Intramolecular fischer indole synthesis and its combination with an aromatic [3,3]-sigmatropic rearrangement for the preparation of tricyclic benzo[cd]indoles

Article abstract of DOI:10.1002/anie.201108970

At the end of the tether: Aryl hydrazides that have carbonyl groups tethered at the para position of the aromatic ring undergo an intramolecular Fischer indolization reaction to give the corresponding indolophanes. Strategic insertion of a double bond in the tether enables a tandem aromatic [3,3] sigmatropic rearrangement reaction to occur to give tricyclic benzo[cd]indoles. Copyright

Full text of DOI:10.1002/anie.201108970

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Angewandte
Communications
DOI: 10.1002/anie.201108970
Synthetic Methods
Intramolecular Fischer Indole Synthesis and its Combination with an
Aromatic [3,3]-Sigmatropic Rearrangement for the Preparation of
Tricyclic Benzo[cd]indoles**
In-Keol Park, Jun Park, and Cheon-Gyu Cho*
Indoles are arguably the most privileged molecular scaffolds
that are present in nature.[1] A wide variety of important
biological activities that are exhibited by many indole-based
natural products has made them attractive synthetic targets
over the years.[2] Accordingly, many elegant methods and
strategies have been devised and used for their synthesis. The
venerable Fischer indole synthesis, which was reported over
100 years ago, still remains of considerable value for its
operational simplicity, despite the limited availability of the
starting aryl hydrazines.[3] A few years ago, we reported that
aryl hydrazide 1 is an effective surrogate for aryl hydrazines as
it readily undergoes a Fischer indolization process to give the
corresponding indole 2 (Scheme 1).[4] It was reported more
Scheme 2. Selected examples of benzo[cd]indole alkaloids.
adequate synthetic methods for producing the tricyclic
Scheme 1. Fischer indolization of aryl hydrazides.
benzo[cd]indole cores.
Our continuing interest in exploring the synthetic appli-
cation of aryl hydrazides led us to envisage that an intra-
molecular Fischer indole synthesis could provide expedient
access to tricyclic benzo[cd]indole systems. As depicted in
Scheme 3, aryl hydrazide 9 with the carbonyl group attached
to the meta position may cyclize into tricyclic benzo[cd]indole
11 after the hydrazone intermediate 10 is formed.[4a,5,14]
recently that the Fischer indolization reaction of aryl hydra-
zide 3, which contains the less acid-labile carboxybenzyl
(Cbz) group, can proceed with the Cbz group remaining intact
to give N-Cbz indole 4.[5] The starting aryl hydrazides 1 and 3
in both cases are readily accessed from aryl halides by Pd0- or
CuI-catalyzed coupling reactions with the corresponding
carbazate,[6] which expands the substrate scope of the conven-
tional Fischer indole synthesis.[7]
Indole-based natural products that contain tricyclic ben-
zo[cd]indole cores[8] have emerged as a target of interest[9] for
their intriguing biological activities and molecular architec-
tures, as exemplified by clavicipitic acid (5),[10] communesin F
(6),[11] lysergic acid (7),[12] and welwitindolinone C (8)[13]
(Scheme 2). In spite of recent advances, the synthesis of
such natural products is often complicated by the lack of
Scheme 3. Intramolecular Fischer indolization.
[*] I.-K. Park, J. Park, Prof. C.-G. Cho
To probe the feasibility of this concept, we prepared aryl
hydrazide 12a and subjected it to the typical Fischer indole
synthesis conditions by heating it in EtOH that contained
a few drops of aqueous HCl (Scheme 4). However, the
reaction stopped at hydrazone 10a, with no evidence of the
Fischer indolization reaction proceeding. Elongation of the
tether gave no improvement (12b and 12c). All of the
attempts to push the reaction forward by increasing the
harshness of the reaction conditions were in vain and mostly
Department of Chemistry, Hanyang University
17 Haengdang-Dong, Sungdong-Ku, Seoul 133-791 (Korea)
E-mail: ccho@hanyang.ac.kr
Homepage: http://bmsl.hanyang.ac.kr
[**] This work was supported by the grants from the National Research
Foundation of Korea (2009-0080752 and 2011-0022343). I.K.P. and
J.P. are grateful for a BK21 Fellowship and a Seoul Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108970.
