A versatile synthetic route to 11H-indolo[3,2-c]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2009.07.107

A wide variety of indoloisoquinoline derivatives are prepared from the acid-catalyzed cyclization of 3-amido-2-phenylindoles, which in turn were obtained from the Beckmann rearrangement of 2-phenylindole-3-oximes.

Full text of DOI:10.1016/j.tetlet.2009.07.107

Tetrahedron Letters 50 (2009) 5628–5630
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A versatile synthetic route to 11H-indolo[3,2-c]isoquinolines
*
Ji Qu, Naresh Kumar, Mahiuddin Alamgir, David StC. Black
School of Chemistry, The University of New South Wales, UNSW 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 wide variety of indoloisoquinoline derivatives are prepared from the acid-catalyzed cyclization of
3-amido-2-phenylindoles, which in turn were obtained from the Beckmann rearrangement of 2-phenyl-
indole-3-oximes.
Received 5 June 2009
Revised 10 July 2009
Accepted 17 July 2009
Available online 24 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Indoloisoquinoline
Beckmann rearrangement
Acid-catalyzed cyclization
Indoles exhibit potent biological activity and there is a contin-
uing demand for novel synthetic methods to prepare new indole
derivatives.1–3 The tetracyclic structures related to the indoloiso-
quinolines have received considerable attention due to their inter-
esting biological properties including anti-tumour, fungicidal,
analgesic, anti-inflammatory, anthelmintic and antibacterial activ-
ities.4–6 The parent compound 11H-indolo[3,2-c]isoquinoline 1 has
not yet been found in Nature. However, the related indoloquinoline
and quindoline ring systems constitute important structural moie-
ties in natural products, as exemplified by the biologically active
compounds cryptosanguinolentine 2, cryptolepine 3 and neocry-
ptolepine 4 (Fig. 1).7,8 We have recently described the synthesis
of 7H-indolo[2,3-c]quinolines9,10 5. Although the parent 11H-indo-
indolo[3,2-c]isoquinolines 1, employing the Beckmann rearrange-
ment of a variety of 2-phenylindole-3-oximes and cyclization of
the intermediate amides.
2-Phenylindole18 6 was formylated with the Vilsmeier reagent
at 0 °C to afford indole-3-carbaldehyde19 7 in 89% yield (Scheme
1). Treatment of 3-formylindole 7 with hydroxylamine hydrochlo-
ride and potassium hydroxide gave the desired indole-3-car-
baldoxime20 8 in high yield. However, attempts to cyclize the
oxime 8 by the reported procedure were unsuccessful. Instead, 3-
cyano-2-phenylindole21 9 and 2-phenylindole 6 were obtained as
the only products. The Beckmann rearrangement reaction condi-
tions were varied with respect to solvent but again led to the for-
mation of the 3-cyano-indole 9.
lo[3,2-c]isoquinoline
1
and its 5-substituted analogues are
Treatment of 3-acetyl-2-phenylindoles 10 with hydroxylamine
hydrochloride in 95% ethanol containing sodium acetate gave the
known,11–14 further functionalized derivatives are rare. Therefore
a general synthetic route to substituted 11H-indolo[3,2-c]isoquin-
olines 1 is of particular interest.
Me
N
Me
Syntheses of isoquinolines have been extensively reported in
the literature and typically involve Pomeranz–Fritsch, Bischler–
Napieralski and Pictet–Spengler reactions.15 However, recently,
11H-indolo[3,2-c]isoquinoline 1 has been prepared via a selective
Buchwald–Hartwig reaction followed by a Pd-catalyzed intramo-
lecular direct arylation reaction.16 Hiremath et al. have reported17
the formation of indolo[3,2-c]isoquinolines by cyclization of in-
dole-3-carbaldoximes with alcoholic sulfuric acid. This reaction
proceeds through Beckmann rearrangement followed by Bisch-
ler–Napieralski cyclization of the 3-amidoindole to the indoloiso-
quinoline. Here we describe an efficient synthesis of 11H-
N
N
N
NH
N
1
2
3
N
N
Me
N
NH
4
5
* Corresponding author. Tel.: +61 2 9385 4657; fax: +61 2 9385 6141.
E-mail address: d.black@unsw.edu.au (D.StC. Black).
Figure 1. 11H-indolo[3,2-c]isoquinoline 1, cryptosanguinolentine 2, cryptolepine 3,
neocryptolepine 4 and 7H-indolo[3,2-c]quinoline 5.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.107

