A new method for the generation of indole-2,3-quinodimethanes from allenamides

Article abstract of DOI:10.1246/cl.2008.904

A new method for the generation of indole-2,3-quinodimethanes based on a palladium-catalyzed cascade process starting from N-(o-iodophenyl)allenamides has been developed. Copyright

Full text of DOI:10.1246/cl.2008.904

904
Chemistry Letters Vol.37, No.9 (2008)
A New Method for the Generation of Indole-2,3-quinodimethanes from Allenamides
Haruhiko Fuwa,ꢀ Tomomi Tako, Makoto Ebine, and Makoto Sasakiꢀ
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University,
1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555
(Received June 12, 2008; CL-080591; E-mail: hfuwa@bios.tohoku.ac.jp)
A new method for the generation of indole-2,3-quinodi-
methanes based on a palladium-catalyzed cascade process
starting from N-(o-iodophenyl)allenamides has been developed.
13C NMR, COSY, HSQC, and HMBC spectra. A plausible
mechanism that accounts for the formation of the by-product 7
is summarized in Scheme 2. Oxidative addition of 4 to the
palladium catalyst generates 8, which upon cyclization onto
the allenamide moiety gives a ꢀ-allylpalladium intermediate
5.6 The expected tetrahydrocarbazole 6 should arise from the
second cyclization (Heck cyclization7) onto the alkene tether.
On the other hand, by the action of Ag2CO3, a cationic palladi-
um species 9 may possibly be generated and could undergo elim-
ination to provide an indole-2,3-quinodimethane intermediate
10, from which diene 7 would be delivered via a [1,5]-sigma-
tropic hydrogen shift.8 In this reaction, the use of Ag2CO3 as
a base was found to be critical; the reaction using K2CO3 gave
6 as a sole isolatable product in 56% yield.9 These results
suggested the importance of cationic palladium intermediate 9
for the generation of 7.
Since substituted indole nucleus is widely found in natural
products and pharmaceuticals, the development of efficient and
versatile methodologies for the synthesis of indole derivatives
has long been an intense area of research for organic chemists.1
We have recently reported a strategy for the synthesis of indole
derivatives 3 starting from N-(o-halophenyl)allenamides 1,
wherein an allenamide functionality acts as a relay unit to gen-
erate a ꢀ-allylpalladium intermediate 2, which is subsequently
trapped with an appropriate nucleophile2,3 (Scheme 1). Although
our strategy has successfully provided a series of 3-substituted
and 2,3-disubstituted indoles in good yields, its extension to
the synthesis of polycyclic nitrogen heterocycles has yet to be
realized (e.g., 4 ! 6).
Indole-2,3-quinodimethane is a highly reactive diene that
readily undergoes Diels–Alder cycloaddition to deliver tetrahy-
drocarbazoles and related compounds.4,5 Its synthetic utility has
been demonstrated by Magnus and co-workers in their total syn-
thesis of Aspidosperma alkaloids.4a The majority of the reported
methods for the generation of indole-2,3-quinodimethanes
requires multistep synthetic manipulations for elaboration of ap-
propriately functionalized 2,3-disubstituted indole derivatives.
During the course of our ongoing studies on the synthesis of
3-substituted tetrahydrocarbazoles based on palladium-cata-
lyzed cascade cyclizations starting from allenamides, we found
a new and efficient method for the generation of indole-2,3-qui-
nodimethanes. Thus, upon exposure of allenamide 4 to 10 mol %
of Pd(PPh3)4 and 1.5 equiv of Ag2CO3 in DMF at 60 ꢁC, an
approximately 1:1 mixture of tetrahydrocarbazole 6 and diene
7 was obtained in 56% combined yield (eq 1). The structure
of 7 was deduced based on a careful inspection of the 1H,
ð1Þ
The formation of 7 suggested the possibility of the genera-
tion of indole-2,3-quinodimethane 10 via a novel mechanism.
Therefore, we undertook several proof-of-concept experiments
to confirm this hypothetical mechanism, and the results are sum-
marized in Table 1. We surmised that a highly reactive indole-
2,3-quinodimethane 12 generated from an allenamide 11 would
be trapped efficiently by an appropriate dienophile in the reac-
tion mixture, giving a substituted tetrahydrocarbazole derivative
13. In the event, upon treatment of allenamide 14 with 10 mol %
of Pd(PPh3)4, 1.5 equiv of Ag2CO3, 10 equiv of methyl acrylate
in DMF at 60 ꢁC, an approximiately 2:1 mixture of 2- and 3-
methoxycarbonyl tetrahydrocarbazoles 15a and 15b was
Scheme 1. A strategy for the synthesis of 3-substituted and 2,3-
disubstituted indoles 3 based on palladium-catalyzed cascade