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Table 1: Intramolecular Fischer indolization of aryl hydrazides 14.
Entry
n
14
15
Yield [%]
Scheme 4. Intramolecular Fischer indolization with compounds teth-
ered at the C3 position. Bn=benzyl.
1
2
3
4
5
6
1
2
3
1
2
3
14d (X=O, R=H)
14e (X=O, R=H)
14 f (X=O, R=H)
14g (X=NTs, R=Me) 15g (X=NTs, R=Me) 50
14h (X=NTs, R=Me) 15h (X=NTs, R=Me) 50
14i (X=NTs, R=Me) 15i (X=NTs, R=Me) 80
15d (X=O, R=H)
15e (X=O, R=H)
15 f (X=O, R=H)
trace[a]
50
52
resulted in the formation of a complex mixture of unidentifi-
able decomposition products. The corresponding transition
states for the desired products would have too much strain, as
suggested by a simple molecular modeling study.[15]
[a] Dimeric indole 16d (n=1) was produced in 68% yield.
We then examined the reactions of aryl hydrazides 14a–c,
in which the latent carbonyl group is tethered to the para
position of the aromatic ring (Scheme 5). Surprisingly, aryl
hydrazides 14b and 14c did undergo the intramolecular
in 68% yield (Table 1, entry 1). However, aryl hydrazides 14e
and 14 f, which contain a longer tether, did undergo the
Fischer indolization to afford the expected indoles 15e and
15 f in good yield (50% and 52%, respectively, Table 1,
entries 2 and 3). Compounds 14e and 14 f pertain to the rare
cases of the Fischer indolization reaction that can be
conducted effectively with aldehydes. Aryl hydrazides that
contain the N-Ts bridge 14g–14i also undergo the Fischer
indolization reaction to give 15g–15i. In all series, those
compounds that have longer tethers gave higher yields of
products.
In further pursuit of a way of providing access to tricyclic
À
benzo[cd]indole systems, we decided to incorporate a C C
double bond within the tether. We hypothesized that indole
18 would undergo an aromatic [3,3] sigmatropic rearrange-
À
ment in a tandem fashion to construct the pivotal C C bond
at the C4-position (Scheme 6).
Scheme 5. Intramolecular Fischer indolization with compounds teth-
ered at the C4 position.
Fischer indolization reaction to afford indolophanes 16b and
16c. In the case of the aryl hydrazide with the shorter tether
(14a), intermolecular Fischer indolization prevailed to give
dimeric indole 16a. Evidently, the tether is not long enough in
this case for the carbonyl group to wrap around and meet the
amine group. The reaction was optimized by varying the
reaction parameters, which include solvent, acid catalyst,
reaction temperature, and the concentration of the reagents.
Running the reaction in n-PrOH at reflux and at a concen-
tration of 5 mm of the starting material gave the best rate of
reaction and yield of isolated product (15b = 67%; 15c =
84%). In this set of experiments, the N-Cbz group was
replaced by ethyl carbamate to increase the solubility of the
product for easier handling.
Enthused by these initial results, we next aimed to explore
the substrate scope of the reaction by using two sets of aryl
hydrazides that contain an acetal group (R = H) as well as an
N-tosyl (N-Ts) linker (Table 1). Similar to 14a, aryl hydrazide
14d, which contains a latent aldehyde group, did not give the
corresponding indolophane 15d, but instead gave dimer 16d
Scheme 6. Intramolecular Fischer indolization/aromatic Claisen rear-
rangement cascade.
To this end, aryl hydrazides 17a–17c were prepared and
subjected to the Fischer indolization conditions. Aryl hydra-
zides 17a and 17b underwent the aforementioned tandem
process to give the corresponding tricyclic benzo[cd]indoles
19a and 19b in good overall yields (Table 2, entries 1 and 2).
However, adding one extra methylene group to tether of the
aryl hydrazide gave a complex product mixture (Table 2,
entry 3). Reactions with aryl hydrazides 17d and 17e that
contain the N-Ts bridge also afforded the expected tricyclic
benzo[cd]indoles 19d and 19e (Table 2, entries 4 and 5).
