Domino process in silver-catalyzed reactions of N-arylformimidates and active methylene compounds involving cycloisomerization and 1,3-alkenyl shift

Article abstract of DOI:10.1021/ja9106226

(Formula Presented) We have developed an efficient method for the synthesis of 2,3-disubstituted indoles from alkyne iminoethers 1 that employs a domino process involving Ag-catalyzed condensation followed by a tandem Ag-induced cycloisomerization and 1,3

Full text of DOI:10.1021/ja9106226

Published on Web 01/27/2010
Domino Process in Silver-Catalyzed Reactions of N-Arylformimidates and
Active Methylene Compounds Involving Cycloisomerization and 1,3-Alkenyl
Shift
Chang Ho Oh,* Swastik Karmakar, HyoSeung Park, YoungCheon Ahn, and Jung Wook Kim
Department of Chemistry, Hanyang UniVersity, Sungdong-Gu, Seoul 133-791, Korea
Received December 16, 2009; E-mail: changho@hanyang.ac.kr
Scheme 1. Proposed Mechanism
Substituted indoles form the core skeletons of a wide range of
pharmaceuticals and naturally occurring alkaloids.1 To date, numer-
ous elegant approaches have been developed to generate this unique
ring system via transition-metal catalysis.2 Recently, indole deriva-
tives have been synthesized by employing inter- or intramolucular
cyclization of alkynes and imines.3 In this communication, we report
an atom-economical and highly efficient approach for the construc-
tion of 2,3-substituted indoles via silver-catalyzed condensation of
N-arylformimidates and active methylene compounds followed by
cycloisomerization and a novel and unprecedented 1,3-alkenyl shift
to the Ag-activated site. Previously, Li and co-workers4 introduced
an effective methodology for gold- and silver-catalyzed addition
of active methylenes to alkenes. Later, Arcadi et al.5 reported gold-
catalyzed coupling of active methylenes at the C3 position of indole.
We considered the possibility of gold- and silver-catalyzed con-
densation of N-arylformimdate 1a and dimethyl malonate followed
by in situ cycloisomerization with the triple bond, leading to the
N-alkenylindole derivative. Our approach seemed to work well, but
the reaction product turned out to be 3a, which was presumably
formed via a 1,3-alkenyl shift in 2a or its equivalent. This result
prompted us to examine 1,3-alkenyl migration from the synthetic
and mechanistic points of view (Table 1).6
Several gold compounds did not catalyze this reaction, but those
in conjunction with silver triflate catalyzed this reaction to furnish
the product 3a in moderate yields. We fortunately found that the
Ag(I) cation itself (5 mol %) catalyzed this reaction effectively,
with AgOTf showing much better catalytic activity than AgSbF6
in toluene at 60 °C. Methanesulfonic acid did not act as a catalyst,
and the role of PtCl2 was insignificant in this reaction. To rationalize
this domino process, we could propose a plausible mechanism by
introducing unusual alkenyl migration (Scheme 1). Condensation
of an enolate with activated alkynes is now quite general, as
proposed by Toste and co-workers.7 In our substrates, however,
the electron-rich nitrogen in the imidate group should be activated
prior to alkyne activation. Therefore, the Ag(I) cation might
coordinate with the N-arylformimidate in the first step to give A,
which would be susceptible to reaction with malonate to form B.
The elimination of ethanol from B via regeneration of Ag(I) would
lead to C, which upon subsequent Ag(I)-induced 5-endo-dig
cyclization would form the key intermediate D. Such an intermedi-
ate always has a provision to exist as a metal carbene intermediate
E. Most probably, the captodative effect of the coordinated silver
would increase the electron density on the nitrogen atom, which
would drive the 1,3-alkenyl migration to the silver carbene F,
furnishing intermediate G. Similar 1,3-migrations of R-alkoxyalkyl
and R-alkoxyacyl groups have been reported by the Nakamura
group.8 In its final stage, simple protodemetalation would convert
G into 2,3-disubstituted indole 3a.
