Synthesis of the azocino[cd]indole framework through Pd-catalyzed intramolecular acetylene hydroarylation

Article abstract of DOI:10.1002/ejoc.201001669

The regio- and stereoselective construction of the azocino[cd]indole core was achieved by applying a Pd-catalyzed intramolecular acetylene hydroarylation protocol. The applicability of a similar strategy for the synthesis of the azepino[b]indole framework

Full text of DOI:10.1002/ejoc.201001669

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001669
Synthesis of the Azocino[cd]indole Framework through Pd-Catalyzed
Intramolecular Acetylene Hydroarylation
Vsevolod A. Peshkov,[a] Sofie Van Hove,[a] Pavel A. Donets,[a] Olga P. Pereshivko,[a]
Kristof Van Hecke,[b] Luc Van Meervelt,[b] and Erik V. Van der Eycken*[a]
Keywords: C-C coupling / Cyclization / Nitrogen heterocycles / Medium-ring compounds / Palladium
The regio- and stereoselective construction of the azocino-
[cd]indole core was achieved by applying a Pd-catalyzed in-
tramolecular acetylene hydroarylation protocol. The applica-
bility of a similar strategy for the synthesis of the azepino[b]-
indole framework is demonstrated.
(Figure 1). The key step is the construction of the eight-
membered ring by applying a Pd-catalyzed intramolecular
acetylene hydroarylation reaction,[9,10] which occurs regio-
and stereoselectively.[11]
Introduction
Natural compounds containing a medium-sized ring
fused with the indole core[1] have attracted substantial inter-
est in recent years. Several efforts have been made towards
the synthesis of subincanadine F (1)[2] and balasubramide
(2),[3] which are members of the azepino[b]indole and azoci-
no[b]indole alkaloid family, respectively. The natural prod-
uct decursivine (3) was isolated in 2002 from Rhaphidophora
decursiva, a plant found in the Cuc Phuong National Park
in Vietnam.[4] Spectroscopic analysis of 3 showed a remark-
able resemblance with serotobenine (4), a natural product
isolated from safflower seeds (Carthamus tinctorius L.) by
Sato and co-workers in 1985.[5] Both decursivine and sero-
tobenine supposedly[6] share a common biosynthesis from
serotonin and an appropriately substituted cinnamic acid.
The total syntheses of (Ϯ)-decursivine[6] and (–)-seroto-
benine[7] have been reported recently.
Figure 1. Alkaloids and related compounds containing a medium-
sized ring fused with indole.
Results and Discussion
As a part of our continued interest in the synthesis of
medium-sized rings we have recently described a micro-
wave-assisted Hg(OTf)2-catalyzed intramolecular alkyne
carbocyclization reaction that allows fast access to vari-
ously substituted azocino[b]indoles.[8] Herein we report an
efficient protocol for the synthesis of azocino[cd]indoles of
type 5, which are structurally related to alkaloids 3 and 4
The sequence starts with readily available 4-bromo-
tryptamines 6a,b,[12] which after coupling with variously 3-
substituted 2-propynoic acids deliver substrates 7a–h for in-
tramolecular acetylene hydroarylation (Scheme 1). Tertiary
propargylamides 7a–f were obtained in good yields as mix-
tures of rotamers mainly in a 3:2 ratio. Secondary prop-
argylamide 7g was obtained in 70% yield as a 5:1 mixture
of rotamers. Secondary propargylamide 7h was directly
transferred to the next step without characterization due to
difficulties with isolation.
[a] Laboratory for Organic and Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, Katholieke Universiteit
Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32-16-32-79-90
E-mail: erik.vandereycken@chem.kuleuven.be
[b] Biomolecular Architecture, Department of Chemistry,
Katholieke Universiteit Leuven,
Then we investigated the cyclization of generated propar-
gylamides 7a–h through a Pd-catalyzed intramolecular
acetylene hydroarylation reaction similar to our previously
described protocol for the synthesis of 3-benzazepines.[10b]
Celestijnenlaan 200F, 3001 Leuven, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001669.
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E. V. Van der Eycken et al.
SHORT COMMUNICATION
tion of secondary amides 7g,h could be ascribed to competi-
tive side processes involving the unprotected nitrogen atom.
We were able to purify new azocino[cd]indoles 5a–h by
column chromatography on silica gel, and their structures
were confirmed by 1H and 13C NMR spectroscopy and
HRMS (EI).[14] In addition, the structure of 5b was con-
firmed by X-ray crystallography (Figure 2).[15] The 1H
NMR spectra of azocino[cd]indoles 5a–h recorded at room
temperature show that 5a–h exist as a mixtures of two enan-
tiomeric conformers (atropisomers) due to hindered rota-
Scheme 1. Synthesis of propargylamides 7a–f.
