQ (1.8)
room temp/8
room temp/10 71 trace
room temp/30 trace
73 trace
5
6
7c
8
as solvent
BQ (1.8)
BQ (1.2)
room temp/20 complicated
room temp/20 40 trace
10
10
10
10
10
10
10
9
CuCl2 (2.2)
Cu(OAc)2 (2.2)
BQ/MnO2 (0.2/1.2) room temp/30
BQ/MnO2 (0.2/1.2) 50/15
BQ/MnO2 (0.1/1.2) room temp/30
BQ/MnO2 (0.1/1.2) 50/20
room temp/30
room temp/30
NR
NR
trace
60 20
trace
68 10
10
11
12
13
14
a Reaction was performed with 1a (0.3 mmol) in the presence of
Pd(OAc)2 (0.015 mmol) in toluene (3 mL). b Isolated yield. c HOAc was
the only solvent.
while the time required was somewhat longer (Table 1,
entries 1 and 2). When the reaction was performed at lower
temperature (10 °C), only a trace of 3aa was formed, and
most of the starting material remained even after 30 h (Table
1, entry 3). Fortunately, a 73% yield of 3aa was obtained
when the ratio of solvent was changed from toluene:HOAc
) 4:1 (the amount of HOAc was 33 equiv with respect to
1a) to 9:1 (the amount of HOAc was 20 equiv with respect
Indoles 1e and 1f were also tried. Compound 1e can react
with acetic acid smoothly at 40 °C, just like the substrate
1b, but its methylated derivative 1f does not react even when
the temperature was raised to 100 °C (Scheme 3). The
presence of the olefinic methyl group in substrates 1 is
(5) (a) Ba¨ckvall, J. E.; Hopkins, R. B.; Grennberg, H.; Mader, M. M.;
Awasthi, A. K. J. Am. Chem. Soc. 1990, 112, 5160. (b) Heumann, A.;
˚
(4) The structure of 3aa was confirmed by X-ray crystallography.
Akermark, B.; Hansson, S.; Rein, T. Org. Synth. 1990, 68, 109.
2382
Org. Lett., Vol. 11, No. 11, 2009

reacted in the presence of 2.1 equiv of BQ and 5 mol % of
Pd(OAc)2 in the solvent (toluene:HOAc ) 4:1) at 80 °C
overnight, 4aa was obtained in 40% yield. No reaction
occurred in the case without Pd(OAc)2 and BQ. On the other
hand, when the 3-substituted indole 5 was used to conduct
the reaction at room temperature, the same carbazole product,
which is identical with that produced at 80 °C,3j was obtained
in low yield without the formation of acetoxypalladation
product (Scheme 3). These results showed that the reaction
behaviors of 2- and 3-substituted3j indoles are different,
which may be due to the different reactivities of the C-2
and C-3 of indoles.
Table 2. Palladium-Catalyzed Reactions of 1 with Different
Nucleophilesa
entry
indole
nucleophile (NuH)
yield, %b
In the reported palladium-catalyzed reactions in the
presence of BQ, there are two roles played by BQ:6 (1) it
serves as the oxidant, resulting in the formation of Pd(II)
species and hydroquinone; (2) it can also act as a ligand to
stabilize the Pd species present in the catalytic cycle. To
examine the role of BQ in our reaction, we conducted two
experiments in the presence of a stoichiometric amount of
Pd(OAc)2 with or without BQ, and it was surprising that a
totally different result was obtained. In the presence of a
stoichiometric amount of BQ, the acyloxypalladation product
3aa was obtained just as previously mentioned, but only
carbopalladation product 4aa was produced in the absence
of BQ (Scheme 4). These results suggest that BQ may have
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
CH3COOH (2a)
BrCH2COOH (2b)
ClCH2COOH (2c)
CH2dCHCOOH (2d)
n-C3H7COOH (2e)
C6H5COOH (2f)
o-NO2-C6H4COOH (2g)
C6F5OH (2h)
71 (3aa)
52 (3ab)
55 (3ac)
32 (3ad)
42 (3ae)
38 (3af)
64 (3ag)
74 (3ah)
0 (3ai)
2c
3c
4
5d
6
7
8e
9
C6H5OH (2i)
10
11f
12
13
C6H5CH2OH (2j)
CH3COOH (2a)
CH3COOH (2a)
CH3COOH (2a)
0 (3aj)
70 (3ba)
64 (3ca)
trace (3da)
a A solution of 1 (0.3 mmol, 1.0 equiv), Pd(OAc)2 (0.015 mmol, 0.05
equiv), BQ (0.54 mmol, 1.8 equiv) and nucleophile (10 equiv) in toluene
(3 mL) was stirred for 8 h at room temperature. b Isolated yield. c The amount
of NuH was 1.2 equiv with respect to 1a. d The reaction time was 72 h.
e The amount of 2h was 2 equiv with respect to 1a. f The reaction
temperature was 40 °C.
Scheme 4
.
Stoichiometric Reaction of Pd(OAc)2 and 1a in the
Presence or Absence of Benzoquinone
important in yielding products 3 with high selectivity, similar
to their influence in yielding carbazoles from 3-(3′-
alkenyl)indoles.3j When the reaction of substrate 1g was
Scheme 3
a special function as a π-acid ligand here. It might act to
transfer the pathway of this reaction from carbopalladation
to acyloxypalladation. Then another π-acid ligand, maleic
anhydride (MA),7 was used to perform the above stoichio-
metric reaction again, and the acyloxypalladation product
3aa was also obtained similarly (Scheme 4).
From Scheme 4, it is obvious that BQ or MA is the key
in our cyclization reactions, as illustrated in Scheme 5.
