Divergent synthesis of isoindolo[2,1-a]indole and indolo[1,2-a]indole through copper-catalysed C- and N-arylations

Article abstract of DOI:10.1016/j.tetlet.2009.02.175

A simple and efficient synthetic route to both isoindolo[2,1-a]indole and its structural isomer indolo[1,2-a]indole skeletons is presented. The key steps of the strategy are based on copper-catalysed C_aryl-C and C_aryl-N bond formatio

Full text of DOI:10.1016/j.tetlet.2009.02.175

Tetrahedron Letters 50 (2009) 2129–2131
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent synthesis of isoindolo[2,1-a]indole and indolo[1,2-a]indole through
copper-catalysed C- and N-arylations
*
*
Nekane Barbero, Raul SanMartin , Esther Domínguez
Kimika Organikoa II Saila, Zientzia eta Teknologia Facultatea, Euskal Herriko Unibertsitatea, PO Box 644, 48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthetic route to both isoindolo[2,1-a]indole and its structural isomer indolo[1,2-
a]indole skeletons is presented. The key steps of the strategy are based on copper-catalysed Caryl–C and
Caryl–N bond formation reactions, respectively. Moreover, we report the first copper-mediated intramo-
lecular C–H functionalisation of an indole.
Received 11 January 2009
Revised 17 February 2009
Accepted 20 February 2009
Available online 26 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Copper catalysts
Arylation
The indole is among the most important and ubiquitous hetero-
cyclic frameworks in nature.1 Its nucleus is present in plenty of
biologically active molecules, among which there are several inter-
esting dimeric alkaloid families, such as Vocanga and Vinca.2,3 The
interest in isoindolo[2,1-a]indoles 1, a relatively unexplored family
of heterocycle-fused indoles, has notably increased in the last
years. Their high affinity for the melatonin MT3 binding site and
their effectiveness against several carcinogenic tumours make
them certainly appealing for medicinal chemistry.4 Closely related
to isoindolo[2,1-a]indoles 1 are their structural isomers indolo[1,2-
a]indoles 2 (Scheme 1).
To the best of our knowledge, there is no general protocol to
prepare the indolo[1,2-a]indole core 2.5 On the other hand, the iso-
indolo[2,1-a]indole skeleton 1 has been constructed employing dif-
ferent strategies, such as palladium-catalysed annulation of
internal alkynes by imines,6 intramolecular addition of 2-indolyl
radicals to aromatic rings7 and palladium-catalysed carbon–hydro-
gen (C–H) activation processes,8,9 among others.
Indeed, transition metal-catalysed coupling reactions through
C–H activation have attracted much attention over the last few
decades.8–10 Most of the already developed methods imply the
use of expensive transition metals, such as palladium, rhodium
and ruthenium.8–11 Surprisingly, although copper was the first
transition metal effecting C–H bond functionalisation,12 it has been
scarcely employed in this ambit,13–15 and still shows important
limitations. The necessity of stoichiometric amounts of copper,14a,b
strong and/or bulky bases13 and the reduced number of substrates
that can undergo the latter processes have restrained their general
use. It should be also pointed out that most of the existing methods
are not suitable for the direct arylation of indoles.14b,16
In this context, the development of a transition metal-catalysed
C–H arylation of indoles to prepare the valuable isoindolo[2,1-a]in-
dole scaffold 1 would be desirable. Besides, a new and short route
to synthesise scarcely studied indolo[1,2-a]indoles 2 is a matter of
interest.
Herein, we wish to report a straightforward approach to isoin-
doloindole 1 and indoloindole 2 by means of a strategy based on
copper-catalysed direct C- and N-arylations, and shared starting
materials and intermediates.
The synthesis was started by preparing the N-(2-haloben-
zyl)indoles 3a–b by means of a simple and quantitative N-ben-
zylation of commercially available indole (Scheme 1).17 With
the substrate 3b in hand, a migration of the 2-bromobenzyl
group from the nitrogen to the C2 position of the indole was
carried out upon heating with polyphosphoric acid (PPA), to ob-
tain the 2-benzyl derivative 4 (58%).18 Once the required N- and
2-substituted intermediates 3a and 4 were synthesised, we be-
gan to study the corresponding copper-catalysed intramolecular
arylation reactions.
