An efficient synthesis of 9H-pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1016/j.tetlet.2008.11.064

A novel and effective method has been developed for the synthesis of 9H-pyrrolo[1,2-a]indoles by treatment of 3-substituted-4,6-dimethoxyindoles with chalcones in the presence of hydrochloric acid.

Full text of DOI:10.1016/j.tetlet.2008.11.064

Tetrahedron Letters 50 (2009) 574–576
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Tetrahedron Letters
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An efficient synthesis of 9H-pyrrolo[1,2-a]indoles
*
Kasey Wood, David StC. Black, Naresh Kumar
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and effective method has been developed for the synthesis of 9H-pyrrolo[1,2-a]indoles by treat-
ment of 3-substituted-4,6-dimethoxyindoles with chalcones in the presence of hydrochloric acid.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 24 September 2008
Revised 10 November 2008
Accepted 19 November 2008
Available online 24 November 2008
Keywords:
Indole
Pyrroloindole
Chalcone
Acid-catalyzed reaction
Indoles are widely distributed in Nature, and possess a variety
of significant biological activities.1 They also serve as useful inter-
mediates for the synthesis of a wide range of more complex het-
erocyclic compounds. Consequently, the synthesis and reactions
of indoles are continuing areas of interest.2
We have previously reported that 4,6-dimethoxy-3-methylin-
dole 1 undergoes acid-catalyzed reactions with aryl aldehydes to
give 2,20-di-indolylmethanes and macrocyclic calixindoles.3 Simi-
lar treatment of indole 1 with ketones such as acetone and ace-
tophenones in methanolic hydrochloric acid gave reduced
pyrroloindoles of the isoborreverine type.4
um bromide. A tandem Wittig-metathesis reaction uses N-allylin-
dole-2-carbaldehyde to generate the target compound.11 Caddick
et al. developed a radical cyclization procedure to synthesize 9H-
pyrroloindole from N-(3-bromopropyl)-2-(4-methylbenzenesulfo-
nyl)indole.12 However, these preparations of 9H-pyrroloindoles in-
volve multiple steps and the yields are often poor. Despite the
numerous advances made, the synthesis of functionalized indoles
still represents a significant synthetic challenge.
The structures of 9H-pyrrolo[1,2-a]indoles 2 were determined
through 1D and 2D NMR spectroscopy. The 1H NMR spectrum
As part of our continuing interest in the development of new
synthetic methods for the preparation of indole alkaloids and to
MeO
MeO
Me
Me
O
extend our earlier work on
a,b-unsaturated ketones, the
R1
HCl
+
R1
R2
dimethoxy indole 1 was treated with a range of chalcones in the
presence of hydrochloric acid. Surprisingly, we observed the for-
mation of a new series of 9H-pyrrolo[1,2-a]indoles 2 (Scheme 1).
9H-Pyrroloindole is an important precursor for the synthesis of
mitomycin antibiotics.5 In addition, the parent 9H-pyrrolo[1,2-
a]indole (fluorazine) is known for its anticholinergic activity,6
and for inhibition of GABA transport and Na+/K+-ATPase.7
Synthetic routes to 9H-pyrrolo[1,2-a]indoles have been re-
ported in the literature;8 however, most of them have been direc-
ted towards the synthesis of mitomycin antibiotics. 9H-
Pyrroloindole can be obtained from the Wolff–Kishner reduction
of corresponding 9-keto-9H-pyrroloindole.5 Hirata et al.9 and
Cotterill et al.10 prepared 9H-pyrroloindole by treating indole-2-
carbaldehyde with sodium hydride and vinyltriphenylphosphoni-
N
N
MeO
MeO
H
R2
1
2
R1
R2
Yield %
59
Entry Product
1
2
2a
2b
2c
2d
Cl
OMe
Cl
36
31
79
Me
Cl
3
4
OMe
Cl
Cl
* Corresponding author. Tel.: +61 2 9385 4698; fax: +61 2 9385 6141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
Scheme 1. Reagents and conditions: HCl, i-PrOH, reflux, 2 h.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.064