Microwave-assisted cyclization of substrates 7a–e into
azocino[cd]indoles 5a–e proceeded very smoothly in DMF/
water (3:1) at a ceiling temperature of 110 °C with complete
conversion of the starting material in a mere 15 min
(Table 1, Entries 1–5). The eight-membered ring was selec-
tively formed in good yields with full control of the geome-
try around the exocyclic double bond. The lower yield ob-
tained for 5d could be ascribed to the bulkiness of the tert-
butyl substituent of the acetylene (Table 1, Entry 4). How-
ever, when compound 7f was used, a significant drop in
the yield was observed (Table 1, Entry 6) even though the
reaction was run under mild conventional heating at 65 °C
in DME/water (4:1).[13] Desired compound 5f could be ob-
tained in 34% yield, next to decomposed material due to
the competitive cleavage of the labile TIPS protecting
group.
Next we applied our protocol for the construction of
azocino[cd]indoles bearing a free NH group in the azocine
ring. Carrying out the reactions with propargylamides 7g,h
under microwave-assisted protocol, desired azocino[cd]-
indoles 5g,h were obtained in 46 and 26% yield, respectively
Figure 2. X-ray crystallographic structure of compound 5b, show-
ing thermal ellipsoids at the 50% probability level and atom label-
(Table 1, Entries 7 and 8). The lower yields of the cycliza- ing scheme.
Table 1. Synthesis of azocino[cd]indoles 5a–h.
Entry
R1
R2
Conditions
Product
Yield [%][a]
1
2
3
4
5
6
7
8
Me
Et
Pr
tBu
PMB
PMB
PMB
PMB
PMB
PMB
H
MW, 15 min, 110 °C, DMF/water (3:1)
MW, 15 min, 110 °C, DMF/water (3:1)
MW, 15 min, 110 °C, DMF/water (3:1)
MW, 15 min, 110 °C, DMF/water (3:1)
MW, 15 min, 110 °C, DMF/water (3:1)
conventional, 6 h, 65 °C, DME/water (4:1)
MW, 15 min, 110 °C, DMF/water (3:1)
MW, 15 min, 110 °C, DMF/water (3:1)
5a
5b
5c
5d
5e
5f
77
75
67
47
65
3,4,5-(MeO)3C6H2
TIPS
Pent
Ph
34
5g
5h
46
H
26[b]
[a] Isolated yield is reported. [b] Yield over two steps based on 6b.
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Pd-Catalyzed Synthesis of the Azocino[cd]indole Framework
tion about the vinyl–aryl (C5–C9 for 5b) bond.[16] Com-
pound 5b crystallized in the chiral space group P212121;
hence, only one enantiomer should be present in the asym-
metric unit. However, additional racemic twinning was ob-
served with a twin fraction of 0.1(3).
123.02, 122.96, 120.49, 120.12, 113.87, 111.31, 110.69, 55.00, 44.80,
44.58, 25.39, 14.80 ppm. HRMS (EI): calcd. for C22H22O2N2
346.1681; found 346.1685.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data along with
To explore the general applicability of our strategy for copies of the NMR spectra.
the synthesis of medium-sized rings fused with an indole
core, we evaluated the protocol for the generation of azep-
ino[b]indoles. The Pd-catalyzed cyclization of more reactive
2-iodoindole derivatives 8a,b required the use of milder
Acknowledgments
conditions compared to 4-bromoindole derivatives 7a–f.
Support was provided by the Fund for Scientific Research (FWO),
Therefore, propargylamides 8a,b[12] were treated under con-
ventional heating at 80 °C to deliver the seven-membered
ring of the azepino[b]indole core in 68 and 56% yield for
9a,b, respectively (Scheme 2).
Flanders and by the Research Fund of the Katholieke Universiteit
Leuven. P.V.A. is grateful to the EMECW (Triple I) for obtaining
a doctoral scholarship. P.A.D. is grateful to the Katholieke Uni-
versiteit Leuven for obtaining a doctoral scholarship. The authors
thank Ir. B. Demarsin for valuable help with HRMS.
[1] For general approaches towards indole-fused medium-ring
compounds, see: a) A. V. Kalinin, B. A. Chauder, S. Rakhit, V.
Snieckus, Org. Lett. 2003, 5, 3519–3521; b) C. Ferrer, A. M.
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Echavarren, Chem. Eur. J. 2007, 13, 1358–1373; d) S. G. Ste-
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2010, 944–946.
Scheme 2. Synthesis of azepino[b]indoles 9a,b.
[2] For the synthesis, see: a) P. Chen, L. Cao, C. Li, J. Org. Chem.