With regard to the copper-catalysed C–H functionalisation of
i
substrate 3a, the use of either protic polar (H2O, EtOH, PrOH) or
non-polar solvents (PhMe, o-xylene) was unsuccessful, recovering
the unreacted starting material in all cases. The use of high-boiling
aprotic solvents, such as N-methylpyrrolidinone, DMF or DMSO
also afforded negligible results. However, when we stirred N-ben-
zylated derivative 3a along with Cu powder (10 mol %) and Na2CO3
(2.0 equiv) in poly(ethylene glycol)-400 (PEG-400) at 180 °C over-
* Corresponding authors. Tel.: +34 946015435; fax: +34 946012748 (R.S.).
E-mail address: raul.sanmartin@ehu.es (R. Sanmartin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.175

2130
N. Barbero et al. / Tetrahedron Letters 50 (2009) 2129–2131
Br
H
N
N
N
X
[Cu]
X
(X = I)
DMSO, rt
X = I, Br
3a X = I
1
3b X = Br
PPA
(X = Br)
160ºC
H
N
[Cu]
N
Br
2
4
Scheme 1. Detailed route to isoindolo[2,1-a]indole 1 and indolo[1,2-a]indole 2.
night target isoindolo[2,1-a]indole 1 was isolated in a 65% yield
(Table 1, entry 5). Based on this good result, the influence of the
base, molecular weight of PEG and copper source in the reaction
outcome were examined, as shown in Table 1. While Cs2CO3 and
Na2CO3 provided the cyclised product with similar results (entries
7 and 5, 67% vs 65%, respectively), K2CO3 furnished it in an excel-
lent yield of 88% (entry 2). All attempts to perform the same trans-
formation on bromoderivative 3b failed.
The use of other copper sources, such as CuI, CuCl and Cu(OAc)2,
did not improve the yield in any case (entries 1 and 8–9). The
molecular weight of PEG seemed to be a crucial factor.19 Indeed,
when we changed from PEG-400 to PEG-1500, only traces of the
product (entry 3) were detected. As PEG-400 apparently played
the role of both solvent and ligand, we thought that its monomer
ethylene glycol (ETG) could act in the same way. Although ETG
was still an effective reaction medium for performing such trans-
formation, the yield decreased to 58% (entry 6).
sustainable solvent as PEG cannot be ignored. At this stage, we
concluded that isoindolo[2,1-a]indole 1 can be synthesised in an
excellent overall yield of 88% from commercially available, cheap
indole.
Accordingly, and continuing with our scheduled studies, the
previously prepared 2-(2-bromobenzyl)indole 4 was subjected to
several copper-catalysed N-arylation assays, as shown in Table 2.
Basedontheexperienceof ourgroupin thepreparationof hetero-
cycles through copper-catalysed arylation processes in aqueous
media,20 we decided to examine the reaction outcome using a cata-
lytic amountof a copper saltwith 3.5 equiv of an aliphatic diaminein
boiling water.21 To our delight, target product 2 was isolated in mod-
erate yields of 55% and 57% using CuBr and Cu(OTf)2, respectively
(Table 2, entries 3 and 4). An attempt to improve the yield by chang-
ing both the diamine and the copper source and maintaining the
Table 2
Selected assays for the preparation of indolo[1,2-a]indole 2a
To the best of our knowledge, this is the first regiocontrolled
copper-catalysed intramolecular C-arylation of indoles by C–H
activation. Moreover, the use in this key transformation of such a
H
N
[Cu], base, L
N
solvent, 105ºC
Br
Table 1
Representative assays for the C–H arylation of indole 3aa
4
2
Entry
Copper source
Base
Ligandb
Solvent
2c (%)
1d
2e,f
3g
4g,h
5
6
7
8
9
CuI
K2CO3
K2CO3
CHDA
CHDA
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K3PO4
CHDA
DMEDA
Dioxane
DMF
H2O
44
0
Cu2O
CuBr
Cu(OTf)2
CuI
CuI
CuI
CuI
CuI
Cu
CuI
N
[Cu], base
N
I
55
57
88
40
27
47
79
0
PEG or ETG
H2O
CHDA
Phe
NMP
P2CA
2AP
PEG-400
CHDA
PhMe
PhMe
PhMe
PhMe
PhMe
3a
1
Entry
Copper source
Base
Solvent/ligand
1 (%)b
1c
2
Cu(OAc)2
Cu
Na2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
PEG-1500
PEG-400
PEG-1500
PEG-400
PEG-400
ETG
PEG-400
PEG-400
PEG-400
Tr.