Table 1. Optimization of Catalysts for Constructing
2,3-Disubstituted Indoles
Since such a 1,3-alkenyl transfer reaction has not been reported
in any literature to date, we became interested in exploring its
synthetic utility and finding evidence in support of the proposed
mechanism for this novel phenomenon. First, we prepared 4a, the
tautomeric form of intermediate C, by simple condensation of
o-alkynylaniline Pro-1a with dimethyl ethoxymethylenemalonate
in the presence of acid catalyst. Enamine 4a was then subjected to
our reaction conditions, but only simple cyclization occurred,
affording N-alkenylindole derivative 2a as a major product (Scheme
2). This experiment supports the idea that it is not enamine 2a but
rather a metal-bound species like C that may be a possible
intermediate during this domino process. The second experiment
was done on the substrate 1b having a carbene-trapping handle.
The predicted Ag-carbene intermediate F-b formed from 1b was
entry
catalyst (mol %)
time (h)
isolated % yield of 3a
1
2
3
4
5
6
7
8
9
AuCl3 (5)
AuBr3 (5)
6
6
6
12
12
12
12
12
12
12
decomposition
decomposition
decomposition
82
58
80
91
75
10
5
NaAuCl4 ·2H2O (5)
AuBr3 (5)/AgOTf (15)
AuCl3 (5)/AgOTf (15)
AuCl(PPh3)/AgOTf (5)
AgOTf (5)
AgSbF6 (5)
CF3SO3H (10)
PtCl2 (5)
10
9
1792 J. AM. CHEM. SOC. 2010, 132, 1792–1793
10.1021/ja9106226  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Search for Mechanistic Insight
In conclusion, we have developed an efficient domino process
for the synthesis of 2,3-disubstituted indoles from alkyne imino-
ethers 1 that employs a silver-catalyzed two-component condensa-
tion followed by a tandem Ag-induced cycloisomerization and 1,3-
alkenyl shift to the Ag-activated carbon. This methodology may
be an ideal protocol for in situ metal-mediated synthesis of olefin
and its regioselective migration to the metal-activated site and can
be useful in constructing 3-alkylated indoles, which are part of the
structures of biologically active compounds and important alkaloids.
The scope of this reaction is currently under investigation in our
laboratories.
Acknowledgment. We thank the National Research Foundation
of Korea (NRF 31200900000001826) for financial support and
BK21 for fellowships.
expected to undergo benzylic C-H insertion to provide the cyclized
product 5b, but in practice, no such product was formed; instead,
1b smoothly underwent sequential cycloisomerization and 1,3-
alkenyl migration to furnish 3b in moderate yield (67%).
The above two experiments revealed that this transformation
would occur via a complicated concerted-metal-associated mech-
anism without forming the real intermediate 2a or Ag-carbene
species such as F.
Next, turning our attention to the synthetic point of view, we
prepared a series of indole derivatives (3c-m) from the corre-
sponding N-arylformimidates (Figure 1). All of the substrates were
transformed into the corresponding indoles 3c-m in good yields.
The substituent at C2 in our products could vary from primary,
secondary, or tertiary alkyl groups to phenyl, naphthyl, or substituted
phenyl groups. These indole derivatives may have biological
importance, since the two derivatives 3k and 3l are known to have
antiproliferative activity on human MDA-MB 231 and MCF-7
breast cancer cells in a microplate assay.9 This methodology may
provide a general entry to the synthesis of various indole derivatives.
Since the present 1,3-alkenyl transfer is a new observation in the
organic chemistry field, we confirmed the structure of a representa-
tive product (3a) by X-ray analysis as well as its full spectral data.10
Supporting Information Available: Full experimental details,
compound characterization data, complete ref 1e, and a CIF file for
3a. This material is available free of charge via the Internet at http://
pubs.acs.org.
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Figure 1. 2,3-Substituted indoles from this study.
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