J. Qu et al. / Tetrahedron Letters 50 (2009) 5628–5630
5629
Table 1
H
O
Synthesis of compounds 10–13
DMF/POCl3
89%
Entry
R
R1
Product
Yielda (%)
Mp (°C)
220–22222
N
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
H
Me
MeO
H
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
93
80
88
93
96
95
72
72
64
60
44
42
43
48
65
30
N
H
66–6823
208–211
227–23024
177–180
212–214
184–187
186–188
203–20511
171–17425
135–138
247–250
238–24111
115–117
232–235
233–236
6
7
NH2OH.HCl/KOH
95%
H
Me
MeO
H
OH
H
H
N
Me
MeO
H
H
Me
MeO
conc. H2SO4
CN
ethanol
N
H
10%
N
H
8
9
a
Yield of isolated pure product.
Scheme 1.
OH
Me
OH
N
N
Me
Me
conc. H2SO4
ethanol
NH2
O
NH2OH.HCl
NaOAc
R1
R1
N
H
60%
N
H
N
80-90%
N
R
R
14
11a
11a-d
10a-d
R
18-51%
conc. H2SO4
MeCN
30-60%
COCl
Me
O
Me
R
O
HN
N
R
P2O5
R1
R1
N
R
26-60%
N
R
HN
N
13a-d
12a-d
P2O5
Scheme 2.
N
H
26-67%
N
H
16a-e
15a-e
corresponding 2-phenylindole-3-acetoximes 11 in 80–90% yield
(Scheme 2). 3-Acetamido-2-phenylindoles 12 were produced by
Beckmann rearrangement of 2-phenylindole-3-acetoximes 11 with
concentrated sulfuric acid in acetonitrile under reflux for 2–6 h in
30–60% yields. The final cyclization step was carried out by heating
with P2O5 in toluene, to afford the 11H-indolo[3,2-c]isoquinolines
13 (Table 1).
However, the same reaction when carried out on 2-phenylin-
dole-3-acetoxime 11a with concentrated sulfuric acid in ethanol
gave 3-amino-2-phenylindole26 14 in 60% yield (Scheme 3). The
isolation of the 3-aminoindole rather than the 3-acetamidoindole
afforded an opportunity to synthesize differently substituted indo-
loisoquinolines, without the need to start from 2-phenylindole 6 in
each case. Furthermore, this synthesis of the known 3-amino-2-
phenylindole 14 is more efficient than the previously reported
method, which utilized hydrogenation of the related 3-nitroindole
with a palladium catalyst.26
Scheme 3.
the 11H-indolo[3,2-c]isoquinolines 16 was achieved by heating with
P2O5 in toluene in moderate yields28 (Table 2).
The structures of the indoloisoquinolines were established on
the basis of NMR spectroscopy and on reported spectroscopic data.
Also, an X-ray crystal structure (Fig. 2) of compound 16d was ob-
Table 2
Synthesis of compounds 15–16
Entry
R
Product
Yielda (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
Br
Cl
F
15a
15b
15c
15d
15e
16a
16b
16c
16d
16e
32
18
51
31
44
67
32
26
53
43
195–19827
208–21127
178–181
188–190
199–20327
291–293
300–302
296–298
256–258
234–23729
MeO
H
Treatment of 3-amino-2-phenylindole 14 with 4-substituted ben-
zoyl chlorides in the presence of sodium bicarbonate gave the corre-
sponding 3-benzamido-2-phenylindoles 15 (Scheme 3). The amides
15a,b,e have been prepared previously by Przheval’skii et al. via the
Fischer synthesis of the phenylhydrazones of benzamidoacetophe-
nones.27 The cyclization of 3-benzamido-2-phenylindoles 15 to give
Br
Cl
F
MeO
H
10
a
Yield of isolated pure product.