Analogous to 17c, the reaction with aryl hydrazide 17 f, which
contains a longer tether, did not give the tandem reaction
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J = 7.0 Hz, 3H), 1.36–1.24 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d = 153.8, 152.5, 133.3, 133.1, 129.4, 120.4, 116.7, 113.7,
106.9, 70.6, 62.7, 30.2, 29.0, 28.9, 28.8, 22.1, 14.6, 13.6 ppm; FT-IR
Table 2: Tandem intramolecular Fischer indole synthesis/aromatic [3,3]-
sigmatropic rearrangement.
(CH2Cl2): n = 2928, 1730, 1482, 1377, 1330, 1129 cmÀ1; HRMS (FAB)
˜
m/z: calcd for C18H23NO3: 301.1678 [M+]; found: 301.1678.
Representative procedure for tricyclic benzo[cd]indoles 19. Syn-
thesis of 19a. A solution of 17a (0.1 mmol, 5 mm) in nPrOH (20 mL)
was added slowly over 1 h to a solution of nPrOH (20 mL) that
contained conc. HCl (three drops by Pasteur pipette) at 1008C. The
resulting mixture was heated for 12 h, before cooling to room
temperature. The reaction mixture was then concentrated in vacuo,
diluted with CH2Cl2 (20 mL), and neutralized by adding saturated
aq. NaHCO3. The separated organic solution was washed with water,
dried over Na2SO4, concentrated in vacuo, and purified by chroma-
tography on a silica gel column (100% CH2Cl2) to give 19a (16 mg,
Entry
n
17
19
Yield [%]
1
2
3
4
5
1
2
3
1
2
17a (X=O, R=Me)
17b (X=O, R=Me)
17c (X=O, R=Me)
17d (X=NTs, R=Me) 19d 62
17e (X=NTs, R=Me) 19e 63
19a 56
19b 63
19c trace
1
56%) as a colorless liquid. H NMR (400 MHz, CDCl3): d = 7.68 (d,
J = 8.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.05 (ddd, J = 16.8 Hz,
10.2 Hz, 7.0 Hz, 1H), 5.22 (d, J = 10.2 Hz, 1H), 5.07 (s, 1H, OH), 5.06
(d, J = 16.8 Hz, 1H), 4.46 (q, J = 7.0 Hz, 2H), 3.77 (dt, J = 7.0 Hz,
5.4 Hz, 1H), 2.63 (t, J = 5.4 Hz, 2H), 2.50 (s, 3H), 2.04–2.00 (m, 2H),
1.47 ppm (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 152.6,
148.7, 140.5, 131.1, 129.4, 129.0, 116.9, 115.8, 114.9, 114.6, 112.7, 62.7,
6
7
3
2
17 f (X=NTs, R=Me) 19 f trace
17g (X=O, R=H)
19g 42
˜
37.7, 30.0, 18.0, 14.6, 14.1 ppm; FT-IR (CH2Cl2) n = 3428, 2976, 2926,
2854, 1730, 1701, 1405, 1339, 1148 cmÀ1; HRMS (EI): m/z: calcd for
C17H19NO3: 285.1365 [M+]; found: 285.1393.
product, but instead gave indolophane 18 f in 70% yield
(Table 2, entry 6). The formation of 18 f in such a high yield
strongly implies that the Fischer indolization takes place
before the aromatic aza-Cope rearrangement in this tandem
process (Scheme 5). A simple molecular modeling study with
18 f suggests that the extra carbon unit on the tether may act
as a hinge to force the olefin out and away from the aryl
group, which prevents the ensuing sigmatropic rearrangement
reaction. This tandem process is also effective with com-
pounds that contain an acetal group. When subjected to the
identical reaction conditions, aryl hydrazide 17g was con-
verted into the expected tricyclic indole 19g, albeit in slightly
lower yield (42%, Table 2, entry 7).
Received: December 20, 2011
Revised: January 3, 2012
Published online: January 19, 2012
Keywords: aryl hydrazides · benzo[cd]indoles ·
.
Fischer indole synthesis · polycycles ·
sigmatropic rearrangement
[1] a) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875;
b) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873; c) G. W.
Gribble, J. Chem. Soc. Perkin Trans. 1 2000, 1045; d) J. E. Saxton,
The Chemistry of Heterocyclic Compounds, Vol. 25, Part IV,
Wiley, New York, 1983.