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[3] For the synthesis of both antipodes of balasubramide, see: a)
M. B. Johansen, A. B. Leduc, M. A. Kerr, Synlett 2007, 2593–
2595; for the synthesis of (–)-balasubramide, see: b) L. Yang,
G. Deng, D.-X. Wang, Z.-T. Huang, J.-P. Zhu, M.-X. Wang,
Org. Lett. 2007, 9, 1387–1390.
[4] H. Zhang, S. Qiu, P. Tamez, G. T. Tan, Z. Aydogmus, N.
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Conclusions
In conclusion we have elaborated a novel procedure for
the construction of the azocino[cd]indole framework
through a Pd-catalyzed intramolecular acetylene hydroaryl-
ation reaction. The conversion is rapid, regioselective, and
stereoselective and proceeds with moderate to good yields.
The applicability of a similar strategy for the synthesis of
the azepino[b]indole framework is demonstrated.
Experimental Section
General Procedure for the Synthesis of the Azocino[cd]indole Frame-
work by Pd-Catalyzed Intramolecular Acetylene Hydroarylation:
Pd(PPh3)4 (9 mg, 3 mol-%) and HCOONa (26 mg, 0.38 mmol)
were loaded into a microwave instrument vial. Propargylamide 7a
(106 mg, 0.25 mmol) dissolved in DMF (2.8 mL) was added, fol-
lowed by distilled water (0.9 mL). The vial was evacuated and
flushed with argon. The reaction mixture was sealed and irradiated
with stirring at the set temperature of 110 °C at 100 W maximum
power level for 15 min. Upon completion of the reaction, the vial
was cooled with a stream of air. The reaction mixture was concen-
trated to dryness under reduced pressure. The crude product was
isolated by column chromatography on silica gel (Et2O/DCM, 1:20)
to yield 5a (67 mg, 77%). 1H NMR (300 MHz, [D6]DMSO): δ =
11.20 (br. s, 1 H), 7.37–7.25 (m, 3 H), 7.23–7.17 (m, 1 H), 7.07–
6.99 (m, 1 H), 6.95–6.84 (m, 3 H), 5.75 (q, J = 6.8 Hz, 1 H), 5.04
(d, J = 14.6 Hz, 1 H), 4.33–4.16 (m, 1 H), 4.01 (d, J = 14.6 Hz, 1
H), 3.75 (s, 3 H), 3.45–3.25 (m, 2 H), 3.03–2.86 (m, 1 H), 1.73 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
169.69, 158.45, 141.94, 136.45, 130.98, 129.72, 129.21, 124.92,
[6] A. B. Leduc, M. A. Kerr, Eur. J. Org. Chem. 2007, 237–240.
[7] Y. Koizumi, H. Kobayashi, T. Wakimoto, T. Furuta, T. Fukuy-
ama, T. Kan, J. Am. Chem. Soc. 2008, 130, 16854–16855.
[8] P. A. Donets, K. Van Hecke, L. Van Meervelt, E. V.
Van der Eycken, Org. Lett. 2009, 11, 3618–3621.
[9] For a review, see: S. Cacchi, Pure Appl. Chem. 1990, 62, 713–
722.
[10] For the synthesis of medium-sized benzazepine rings applying
a Pd-catalyzed intramolecular acetylene hydroarylation, see: a)
L. F. Tietze, R. Schimpf, Chem. Ber. 1994, 127, 2235–2240; b)
P. A. Donets, E. V. Van der Eycken, Org. Lett. 2007, 9, 3017–
3020; c) P. A. Donets, J. L. Goeman, J. Van der Eycken, K. Ro-
beyns, L. Van Meervelt, E. V. Van der Eycken, Eur. J. Org.
Chem. 2009, 793–796; d) V. A. Peshkov, O. P. Pereshivko, P. A.
Donets, V. P. Mehta, E. V. Van der Eycken, Eur. J. Org. Chem.
2010, 4861–4867.
[11] Azocino[cd]indoles thus obtained possess the (Z) configuration
of the exocyclic double bond.
[12] See the Supporting Information for details.
[13] The experimental conditions for this transformation were taken
in accordance with our previous experience with the intramo-
Eur. J. Org. Chem. 2011, 1837–1840
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E. V. Van der Eycken et al.
SHORT COMMUNICATION
lecular hydroarylation of silyl-protected acetylenes (see
ref.[10b,10c]). A relatively low temperature of 65 °C was applied
to prevent fast decomposition of starting propargyl amide 7f
and nascent azocino[cd]indole 5f.
[14]
For compound 5f, MS (CI) was recorded.
[15] CCDC-804480 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[16] For the NMR spectroscopic variable-temperature experiment
with compound 5a, see the Supporting Information.
Received: December 13, 2010
Published Online: February 17, 2011
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Eur. J. Org. Chem. 2011, 1837–1840