5630
J. Qu et al. / Tetrahedron Letters 50 (2009) 5628–5630
3. Joule, J. A.. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme: Stuttgart,
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5. Winters, G.; Di Mola, N.; Berti, M.; Arioli, V. Farmaco 1979, 34, 507–517.
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D. Orient. J. Chem. 1998, 14, 251–254.
7. Paulo, A.; Gomes, E. T.; Houghton, P. J. J. Nat. Prod. 1995, 58, 1485–1491.
8. Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A. Tetrahedron Lett.
1996, 37, 1703–1706.
9. Wahyuningsih, T. D.; Kumar, N.; Black, D. StC. Tetrahedron 2007, 63, 6713–
6719.
10. Clayton, K. A.; Black, D. StC.; Harper, J. B. Tetrahedron 2007, 63, 10615–10621.
11. Huang-Hsinmin; Mann, F. G. J. Chem. Soc. 1949, 2911–2914.
12. Gawley, R. E. Org. React. 1988, 35, 1–420.
O24
O1w
N9
C21
C20
C18
C19
C22
C5
C6
C23
C10
C7
C4
C8
13. Beres, M.; Timari, G.; Hajos, G. Tetrahedron Lett. 2002, 43, 6035–6038.
14. Govindachari, T. R.; Sudarsanam, V. Ind. J. Chem. 1967, 5, 16–18.
15. Alvarez, M.; Joule, J. A.. In Science of Synthesis; Black, D. StC., Ed.; Georg Thieme:
Stuttgart, Germany, 2005; Vol. 15, p 661.
16. Van Baelen, G.; Meyers, C.; Lemiere, G. L. F.; Hostyn, S.; Dommisse, R.; Maes, L.;
Augustyns, K.; Haemers, A.; Pieters, L.; Maes, B. U. W. Tetrahedron 2008, 64,
11802–11809.
C11
C3
C2
C12
C17
N1
C16
C15
C13
17. Hiremath, S. P.; Biradar, J. S.; Purohit, M. G. Indian J. Chem., Sect. B 1982, 21,
249–251.
18. Houlihan, W. J.; Parrino, V. A.; Uike, Y. J. Org. Chem. 1981, 46, 4511–4515.
19. Mudry, C. A.; Frasca, A. R. Tetrahedron 1973, 29, 603–613.
20. Blume, R. C.; Lindwall, H. G. J. Org. Chem. 1945, 10, 255–258.
21. Bergman, J.; Pelcman, B. Tetrahedron 1988, 44, 5215–5228.
22. De Cointet, P.; Pigerol, C.; Broll, M.; Eymard, P.; Werbenec, J. P. Eur. J. Med.
Chem. 1976, 11, 471–479.
C14
Figure 2. ORTEP diagram of compound 16d.
23. Colonna, M.; Greci, L.; Poloni, M. J. Chem. Soc., Perkin Trans. 2 1981, 4, 628–632.
24. Broggini, G.; Diliddo, D.; Zecchi, G. J. Heterocycl. Chem. 1991, 28, 89–91.
25. Kempter, G.; Schiewald, E. J. Prakt. Chem. 1965, 28, 169–177.
26. Bahekar, R. H.; Jain, M. R.; Goel, A.; Patel, D. N.; Prajapati, V. M.; Gupta, A. A.;
Jadav, P. A.; Patel, P. R. Bioorg. Med. Chem. 2007, 15, 3248–3265.
27. Przheval’skii, N. M.; Skvortsova, N. S.; Magedov, I. V. Chem. Heterocycl. Compd.
2002, 38, 1055–1061.
28. Representative procedure for indolo[3,2-c]isoquinoline 16a. To a solution of 3-
benzamido-2-phenylindole 15a (70 mg, 0.2 mmol) in toluene (20 mL) was
added P2O5 (0.5 g, 3.5 mmol). The yellow mixture was heated at 120–130 °C
overnight. The reaction mixture was cooled to room temperature and poured
into ice-cold water (20 mL). The solution was neutralized with 2 M NaOH, and
extracted with EtOAc (3 Â 30 mL). The organic layer was collected and dried
over anhydrous sodium sulfate. After evaporation of the solvent, the residue
was chromatographed on silica gel using dichloromethane/light petroleum
(70:30) as eluent to yield indoloisoquinoline 16a as a yellow solid (45 mg,
67%). Mp 291–293 °C. Elem. Anal. Calcd for C21H13BrN2.0.5CH2Cl2 requires C,
tained,30 and the 11H-indolo[3,2-c]isoquinoline structure was con-
firmed. All new compounds were fully characterized by 1H and 13
NMR spectroscopies, IR spectra, mass spectra and elemental anal-
yses, and several by X-ray crystallographic analysis. Known prod-
ucts were characterized by comparison of their 1H NMR spectra
and melting points with those reported in the literature.
In summary, a series of new indolo[3,2-c]isoquinolines has been
produced by the acid-catalyzed cyclization of 3-acetamido-2-
phenylindoles and 3-benzamido-2-phenylindoles, which in turn
were obtained by the Beckmann rearrangement of the related oxi-
mes. However, 2-phenylindole-3-carbaldoxime did not undergo
the Beckmann rearrangement, but gave a 3-cyanoindole. This
methodology provides an effective and flexible route to synthesize
a variety of indolo[3,2-c]isoquinolines, and opens the way for their
systematic biological evaluation.
C
62.1; H, 3.4; N, 6.7. Found: C, 62.3; H, 3.6; N, 6.9.
1490, 1460, 1390, 1350, 1280, 1240, 1160, 1100, 1070, 970, 830, 740 cmÀ1. kmax
(MeOH): 211 nm
30,600 cmÀ1 MÀ1), 238 (32,300), 288 (28,900), 371
mmax (KBr): 3430, 1620, 1500,
(e
(10,200). 1H NMR (300 MHz, DMSO-d6): d 7.28 (1H, t, J 7.4 Hz, ArH), 7.48
(1H, t, J 7.5 Hz, ArH), 7.62–7.78 (6H, m, ArH), 7.92 (1H, t, J 7.6 Hz, ArH), 8.08
(1H, d, J 8.3 Hz, ArH), 8.19 (1H, d, J 7.5 Hz, ArH), 8.53 (1H, d, J 7.9 Hz, ArH),
12.42 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): d 112.3, 119.7, 120.3, 122.2,
126.2, 126.8, 128.2, 130.3, 131.6, 132.6 (Ar–CH), 121.8 123.0, 124.4, 124.5,
127.5, 133.1, 139.2, 139.8, 151.3 (Ar–C). HRMS (+ESI) m/z 373.0316 (M+H+)
C21H14BrN2, requires 373.0335.
Acknowledgement
We thank the Australian Research Council for financial support.
References and notes
29. Marsili, A. Tetrahedron 1968, 24, 4981–4991.
30. Crystallographic data for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 718540. X-ray crystal structures were obtained by Mohan Bhadbhade,
Crystallography Laboratory, Analytical Centre, The University of New South
Wales, Sydney, Australia.
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