A novel one-pot, two-step synthesis of polycyclic indoles via tandem intramolecular hydroamidation/palladium-catalyzed annulation

Article abstract of DOI:10.1002/adsc.201000288

A robust one-pot process has been developed for the synthesis of a variety of polycyclic indole skeletons via a consecutive sequence of hydroamidation and palladium-catalyzed annulation, from inexpensive 2-chloroanilines bearing tethered acetylenes.

Full text of DOI:10.1002/adsc.201000288

UPDATES
DOI: 10.1002/adsc.201000288
A Novel One-Pot, Two-Step Synthesis of Polycyclic Indoles via
Tandem Intramolecular Hydroamidation/Palladium-Catalyzed
Annulation
Jianxiu Liu,a Yongda Zhang,b Guisheng Li,b Frank Roschangar,b Vittorio Farina,c
Chris H. Senanayake,b and Bruce Z. Lub,*
a
Current address: Boehringer-Ingelheim Chemicals, Inc., 2820 North Normandy Dr., Petersburg, Virginia 23805, USA
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield,
b
Connecticut 06877, USA
Fax : (+1)-203-837-4608; phone: (+1)-203-798-4264; e-mail: bruce.lu@boehringer-ingelheim.com
Current address: Johnson and Johnson Pharmaceutical R&D Turnhoutseweg 30, 2340 Beerse, Belgium
c
Received: April 13, 2010; Published online: September 14, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000288.
Abstract: A robust one-pot process has been devel-
oped for the synthesis of a variety of polycyclic
indole skeletons via a consecutive sequence of hy-
droamidation and palladium-catalyzed annulation,
from inexpensive 2-chloroanilines bearing tethered
acetylenes.
usually requires multistep approaches.[2] The explora-
tion of new methodologies that allow for the rapid
construction of complex indole skeletons in a single
operation remains an important challenge facing or-
ganic chemists.[3]
Recently, we have disclosed a novel regioselective
Pd-catalyzed indolization from 2-chloroanilides teth-
ered to internal alkynes,[4] based on the previous pro-
tocol developed in this group.[5] This unusual transfor-
mation plausibly involves the formation of the bicyclic
Keywords: chloroanilines; hydroamidation; palladi-
um; polycyclic indoles
palladacycle 4 by syn amidopalladation of the acety-
6,7,8]
lene into the Pd-containing zwitterion 3,
G
followed
by reductive elimination to form the pyrrole ring
The indole structural motif is abundantly found in (Scheme 1). It was observed that in cases where the
natural products and synthetic compounds of vital substrates contained a urea moiety (1, X=NH), the
medicinal value.[1] Construction of polycyclic indoles transformation was significantly slower. For example,
Scheme 1. Synthesis of polycyclic indoles via Pd-catalyzed intramolecular heteroannulation.
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Jianxiu Liu et al.
UPDATES
Table 1. Conditions screened for the intramolecular Pd-cata-
lyzed heteroannulation of 7.[a]
No
Ligand
Cy3P
Conversion [%]
1
2
3
4
5
14
21
64
14
3
AHCTUNGTERN(GNUN t-Bu)3P
Scheme 2. Synthesis of polycyclic indoles via Pd-catalyzed
intramolecular heteroannulation.
DtBPF
10
11
HPLC monitoring of urea 6 (Scheme 2) showed that
the starting material was consumed in about 1 h,
forming a small amount of the desired indole product
8 along with a 1:1 ratio of two intermediates identi-
fied by NMR as the Z/E isomers of the enamides 7.
[a]
All reactions were carried out with anilide 7 (1.0 mmol),
Pd(OAc)2 (5 mol%), ligand (10 mol%), K2CO3 (5 equiv.)
in NMP (10 mL).
AHCTUNGTRENNUNG
These intermediates gradually converted to the prod- ring turned out to be fairly marginal. Good to excel-
uct upon prolonged heating at 1308C (Scheme 2).
lent yields were obtained in all cases (Table 2).