88
Tr.
67
65
58
67
54
Tr.
10
3
Cu
Cu
Cu
Cu
11i
PhMe
71
4d
5
a
10 mol % of copper salt, 10 mol % of ligand and 2.0 equiv of base in the corre-
sponding solvent (2 mL/mmol 4) were used, unless otherwise stated.
6
b
CHDA: trans-1,2-diaminocyclohexane, Phe: 1,10-phenanthroline, DMEDA: N,N0-
7
Cu
8e
9e
CuCl
CuI
dimethylethylenediamine, NMP: N-methylpiperazine, P2CA: piperazine 2-carbox-
ylic acid, 2AP: 2-aminopyridine.
c
Yield of isolated product.
The reaction was run at 110 °C.
The reaction was run at 100 °C.
20 mol % of DMEDA was used.
a
d
10 mol % of copper salt and 2.0 equiv of base were used at 180 °C, unless
otherwise stated. Cu: copper bronze; PEG: poly(ethylene glycol); ETG: ethylene
glycol; tr: traces of product.
e
f
b
g
Yield of isolated product.
A little amount of water was added to the reaction tube.
The reaction was run at 160 °C.
1.5 equiv of K2CO3 were used.
The dilution was increased to 12 mL/mmol 4 and 3.5 equiv of CHDA were used
c
at 120 °C.
d
h
25 mol % of Cu(OTf)2 was used.
2-(2-Iodobenzyl)indole was used as starting material.
e
i

N. Barbero et al. / Tetrahedron Letters 50 (2009) 2129–2131
2131
Lord, P. D. J. Org. Chem. 1969, 34, 2988–2993; (d) Kawashima, K.; Saraie, T.;
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water as solvent was unsuccessful. Apparently, water was not the
optimal solvent for such transformation.
As CHDA seemed to be effective promoting the N-arylation
reaction, we checked the combination of catalytic amounts of the
latter ligand and CuI, with K2CO3 in dioxane (Table 2, entry 1).22
Unfortunately, a lower yield was obtained in this case (44%). A
change to DMEDA and Cu2O in DMF only provided unreacted start-
ing material (entry 2).
Nevertheless, a considerably better yield was obtained by mix-
ing derivative 4 with catalytic amounts of both CuI and CHDA,
K3PO4 in PhMe at 105 °C (88%, entry 5). Accordingly, PhMe and
K3PO4 were chosen as a suitable solvent/base system for this trans-
formation, and a range of experiments varying the ligand were car-
ried out (entries 5–9). CHDA and 2AP turned out to be the best
ones, providing the target tetracycle 2 in 88% and 79% yields,
respectively (entries 5 and 9). When 2-(2-iodobenzyl)indole was
subjected to these optimal conditions (entry 11) target product 2
was obtained in a slightly lower yield of 71%. Finally, the applica-
tion of the optimised conditions for the C–H arylation reaction23
to this C–N bond formation failed completely (entry 10), in the
same way as these N-arylation conditions proved unsuccessful in
the former transformation.
7. Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41, 4209–4211.
8. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. and
references cited therein; (b) Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L.-K.; Tsotinis,
A.; Panoussopoulou, M.; Calogeropoulou, T.; The, M.-T.; Sugden, D. J. Med.
Chem. 2000, 43, 1050–1061.
9. The intramolecular direct arylation of indole with aryl iodides through a
palladium-catalysed process was first reported by Grigg and co-workers. See:
(a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T.