[2] a) A. Rahman, Indole Alkaloids, Harwood Academic Publisher,
Amsterdam, 1998; b) R. F. Raffauf, A Handbook of Alkaloids
and Alkaloid-containing Plants, Wiley-Interscience, New York,
1970; c) A. Stoll, A. Hofman in The Alkaloids Chemistry and
Physiology, Vol. 8 (Ed.: R. H. F. Manske), Academic Press, New
York, 1965, p. 725.
[3] For reviews, see: a) B. Robinson, The Fischer Indole Synthesis,
Wiley, Chichester, 1982; b) D. L. Hugh, Org. Prep. Proced. Int.
1993, 25, 609; for catalytic asymmetric Fischer indolization, see:
c) S. Mꢀller, M. J. Webber, B. List, J. Am. Chem. Soc. 2011, 133,
18534.
In summary, aryl hydrazides that contain a latent carbonyl
group that is tethered to the para position of the aromatic ring
undergo the Fischer indolization reaction in an intramolec-
À
ular fashion. Strategic insertion of a C C double bond in the
tether enabled the indole product to form tricyclic benzo-
[cd]indoles in good overall yield by an aromatic [3,3] sigma-
tropic rearrangement reaction. This intramolecular Fischer
indole synthesis may find further applications in the areas of
related natural product syntheses, as well as pharmaceutical
and materials sciences.
Experimental Section
[4] a) Y.-K. Lim, C.-G. Cho, Tetrahedron Lett. 2004, 45, 1857; b) J.
Chae, S. L. Buchwald, J. Org. Chem. 2004, 69, 3336.
[5] I.-K. Park, S.-E. Suh, B.-Y. Lim, C.-G. Cho, Org. Lett. 2009, 11,
5454.
Representative procedure for indolophanes 15. Synthesis of 15b: A
solution of 14b (0.1 mmol, 5 mm) in nPrOH (20 mL) was added
slowly over 1 h to a solution of nPrOH (20 mL) that contained conc.
HCl (three drops by Pasteur pipette) at 1008C. The resulting mixture
was heated for 12 h, before cooling to room temperature. The
reaction mixture was then concentrated in vacuo, diluted with CH2Cl2
(20 mL), and neutralized by adding saturated aq NaHCO3. The
separated organic solution was washed with water, dried over Na2SO4,
concentrated in vacuo, and purified by chromatography on a silica gel
column (100% CH2Cl2) to give 15b (20 mg, 67%) as a colorless
liquid. 1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 8.6 Hz, 1H), 7.20
(d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 4.48–4.43 (m,
4H), 2.78 (t, J = 5.9 Hz, 2H), 2.51 (s, 3H), 1.62–1.49 (m, 6H), 1.47 (t,
[6] a) L. Jiang, X. Lu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem. 2009,
74, 4542; b) M. S. Lam, H. W. Lee, A. S. C. Chen, F. Y. Kwong,
Tetrahedron Lett. 2008, 49, 6192; c) F. Y. Kwong, A. Klapars,
S. L. Buchwald, Org. Lett. 2002, 4, 581; d) M. Wolter, A. Klapars,
S. L. Buchwald, Org. Lett. 2001, 3, 3803; e) Z. Wang, R. T. Skerlj,
G. J. Bridger, Tetrahedron Lett. 1999, 40, 3543.
[7] For the Pd-catalyzed coupling reaction of hydrazine en route to
aryl hydrazines, see: R. J. Lundgren, M. Stradiotto, Angew.
Chem. 2010, 122, 8868; Angew. Chem. Int. Ed. 2010, 49, 8686.
[8] T. J. Greshock, R. L. Funk, J. Am. Chem. Soc. 2006, 128, 4946.
2498 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 2496 –2499

Angewandte
Chemie
[9] a) R. J. Rafferty, R. M. Williams, J. Org. Chem. 2012, 77, 519;
b) X. Li, X. Gong, M. Zhao, G. Song, J. Deng, X. Li, Org. Lett.
2011, 13, 5808; c) D.-J. Cheng, H.-B. Wu, S.-K. Tian, Org. Lett.
2011, 13, 5636; d) K. S. Feldman, P. Ngernmeesri, Org. Lett. 2011,
13, 5704.
[10] For a recent synthesis, see: a) Z. Xu, Q. Li, L. Zhang, Y. Jia, J.