K. Wood et al. / Tetrahedron Letters 50 (2009) 574–576
575
showed the disappearance of the H2 and NH signals of the starting
material, while the meta-coupled H5 and H7 signals remained in-
tact. It was deduced that the aromaticity of the indole had been
disrupted as the 9-methyl group appeared as a doublet, coupling
to a new signal at 4.4 ppm assigned to H9.13 Finally, a new singlet
at 6.4 ppm was assigned to the pyrrole H2. The chalcone aromatic
rings were assigned through NOE correlations to H5 and H9, and in
all cases the substituent adjacent to the ketone in the chalcone was
found closer to the nitrogen in the product.
In light of the successful cyclization reactions of 3-methylindole
1, the methodology was extended to 3-arylindoles 3. The reaction
proved to be highly versatile, accommodating 3-aryl indoles 3 with
a variety of substituents (Scheme 2). Reaction yields of 9H-pyrro-
loindoles 4 were improved by reducing the solvent volume and
cooling prior to collection in order to maximize the precipitation
of product. A similar reaction of the parent 3-methylindole with
chalcone was very sluggish, and gave only a low yield of the re-
duced pyrroloindole related to structure 4. This is consistent with
an earlier report that the reaction of 3-methylindole with methyl
vinyl ketone gave a complex mixture of products that included a
very low yield of a reduced pyrroloindole (of uncertain structure)
resulting from the addition of 2 equiv of methyl vinyl ketone.14
The structure of compound 4i was confirmed by X-ray crystallog-
raphy (Figure 1).
Formation of these 9H-pyrroloindoles proceeds through the Mi-
chael addition of the indole to the chalcone double bond and sub-
sequent ring closure to the nitrogen with concurrent loss of water.
This was confirmed as the reaction of 1-methylindole 5 with chal-
cone 6 gave the simple Michael addition product 7 (Scheme 3).
Conversely, no reaction occurred when 2,3-dimethyl-4,6-dim-
ethoxyindole was reacted with chalcone. This reaction sequence
determines the nature of the pyrrole ring substituents R2 and R3,
and is consistent with the observed NOE data.
R1
R1
MeO
MeO
O
R2
HCl
+
R2
R3
N
The ratio of indole to chalcone was varied in order to examine
whether the reduced pyrroloindole structure could be obtained
comparable to those found when reacting 3-substituted indoles
with ketones under the same conditions. However, only the mono-
meric pyrroloindoles 4 were obtained even at a 2:1 ratio of indole
to chalcone and in much lower yields.
N
H
MeO
MeO
R3
4
3
R2
R1
R3
Yield %
87
Entry Product
In an attempt to extend this work to non-aryl a,b-unsaturated
1
4a
4b
4c
4d
4e
Cl
OMe
OMe
OMe
OMe
Cl
Me
Cl
ketones, mesityl oxide was reacted with indole 1 in the presence
of hydrochloric acid. The precipitated product was found to be
the reduced pyrroloindole 8 in 70% yield. This compound is the
product of the reaction of indole 1 with acetone under acidic con-
ditions.4 No product could be isolated from the reaction with 3-
penten-2-one. 1,3-Dimethylindole has been shown to react with
2
OMe
Cl
62
59
74
63
65
58
3
Cl
Me
4
Cl
5
OMe
Cl
Cl
Cl
6
4f
Cl
4g
7
Cl
Me
Cl
8
4h
4i
Cl
Br
95
83
58
73
63
81
88
OMe
9
Br
10
11
12
13
14
4j
OMe
Cl
Br
Cl
Figure 1. ORTEP diagram of compound 4i.15
Me
4k
4l
Br
Br
Br
Me
Cl
Me
Me
Me
Cl
O
MeO
MeO
Me
O
HCl
4m
OMe
Cl
+
N
Me
(73%)
7
N
Me
MeO
MeO
Cl
4n
Me
Cl
5
6
Cl
Scheme 2. Reagents and conditions: HCl, i-PrOH, reflux 3 h.
Scheme 3. Reaction of 1-methylindole 5 with chalcone 6.