To further probe the reaction path, we treated urea
We then examined the enamide substrates: the re-
6 with K2CO3 in NMP in the absence of the catalyst. sults varied significantly, depending on the terminal
Indeed, urea 6 was completely converted to 7 at substituents of the acetylene and the ring size of the
1308C in 2 h. The addition of PdACHTNUGRTNEUNG
(OAc)2 and DtBPF formed enamide intermediates (Table 3). In general,
to the Z/E-7 mixture led to indole 8 in 75% isolated the hydroamidation to form five-membered ring en-
yield. It was then decided to further evaluate the two- amides proceeded smoothly at 1308C, furnishing en-
step, one-pot protocol, and compare it with our previ- amides 21, 27, 30 in less than 2 h (Table 3, entries 1, 3,
ously reported “batch” approach.[9]
4). On the contrary, formation of six-membered ring
Urea 6 was used as substrate for further evaluation enamides 24, 33 and 39 required prolonged reaction
of the reaction conditions, mainly focusing on the Pd- time or elevated reaction temperature (Table 3, en-
catalyzed annulation, aiming at faster turnover rate of tries 2, 5, 8). The fact that anilide 32 underwent no re-
the catalyst or milder conditions to minimize product action until the temperature was increased to 1708C,
degradation. Thus, 6 was first converted to 7 in NMP as well as the different reactivities between 26 and 29,
at 1308C, in the presence of 5 equivalents of K2CO3, points to a counterproductive electron-donating effect
and the reaction mixture was used directly to screen of the para-methyl substituent on the benzene ring.
conditions for the subsequent Pd-catalyzed annula- Additives such as CuI, ZnBr2, PdACTHNUTRGNE(UGN OAc)2 and (n-
tion. Several conventional electron-rich, bulky ligands Bu)4NBr, have no effect on the hydroamidation.[12]
suitable for the oxidative addition of aryl chlorides to However, use of Cs2CO3 as the base facilitated the
Pd(0) were examined. As shown in the Table 1, hydroamidation remarkably, allowing the cyclization
DtBPF is the ligand of choice, giving significantly of 32 to be completed in 2 h at 1308C (entry 6,
better results than other ligands.[10,11]
Table 3). But the efficiency was compromised due to
To illustrate the scope of the new methodology, a hydrolysis of the enamide intermediate and formation
variety of polycyclic indoles containing the imidazo- of by-products during the subsequent palladium-cata-
lone moiety (8–19) was synthesized using the follow- lyzed annulation. Nevertheless, the indole product
ing conditions: treatment of the substrates with was obtained in 72% isolated yield. No hydroamida-
K2CO3 in NMP at 1308C for 2 h to form the enam- tion occurred for substrates 35 and 41, even at 1808C
ides, followed by addition of catalytic PdACTHNUTRGNEUNG(OAc)2 and (entries 7 and 9, Table 3), suggesting that the reaction
DtBPF. In all examined cases, the Pd-catalyzed annu- cannot be extended to substrates that involve forma-
lation was completed in ca. 12 h. The influence of tion of seven-membered ring enamides or that con-
substituents on both the acetylene and the benzene tain alkyl substituents at the acetylene terminus.
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A Novel One-Pot, Two-Step Synthesis of Polycyclic Indoles
Table 2. Synthesis of polycyclic indoles via consecutive hy-
droamidation and Pd-catalyzed heteroannulation of tethered
alkynes with 2-chloro-anilides.[a]
A similar trend was observed in the Pd-catalyzed
annulation of enamides 21, 27, and 30 containing a
five-membered ring, which underwent facile cycliza-
tion at 1308C (Table 3, entries 1, 3, 4), whereas the
one bearing a six-membered ring enamide required
prolonged reaction times or higher temperature
(Table 3, entries 2, 5, 8).