Org. Chem. 2010, 75, 6316; b) J.-M. Ku, B.-S. Jeong, S.-S. Jew, H.-
G. Park, J. Org. Chem. 2007, 72, 8115; c) Y. Yokoyama, H.
Hikawa, M. Mitsuhashi, A. Uyama, Y. Hiroki, Y. Murakami,
Eur. J. Org. Chem. 2004, 1244.
[11] a) Z. Zuo, W. Xie, D. Ma, J. Am. Chem. Soc. 2010, 132, 13226;
b) J. H. Seo, P. Liu, S. M. Weinreb, J. Org. Chem. 2010, 75, 2667;
c) J. Yang, H. Wu, L. Shen, Y. Qin, J. Am. Chem. Soc. 2007, 129,
13794.
[12] For a recent synthesis, see: a) S. Inuki, S. Oishi, N. Fujii, H.
Ohno, Org. Lett. 2011, 13, 2145; b) T. Kurokawa, M. Isomura, H.
Tokuyama, T. Fukuyama, Synlett 2009, 775; c) S. K. Bur, A.
Padwa, Org. Lett. 2002, 4, 4135; d) A. Liras, C. L. Lynch, A. M.
Fryer, B. T. Vu, S. F. Martin, J. Am. Chem. Soc. 2001, 123, 5918.
[13] For a recently reported total synthesis, see: a) A. D. Huters,
K. W. Quasdorf, E. D. Styduhar, N. K. Garg, J. Am. Chem. Soc.
2011, 133, 15797; for the synthesis of the welwitindolinone core
or related compounds, see: b) V. Bhat, K. M. Allan, V. H. Rawal,
J. Am. Chem. Soc. 2011, 133, 5798; c) V. Bhat, J. A. MacKay,
V. H. Rawal, Org. Lett. 2011, 13, 3214; d) D. B. Freeman, A. A.
Holubec, M. W. Weiss, J. A. Dixon, A. Kakefuda, M. Ohtsuka,
M. Inoue, R. G. Vaswani, H. Ohki, B. D. Doan, S. E. Reisman,
B. M. Stoltz, J. J. Day, R. N. Tao, N. A. Dieterich, J. Wood,
Tetrahedron 2010, 66, 6647; e) J. A. Brailsford, R. Lauchli, K. J.
Shea, Org. Lett. 2009, 11, 5330; f) T. J. Greshock, R. L. Funk,
Org. Lett. 2006, 8, 2643.
[14] a) S.-E. Suh, I.-K. Park, B.-Y. Lim, C.-G. Cho, Eur. J. Org. Chem.
2011, 455; b) W.-J. Lee, H.-Y. Kim, C.-G. Cho, Org. Lett. 2007, 9,
3185; c) H.-Y. Kim, W.-J. Lee, H.-M. Kang, C.-G. Cho, Bull.
Korean Chem. Soc. 2007, 28, 1821; d) H.-M. Kang, H.-Y. Kim, J.-
W. Jung, C.-G. Cho, J. Org. Chem. 2007, 72, 679; e) H.-M. Kang,
Y.-K. Lim, I.-J. Shin, H.-Y. Kim, C.-G. Cho, Org. Lett. 2006, 8,
2047; f) Y.-K. Lim, J.-W. Jung, C.-G. Cho, J. Org. Chem. 2004, 69,
5778; g) Y.-K. Lim, S. Choi, K. B. Park, C.-G. Cho, J. Org. Chem.
2004, 69, 2603; h) K.-S. Lee, K.-Y. Kim, J.-T. Shin, C.-G. Cho,
Tetrahedron Lett. 2004, 45, 117; i) Y.-K. Lim, S.-J. Pang, S.-U.
Paek, H. Lee, C.-G. Cho, Bull. Korean Chem. Soc. 2003, 24, 543;
j) Y.-K. Lim, K.-S. Lee, C.-G. Cho, Org. Lett. 2003, 5, 979; k) G.-
S. Lee, Y.-K. Lim, C.-G. Cho, Tetrahedron Lett. 2002, 43, 7463.
[15] N. C¸ elebi-ꢁlÅꢀm, B. W. Boal, A. D. Huters, N. K. Garg, K. N.
Houk, J. Am. Chem. Soc. 2011, 133, 5752.
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