Tetrahedron 1990, 46, 4003–4018; Recently, Fagnou et al. published the
preparation of isoindolo[2,1-a]indole 1 through an intramolecular palladium-
catalysed direct arylation of an aryl chloride. See: (b) Campeau, L.-C.; Parisien,
M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–590; (c) Campeau, L.-C.;
Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857–1860;
A palladium-
catalysed indole alkenylation by C-H functionalisation aided by copper
oxidants is reported in: (d) Grimser, N. P.; Gaunlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125–3129.
10. Reviews: (a) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–1101;
(b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698–1712; (c) Ritleng, V.; Sirlin,
C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731–1770.
11. Recently, an iron-catalysed direct arylation of
reported. See: (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858–5859; He et al. reported gold-catalysed
a-benzoquinolines has been
a
functionalisation of aromatic C–H bonds. See: (b) Shi, Z.; He, C. J. Org. Chem.
2004, 69, 3669–3671.
12. (a) Steinkopf, W.; Leitsmann, R.; Hofmann, K. H. Liebigs Ann. Chem. 1941,
546, 180–184; (b) Sease, J. W.; Zechmeister, L. J. Am. Chem. Soc. 1947, 69,
After all these optimisation assays leading to the conditions as
shown in entry 5,24 the synthetic route to indolo[1,2-a]indole 2
was completed with an acceptable overall yield of 51%.
270–273; For
a review on catalytic C–C, C–N and C–O Ullmann-type
coupling reactions, see: (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2008, 47, 3096–3099.
To sum up, a divergent straightforward synthetic sequence for
the access to isomeric isoindolo[2,1-a]indole and indolo[1,2-a]in-
dole is reported, featuring as the key step two copper-catalysed
arylation reactions. Moreover, it cannot be ignored that the former
arylation is the first reported example of a copper-catalysed intra-
molecular C–H functionalisation of an indole. The extension of this
approach to other indoles is now under investigation.
13. (a) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185–
15192; (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404–12405.
14. (a) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49,
1598–1600; Cu(OCOCF3)2 (1.0 equiv) has been used for non-selective, multiple
C–H bond arylation of indoles and pyrroles. See: (b) Ban, I.; Sudo, T.; Taniguchi,
T.; Itami, K. Org. Lett. 2008, 10, 3607–3609; (c) Borduas, N.; Powell, D. A. J. Org.
Chem. 2008, 73, 7822–7825. and references cited therein.
15. (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790–6791; (b) Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842–
843; (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968–6969.
16. Only N-arylation of unprotected indoles has been achieved thus far, as reported
by Buchwald. See: (a) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J.
Org. Chem. 2004, 69, 5578–5587; A direct, elegant arylation of indoles using
diaryl-iodine(III) reagents can be found in: (b) Phipps, R. J.; Grimster, N. P.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172–8174.
17. Sanz, R.; Ignacio, J. M.; Castroviejo, M. P.; Fañanas, F. J. Arkivok 2007, 84–91.
18. Wiedenou, P.; Blechert, S. Synth. Commun. 1997, 27, 2033–2039.
19. The use of PEG as additive and/or solvent in copper-catalysed reactions has
been reported. See: (a) Mao, J.; Guo, J.; Fang, F.; Ji, S.-J. Tetrahedron 2008, 64,
3905–3911; (b) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007,
72, 6190–6199; (c) Colacino, E.; Da, L.; Martinez, J.; Lamaty, F. Synlett 2007,
1279–1283; (d) She, J.; Jiang, Z.; Wang, Y. Tetrahedron Lett. 2009, 50, 593–596.
20. (a) Carril, M.; SanMartin, R.; Domínguez, E. Chem. Soc. Rev. 2008, 37, 639–647.
and references cited therein; (b) Barbero, N.; Carril, M.; SanMartin, R.;
Domínguez, E. Tetrahedron 2008, 64, 7283–7288.
Acknowledgements
This research was supported by the University of the Basque
Country/Regional Government of Biscay/Basque Government (Pro-
jects DIPE 06/10, UNESCO07/08 and GIU06/87/IT-349-07). N.B.
thanks the Spanish Ministry of Education and Science for a predoc-
toral scholarship. The authors also thank Petronor, S.A. (Muskiz,
Bizkaia) for a generous donation of hexane.