It is noteworthy that remarkable differences exist
in both reaction profile and scope between the cur-
rent sequential procedure and the previously reported
“batch” protocol, in which the catalyst was added to-
gether with base at the beginning of the reaction. For
instance, with the sequential procedure, the substrates
containing a terminal acetylene such as 20 and 23,
smoothly underwent hydroamidation and indolization,
producing the desired products in good yield (en-
tries 1, 2, Table 3), while the “batch” protocol afford-
ed complex reactions, suggesting the shuttling of
these substrates toward other Pd-catalyzed processes.
On the other hand, for substrates 32 and 41, which
were very sluggish or totally unreactive toward hydro-
amidation, the “batch” protocol exhibited advantages,
rapidly producing the desired products in good
yield.[4] These results unambiguously illustrate the dis-
tinct mechanisms and the complementary scope of
the two procedures. Further work is ongoing to
extend this stepwise protocol to substrates containing
alkyl substituents at the alkyne terminus.
In summary, we have developed a practical one-pot
process for synthesis of a variety of polycyclic indoles
from readily available, inexpensive 2-chloroanilines
bearing tethered alkynes. Distinct in mechanism from
the previous “batch” method, this alternative protocol
involves consecutive intramolecular hydroamidation
and palladium-catalyzed annulation. In many cases,
the “two-step” approach is more robust and affords
higher yields than the “batch” process, although these
two protocols are complementary with respect to
scope. Further exploration of the reaction conditions
to expand the reaction scope is underway.
Experimental Section
General Procedure for Polycyclic Indole Synthesis
via Consecutive Hydroamidation and Palladium-
Catalyzed Intramolecular Heteroannulation
To a dry round-bottom flask containing a magnetic stir bar
was charged the alkynyl-2-chloroanilide (1.0 mmol), potassi-
um carbonate (690 mg, 5.0 mmol, 5.0 equiv.) and NMP
(10 mL) under nitrogen. The mixture was heated at 1308C,
or the specified temperature until the starting material was
[a]
All reactions were carried out with anilide 7 (1.0 mmol),
consumed completely. PdACHTNUTGRNEUNG
(OAc)2 (5 mol%) and DtBPF
Pd
in NMP (10 mL).[a] All reactions were carried out with
anilide (1.0 mmol), Pd(OAc)2 (5 mol%), ligand
ACHTUNGTRENNUNG(OAc)2 (5 mol%), ligand (10 mol%), K2CO3 (5 equiv.)
(10 mol%) were added at room temperature. The mixture
was degassed and then heated at 1308C or the specified
temperature until the reaction was completed. After being
cooled to room temperature, the mixture was diluted with
7
ACHTUNGTRENNUNG
(10 mol%), K2CO3 (5 equiv.) in NMP (10 mL).
Isolated yield of major product.
[b]
Adv. Synth. Catal. 2010, 352, 2667 – 2671
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Jianxiu Liu et al.
UPDATES
Table 3. Synthesis of polycyclic indoles via consecutive hydroamidation and Pd-cat-
alyzed heteroannulation of tethered alkynes with 2-chloroanilides.[a]
[a]
All reactions were carried out with anilide 7 (1.0 mmol), PdACHTNUTRGNEUNG(OAc)2 (5 mol%),
ligand (10 mol%), K2CO3 (5 equiv.) in NMP (10 mL).
Isolated yield.
The reaction was carried out under the same conditions except for the use of
Cs2CO3 as base.
[b]
[c]
EtOAc and washed with water. The aqueous layer was ex-
tracted with EtOAc. The combined organic layers were
washed with water, brine, and dried over anhydrous Na2SO4
and concentrated. Purification of the crude product by
column chromatography on silica gel gave analytically pure
product.
Acknowledgements
We acknowledge Dr. Heewon Lee of Boehringer-Ingelheim
Pharmaceuticals for analytical support
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A Novel One-Pot, Two-Step Synthesis of Polycyclic Indoles
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