A new entry to polycyclic indole skeletons via palladium-catalyzed intramolecular heteroannulation

Article abstract of DOI:10.1021/ol061440j

A one-step method was developed for elaboration of a variety of polycyclic indole skeletons via a novel palladium-catalyzed intramolecular indolization of 2-chloroanilines bearing tethered acetylenes. This novel intramolecular indolization method unveils

Full text of DOI:10.1021/ol061440j

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3573-3575
A New Entry to Polycyclic Indole
Skeletons via Palladium-Catalyzed
Intramolecular Heteroannulation
Jianxiu Liu, Ming Shen, Yongda Zhang, Guisheng Li, Ahmad Khodabocus,
Sonia Rodriguez, Bo Qu, Vittorio Farina,† Chris H. Senanayake,† and
Bruce Z. Lu*
Department of Chemical DeVelopment, Boehringer-Ingelheim Pharmaceuticals, Inc.,
800 East Leigh Street, Suite 205, Richmond, Virginia 23219
zlu@rdg.boehringer-ingelheim.com
Received June 12, 2006
ABSTRACT
A one-step method was developed for elaboration of a variety of polycyclic indole skeletons via a novel palladium-catalyzed intramolecular
indolization of 2-chloroanilines bearing tethered acetylenes. This novel intramolecular indolization method unveils an unusual syn amidopalladation
pathway of a tethered alkyne.
Alkaloids containing the indole structure motif are found in
numerous natural products and synthetic compounds of vital
medicinal value.1 Construction of polycyclic indoles usually
requires multistep approaches.2 The exploration of new
methodologies that allow rapid establishment of these indole
skeletons in a single operation remains an important chal-
lenge facing organic chemists.3
starting material has significant practical and economical
value from a cost and throughput standpoint. We were
curious whether the same Pd-catalyzed alkyne insertion
protocol could be applied for the preparation of polycyclic
indoles via an intramolecular indolization process (Scheme
1). Herein we report our first results on this program.
Recently we have developed a novel Pd-catalyzed regio-
selective intermolecular indolization of 2-bromo- or chloro-
anilines with internal alkynes,4 based on Larock’s protocol.5
The feasibility of using chloroaniline derivatives as the
Scheme 1. Synthesis of Polycyclic Indoles via Pd-Catalyzed
Intramolecular Heteroannulation
† Current address: Boehringer-Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road, Ridgefield, CT 06877.
(1) For recent reviews of indole-containing natural products, see: (a)
Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (b) Faulkner,
D. J. Nat. Prod. Rep. 1999, 16, 155. (c) Michael, J. P. Nat. Prod. Rep.
1998, 15, 571.
(2) (a) Vice, S. F.; Copeland, C. R.; Forsey, S. P.; Dmitrienko, G. I.
Tetrahedron Lett. 1985, 26, 165. (b) Vice, S. F.; Friesen, R. W.; Dmitrienko,
G. I. Tetrahedron Lett. 1985, 26, 5253. (c) Artis, D. R.; Cho, I.-S.; Jaime-
Figueroa, S.; Muchowski, J. M. J. Org. Chem. 1994, 59, 2456.
(3) Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.; Kato, F.; Hiroi, M.
Synlett 2001, 263.
Mechanistically, to achieve the successful execution of this
catalytic process, one prerequisite is to form the desired
(5) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(4) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, F.;
Senanayake, C. H. Org. Lett. 2004, 6, 4129.
10.1021/ol061440j CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/04/2006