Supplementary data
21. Apparently, the aliphatic diamine could play both the role of base and ligand.
See: Carril, M.; SanMartin, R.; Tellitu, M.; Domínguez, E. Org. Lett. 2006, 8,
1467–1470.
22. These conditions had proved successful for the N-arylation of some nitrogen-
containing heterocycles. See: Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S.
L. J. Am. Chem. Soc. 2001, 123, 7727–7729.
23. Preparation of 6H-Isoindolo[2,1-a]indole (1): A screw-capped tube was charged
with N-(2-iodobenzyl)-1H-indole 3a (98.7 mg, 0.29 mmol), Cu bronze (200
mesh, 1.9 mg, 0.030 mmol) and K2CO3 (82.9 mg, 0.60 mmol) at room
temperature and under argon. Then, PEG-400 (0.6 mL) was added and the
reaction mixture was heated to 180 °C for 16 h. After cooling the reaction, it
was quenched with water (5 mL) and extracted with CH2Cl2 (3 ꢀ 10 mL). Then,
brine was added (10 mL) to the aqueous layer, and was extracted again with
CH2Cl2 (3 ꢀ 10 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. The resulting residue was purified by flash
chromatography (10% AcOEt/n-hexane) to afford the target tetracyclic
Typical experimental procedures, including spectroscopic and
analytical data for all the new intermediates along with NMR spec-
tra of the new compounds. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.175.
References and notes
1. A review of indole-containing natural products: Lounasmaa, M.; Tolvanen, A.
Nat. Prod. Rep. 2000, 17, 175–191.
2. Vinblastine and Vincristine alkaloids belong to Vinca family and they have been
widely used in medicine for treating diverse types of cancer (lymphomas,
sarcomas, testicular and breast cancer, leukaemia, etc.) due to their strong
antineoplastic activity. See: Antitumor Bisindole Alkaloids from Catharanthus
roseus (L.). The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press: New
York, 1990; Vol. 37, pp 1–240. and references cited therein.
3. Rowinsky, E. C.; Donehover, R. C.. In DeVita, V. T., Jr., Hellman, S., Rosenberg, S.
A., Eds., 5th ed.; Cancer Principles and Practice of Oncology; Lippincott-Raven:
Philadelphia, 1997; p 467.
4. Boussard, M.-F.; Truche, S.; Rousseau-Rojas, A.; Briss, S.; Desamps, S.; Droual,
M.; Wierzbicki, M.; Ferry, G.; Audinot, V.; Delagrange, P.; Boutin, J. A. Eur. J.
Med. Chem. 2006, 41, 306–320.
5. Only a few spattered examples of isolated indolo[1,2-a]indoles have been
reported thus far, and mostly as byproducts or in low yields. See: (a)
Samsoniya, Sh. A.; Trapaidze, M. V. Russ. Chem. Rev. 2007, 76, 313–326; (b)
Shirley, D. A.; Roussel, P. A. J. Am. Chem. Soc. 1953, 75, 375–378; (c) Dolby, L. J.;
product
1 as a white powder (52.3 mg, 88%). The physical data were
compared with those found in the literature. See: Ref. 9c.
24. Preparation of 10H-Indolo[2,1-a]indole (2): A screw-capped tube was charged
with 2-(2-bromobenzyl)-1H-indole
0.028 mmol) and K3PO4 (120.1 mg, 0.56 mmol) at room temperature and
under argon. Then, CHDA (3.4 L) and dry PhMe (0.6 mL) were added and the
4 (80.8 mg, 0.28 mmol), CuI (5.4 mg,
l
reaction mixture was heated to 105 °C for 16 h. After cooling the reaction, it
was quenched with water (5 mL) and extracted with CH2Cl2 (3 ꢀ 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concentrated
in vacuo. The resulting residue was purified by flash chromatography (10%
AcOEt/n-hexane) to afford the target tetracyclic product 2 as a white powder
(51.0 mg, 88%). For physical data see Supplementary data.