reactions and its extension to the synthesis of 3-substituted tetra-
hydrocarbazole 6.
Scheme 2. A plausible reaction mechanism for by-product 7.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.9 (2008)
905
Table 1. Synthesis of a variety of substituted tetrahydrocarba-
zoles
yields, respectively, suggesting that a variety of substitution
patterns of the benzene ring could be tolerated. Thus, the present
reaction should provide an efficient means to synthesize a variety
of substituted tetrahydrocarbazoles of biological interest under
mild reaction conditions.
In conclusion, an efficient method for the generation of
indole-2,3-quinodimethanes from N-(o-iodophenyl)allenamides
based on a novel reaction mechanism has been developed. A
variety of substituted tetrahydrocarbazoles were synthesized in
good yields from readily available starting materials. Further in-
vestigations on the palladium-catalyzed reactions of allenamides
are currently underway and will be reported in due course.11
This work was supported in part by a Grant-in-Aid for
Scientific Research for Young Scientists (B) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
References and Notes
1
For recent reviews of the synthesis of indole derivatives, see:
a) G. W. Gribble, J. Chem. Soc., Perkin Trans 1 2000, 1045.
b) T. L. Gilchrist, J. Chem. Soc., Perkin Trans 1 2001, 2491.
c) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875.
H. Fuwa, M. Sasaki, Org. Biomol. Chem. 2007, 5, 2214;
Additions and corrections: H. Fuwa, M. Sasaki, Org. Biomol.
Chem. 2007, 5, 2506.
2
3
4
For a review of carbopalladation/anion capture cascade, see:
R. Grigg, V. Sridharan, J. Organomet. Chem. 1999, 576, 65.
For reviews of indole-2,3-quinodimethanes, see: a) P. Magnus,
T. Gallagher, P. Brown, P. Pappalardo, Acc. Chem. Res. 1984,
17, 35. b) U. Pindur, H. Erfanian-Abdoust, Chem. Rev. 1989,
89, 1681. c) J. L. Segura, N. Martin, Chem. Rev. 1999, 99,
3199.
5
Selected recent reports on the generation of indole-2,3-quino-
dimethanes: a) M. Laronze, J. Sapi, Tetrahedron Lett. 2002,
43, 7925. b) M. Terzidis, C. A. Tsoleridis, J. Stephanidou-
Stephanatou, Tetrahedron Lett. 2005, 46, 7239. c) N. Kuroda,
Y. Takahashi, K. Yoshinaga, C. Mukai, Org. Lett. 2006, 8,
1843. d) H. Fuwa, M. Sasaki, Chem. Commun. 2007, 2876.
´
For a review of carbopalladation, see: E. Negishi, C. Coperet,
S. Ma, S.-Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365.
For selected reviews of Heck reaction, see: a) S. E. Gibson,
R. J. Middleton, Contemp. Org. Synth. 1996, 3, 447. b) I. P.
Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009.
For a discussion on a related [1,5]-sigmatropic hydrogen shift,
6
7
aReactions were performed using Pd(PPh3)4 (10 mol %),
Ag2CO3 (1.5 equiv), dienophile (10 equiv) in DMF at 60 ꢁC.
bReactions were performed using Pd(PPh3)4 (10 mol %),
Ag2CO3 (1.5 equiv), dimethyl fumarate (1.5 equiv) in CH3CN
at 60–70 ꢁC.
8
9
´
see: F. Auge, J. Sapi, J.-Y. Laronze, Tetrahedron 2004, 60,
6005.
M. M. Abelman, T. Oh, L. E. Overman, J. Org. Chem. 1987,
52, 4130.
10 Typical experimental procedure: To a solution of allenamide
14 (69.4 mg, 0.163 mmol) in anhydrous CH3CN (1.7 mL)
under argon atmosphere were added Ag2CO3 (67.6 mg,
0.245 mmol), dimethyl fumarate (35.3 mg, 0.245 mmol), and
Pd(PPh3)4 (19.3 mg, 0.0167 mmol). The resultant mixture
was heated at 60 ꢁC for 2.6 h. After cooling to room tempera-
ture, the reaction mixture was filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography on silica gel (10 to
25% EtOAc/hexanes) gave substituted tetrahydrocarbazole 16
(58.2 mg, 81%) as a yellow oil.
obtained in 53% combined yield.10 Changing the dienophile to
dimethyl fumarate or N-methylmaleimide also provided the
desired products 16 or 17 in excellent yield, respectively. The
use of acetonitrile as a solvent proved to be also effective for
the present reaction to provide the products 16–18 and 22–24.
On the other hand, in the absence of a dienophile, an inseparable
10:1 mixture of the dimerized product 18a and its isomer 18b
was isolated in 55% combined yield. These results clearly
indicated the generation of an indole-2,3-quinodimethane inter-
mediate and its subsequent Diels–Alder trapping.
Additional experiments were performed to investigate the
scope of the reaction. Thus, ꢁ-substituted allenamides 19–21
afforded the corresponding tetrahydrocarbazoles 22–24 in good
11 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Published on the web (Advance View) July 26, 2008; doi:10.1246/cl.2008.904