amidopalladacycle 5 via the “endo-dig” carbopalladation,
which would afford the indoles by subsequent C-N reduc-
tive elimination (path C).5 Given the strained geometry of
amidopallacycle 5, as well as the potential competing “exo-
dig”-carbopalladation of 3 (path B),6 we expected that the
reaction may work only for large rings (i.e., n ) a rather
large number). Surprisingly, we have observed that the
desired product is formed even when n (Schemes 1 and 2)
To the best of our knowledge, intramolecular syn amido-
palladation of this type has never been reported in the
literature.
We started the investigation with the 2-chloroaniline
derivative 9 by evaluating the influence of several important
reaction parameters. On the basis of our previous experience
on intermolecular indolization, DtBPF or Cy3P is superior
to the other conventional electron-rich ligands for the alkyne
insertion to the arylpalladium chloride intermediates. How-
ever, we envisioned that the choice of the optimum base
would be very crucial in order to overcome the “exo-dig”
carbopalladation pathway (to yield 4, path B, Scheme 2).
Thus, our initial efforts were mainly focused on the
investigation of base effects. These results are summarized
in Table 1.
Scheme 2. Mechanism Insight into Pd-Catalyzed
Intramolecular Heteroannulation
Table 1. Conditions Screened for the Intramolecular
Heteroannulation of 9a
temp/time solution
entry
ligand
DtBPF
base
DBU
solvent (°C/ min) assay (%)
1
2
3
4
5
6
7b
8
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
130/120
130/120
130/90
130/40
130/90
130/60
130/150
110/240
130/90
130/20
130 /180
130/40
130/40
trace
trace
25
70
11
50
49
41
26
DtBPF
DtBPF
DtBPF
DtBPF
DtBPF
DtBPF
DtBPF
DtBPF
DtBPF
TMG
KHCO3
K2CO3
Na2CO3
K3PO4
K2CO3
K2CO3
Cs2CO3
NaH
is very small (n ) 1). This observation points, therefore, to
a new and unanticipated mechanism being responsible for
this novel transformation. In this preliminary Letter, we
disclose a novel domino process that involves, most likely,
the following steps: (a) formation of the Pd-containing
zwitterion 6 (Scheme 2, path D) by standard oxidative
addition of Pd(0) to 1, probably through depot form 2;7 (b)
formation of the bicyclic palladacycle 7 by syn amidopal-
ladation of the acetylene into 6;8-10 and (c) reductive
elimination of the palladacycle 7 to afford the indole ring.
9
10
11
12
13
trace
trace
37
CTC-Q-Phos K2CO3
tBu3P
DiPPF
K2CO3
K2CO3
35
a All reactions were carried out with anilide 9 (1.0 mmol), Pd(OAc)2 (5
mol %), DtBPF (10 mol %), and K2CO3 (5 equiv) in NMP (10 mL).
b Pd2(dba)3 (2.5 mol %) was used.
(6) (a) Zhang, Y.; Negishi, E.-I. J. Am. Chem. Soc. 1989, 111, 3454. (b)
Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah, V.; Thornton-Pett, M.
Tetrahedron 1998, 54, 2595. (c) Wang, R.-T.; Chou, F.-L.; Luo, F.-T. J.
Org. Chem. 1990, 55, 4846 and references therein. (d) Luo, F.-T.; Wang,
R.-T. Heterocycles 1991, 32, 2365. (e) Hayashi, M.; Sai, H.; Horikawa, H.
Heterocycles 1998, 48, 1331. (f) Zhang, H.; Larock, R. C. Org. Lett. 2002,
4, 3035. (g) Brase, S.; Meijere, A. Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York,
2002; Vol 1, pp 1369 and 1405. (h) Bolton, G. L.; Hodges, J. C., J. Comb.
Chem. 1999, 1, 130.
(7) Palladation of anilides yields six-membered Pd cycles such as 2,
see: Horino, H.; Inoue, N. J. Org. Chem. 1981, 46, 4416.
(8) (a) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (b)
Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468. (c) Nakhla,
J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893. (d)
Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J.
Am. Chem. Soc. 2005, 127, 2868.
As anticipated, the optimal results were obtained by using
DtBPF as ligand. K2CO3 was the optimal base and NMP
proved to be the superior solvent. The reaction of 9 was
complete within 1 h at 130 °C under these conditions, which
is much faster than the intermolecular reaction under the
same conditions,4 providing the desired product 10 in 70%
isolated yield (entry 4, Table 1).
(9) For anti addition in aminopalladation, see: Cacchi, S.; Marinelli,
F. Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, pp 2227-
2244.
(10) For related chemistry that may have similar mechanism, see:
(a) Maassarani, F.; Pfeffer, M.; Spencer, J.; Wehman, E. J. Organomet.
Chem. 1994, 466, 265. (b) Korivi, R. P.; Cheng, C. H. Org. Lett. 2005, 7,
5179.
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Org. Lett., Vol. 8, No. 16, 2006

the scope of this methodology, a variety of polycyclic indoles
were synthesized with our standard conditions, even though
better yield may be obtainable through re-optimization of
each individual entry. These results are summarized in Table
2. (2-Chloroaryl)carbamate 11 and ureas 17, 19, and 21 are
readily prepared from (2-chlorobenzene)isocyanate with
alkynyl alcohols or amines. Reaction of the carbamate 11 is
very fast. However, reduced yields were obtained due to the
decomposition of the starting material under the reaction
conditions, presumably through the corresponding isocyanate
(Table 2, entry 1). The influence of substituents on both
ends of the acetylene and the ring size are illustrated by the
amides 9, 13, and 15 (Table 2, entries 2-4). Five-, six-, and
seven-membered rings were formed uneventfully. The
major side product frequently observed is the dechlorinated
starting material, the result of a reductive process. Work
toward identifying the source of reducing agent is under-
way as are further studies on the optimization of these
processes.
Table 2. Synthesis of Polycyclic Indoles via Pd-Catalyzed
Intramolecular Heteroannulation of Tethered Alkynes with
2-Chloroanilidesa
At this moment, we have no mechanistic understanding
of this process, but we believe that the rationale presented
in Scheme 2 adequately explains our observations and is
sufficiently precedented in the aminopalladation of alkenes.
In summary, we have developed a one-step method for
elaboration of a variety of polycyclic indole skeletons via a
novel palladium-catalyzed intramolecular indolization of
2-chloroanilines bearing tethered acetylenes. This novel
intramolecular indolization method unveils an unusual syn
amidopalladation pathway of a tethered alkyne. Further
studies on this protocol and its scope are in progress.
Acknowledgment. We acknowledge Dr. Heewon Lee of
Boehringer-Ingelheim Pharmaceuticals for analytical support.
a All reactions were carried out with 2-chloroanilides (1.0 mmol),
Pd(OAc)2 (5 mol %), DtBPF (10 mol %), and K2CO3 (2.5 equiv) in NMP
(10 mL). b Isolated yield of major product.
Supporting Information Available: Reaction procedures
and characterization of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
The dependence on the base used is rather remarkable, as
organic bases are totally ineffective (entries 1 and 2) and
other inorganic bases are also quite inefficient. To illustrate
OL061440J
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