576
K. Wood et al. / Tetrahedron Letters 50 (2009) 574–576
mesityl oxide to give a reduced carbazole.14,16 The presence of the
two activating methoxy groups clearly has a major influence both
on the regioselectivity and the product yields.
3. Black, D. StC.; Craig, D. C.; Kumar, N. J. Chem. Soc., Chem. Commun. 1989, 425–
426.
4. Black, D. StC.; Craig, D. C.; Kumar, N. Tetrahedron Lett. 1991, 32, 1587–1590.
5. Mazzola, V. J.; Bernady, K. F.; Franck, R. W. J. Org. Chem. 1967, 32, 486–489.
6. Azarashvili, A. A. Neurosci. Behav. Physiol. 1997, 27, 341–346.
7. Maisov, N. I.; Sandalov, Y. S.; Glebov, R. N.; Raevskii, K. S. Byull. Eksp. Biol. Med.
1976, 81, 45–47.
8. Bailey, A. S.; Scott, P. W.; Vandrevala, M. H. J. Chem. Soc., Perkin Trans. 1 1980,
97–101.
9. Hirata, T.; Yamada, Y.; Matsui, M. Tetrahedron Lett. 1969, 10, 19–22.
10. Cotterill, A. S.; Hartopp, P.; Jones, G. B.; Moody, C. J.; Norton, C. L.; O’Sullivan,
N.; Swann, E. Tetrahedron 1994, 50, 7657–7674.
MeO
Me
Me
Me
N
MeO
Me
Me
HN
8
11. González-Pérez, P.; Pérez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Pérez-
Castells, J. Tetrahedron Lett. 2002, 43, 4765–4767.
OMe
12. Caddick, S.; Aboutayab, K.; Jenkins, K.; West, R. I. J. Chem. Soc., Perkin Trans. 1
1996, 675–682.
MeO
13. Representative procedure for compound 2d: Indole 1 (1.0 mmol) and 3-(4-
chlorophenyl)-1-(4-chlorophenyl)prop-2-en-1-one (1.5 mmol) were dissolved
together in isopropanol (10 ml), and concentrated hydrochloric acid (1 ml) was
added. The reaction was refluxed for 2 h before cooling. The precipitate was
collected and recrystallized from acetonitrile to give 2d as a white solid. Mp
192–193 °C. 1H NMR (300 MHz, CDCl3): d 1.49 (3H, d, J 6.75 Hz, CH3), 3.67 (3H,
s, OCH3), 3.87 (3H, s, OCH3), 4.40 (1H, q, J 6.78 Hz, H9), 6.23 (1H, d, J 1.89 Hz,
H7), 6.28 (1H, d, J 1.89 Hz, H5), 6.49 (1H, s, H2), 7.34 (2H, d, J 8.67 Hz, Haryl),
7.42 (2H, d, J 8.28 Hz, Haryl), 7.52 (2H, d, J 8.28 Hz, Haryl), 7.53 (2H, d, J 8.67 Hz,
Haryl) ppm; 13C NMR (75 MHz, CDCl3): d 15.4, 34.3, 55.3, 55.4, 91.4, 93.6, 112.6,
116.7, 119.2, 126.9, 127.1, 128.4, 128.7, 130.2, 130.8, 130.9, 133.5, 133.6, 140.4,
141.5, 156.9, 160.8 ppm; IR (KBr): mmax 2968, 2931, 1624, 1599, 1577, 1559,
In conclusion, 3-substituted indoles have been converted effec-
tively, in a single step, to the corresponding 9H-pyrrolo[1,2-a]in-
doles. This newly developed method offers quick access to
building blocks for various molecular constructions.
Acknowledgements
1488, 1468, 1430, 1303, 1202, 1169, 1149, 1090, 1058, 1012, 836, 786 cmꢀ1
UV–vis (MeOH): kmax 204 nm (
53,600 cmꢀ1 Mꢀ1), 211 (46,700), 234 (35,800),
;
e
We thank the University of New South Wales and the Australian
Research Council for their financial support.
293 (33,000); Anal. Calcd for C26H21Cl2NO2: C, 69.34; H, 4.70; N, 3.11. Found C,
69.23; H, 4.82; N, 3.10.
14. Garnick, R. L.; Levery, S. B.; Le Quesne, P. W. J. Org. Chem. 1978, 43, 1226–1229.
15. Crystallographic data for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 703105 (4i). X-ray crystal structures were obtained by Don Craig and
Mohan Bhadbhade, Crystallography Laboratory, UNSW Analytical Centre,
Sydney, Australia.
References and notes
1. Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.. In Comprehensive Heterocyclic
Chemistry II; Elsevier Science Ltd: Oxford, 1996; Vol. 2.
16. Cockerill, D. A.; Robinson, R.; Saxton, J. E. J. Chem. Soc. 1955, 4369–4373.
2. Pelkey, E. T. Prog. Heterocycl. Chem. 2006, 19, 135–175.