(6) (a) Roffia, P.; Conti, F.; Gregorio, G.; Pregaglia, G. F.; Ugo, R. J.
Organomet. Chem. 1973, 56, 391. (b) Ba¨ckvall, J. E.; Andersson, P. J. J. Am.
Chem. Soc. 1992, 114, 6374. (c) Grennberg, H.; Gogoll, A.; Ba¨ckvall, J. E.
Organometallics 1993, 12, 1790. (d) Jia, C.; Kitamura, T.; Fujiwara, Y.
Org. Lett. 1999, 1, 2097. (e) Boele, M. D. K.; van Strijdonck, G. P. F.; de
Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M.
J. Am. Chem. Soc. 2002, 124, 1586.
carried out under the same conditions, no acyloxypalladation
product was detected but a mixture of complicated products
was obtained, indicating that an olefinic methyl group is
crucial for the success of our reactions (Scheme 3).
The question arose that 3aa might be the intermediate of
the formation of 4aa. When the isolated 3aa was further
(7) For examples, see: (a) Doyle, M. J.; McMeeking, J.; Binger, P.
J. Chem. Soc., Chem. Commun. 1976, 376. (b) Kohara, T.; Komiya, S.;
Yamamoto, T.; Yamamoto, A. Chem. Lett. 1979, 1513. (c) Goliaszewski,
A.; Schwartz, J. J. Am. Chem. Soc. 1984, 106, 5028. (d) Goliaszewski, A.;
Schwartz, J. Organometallics 1985, 4, 417.
Org. Lett., Vol. 11, No. 11, 2009
2383

path B, nucleophiles attack the palladium(II)-coordinated
olefin of the substituted indole I′ to form intermediate II′
(oxypalladation8,9 ), which undergoes intramolecular C-H
bond functionalization to form the same intermediate III,
just as in path A. An alternative mechanism involving
insertion of the indole double bond into the C-Pd bond in
intermediate II′ followed by ꢀ-hydride elimination cannot
be excluded. From the literature, it is known that the reaction
of AcOH with a CdC bond activated by the coordination
of Pd(II) could lead to both vinylic acetate and allylic acetate,
depending on the substrates and reaction conditions.10 Thus,
1,2-acyloxypalladation of olefin is suggested in this reaction.
The mechanism for the formation of 4aa in this catalytic
reaction is similar to the mechanism reported,3j and it also
can be produced by the elimination of acetic acid from
3aa.10c
In summary, a new and mild palladium(II)-catalyzed
reaction for the intramolecular acyloxylation/cyclization of
2-(3′-alkenyl)indoles was developed. The newly formed
cycles involve oxygen-containing functionalized groups,
which might be transferred further to provide other indole
derivatives. Moreover, BQ was found to be crucial for the
success of this reaction; it can transfer the pathway of this
reaction from carbopalladation to acyloxypalladation.8,9
Further studies in this area are in progress.
Scheme 5. Benzoquinone or Maleic Anhydride as the Key
Additive between Oxypalladation and Carbopalladation
Two possible pathways for the formation of product 3 are
shown in Scheme 6. In path A, the C-H bond of indole is
Scheme 6. Possible Mechanism for the Intramolecular
Acyloxylation/Cyclization of 2-(3′-Alkenyl)indoles
Acknowledgment. The National Basic Research Program
of China (2006CB806105) is acknowledged. We also thank
the National Natural Science Foundation of China (20732005)
and the Chinese Academy of Sciences for financial support.
Supporting Information Available: Text and figures
giving experimental procedures, characterization data, and
copies of NMR spectra of new compounds and a CIF file
giving crystallographic data for compound 3aa. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9007348
functionalized by Pd(OAc)2 to form intermediate I, followed
by the attack of nucleophiles on the palladium(II)-coordinated
olefin (oxypalladation8,9 ) via intermediate II to generate the
intermediate III; then reductive elimination of III provides
3 and Pd(0), which can be reoxidized to Pd(II) by BQ. In
(9) For intermolecular acyloxypalladation without the dehydropalladation
see: (a) Hosokawa, T.; Shinohara, T.; Ooka, Y.; Murahashi, S.-I. Chem.
Lett. 1989, 2001. (b) Heumann, A.; Reglier, M.; Waegell, B. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 866. (c) Heumann, A.; Kaldy, S.; Tenaglia, T.
Tetrahedron 1994, 50, 539. (d) Trost, B. M.; Burgess, K. J. Chem. Soc.,
Chem. Commun. 1985, 1084. (e) Tamaru, M.; Yasui, T. Chem. Commun.
(London) 1968, 1209. (f) Kuznetsova, N. I.; Likholobov, V. A.; Fodotov,
M. A.; Yermakov, Y. I. J. Chem. Soc., Chem. Commun. 1982, 973.
(10) (a) Negishi, E., Ed. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: New York, 2002. (b) Hansson, S.;
Heumann, A.; Rein, T.; Åkermark, B. J. Org. Chem. 1990, 55, 975. (c)
Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2009, 131, 1372.
(8) For intermolecular acyloxypalladation-dehydropalladation reactions
see: (a) Tanaka, M.; Urata, H.; Fuchikami, T. Tetrahedron Lett. 1986, 27,
3165. (b) Yokota, T.; Fujibayashi, S.; Nishiyama, Y.; Sakaguchi, S.; Ishii,
Y. J. Mol. Catal. A 1996, 114, 113. (c) Jia, C.; Mu¨ller, P.; Mimoun, H. J.
Mol. Catal. A 1995, 101, 127. (d) Ferret, N.; Mussate-Mathieu, L.; Zahra,
J.-P.; Waegell, B. J. Chem. Soc., Chem. Commun. 1994, 2589
.
2384
Org. Lett., Vol. 11, No. 11, 2009