Facile approaches toward the synthesis of 6H-isoindolo[2,1-α]indol-6-ones via palladium-catalyzed carbonylation with carbon monoxide

Article abstract of DOI:10.1016/j.tetlet.2016.07.108

Two facile methods for the preparation of 6H-isoindolo[2,1-α]indol-6-ones were developed. In the first protocol, 6H-isoindolo[2,1-α]indol-6-ones were prepared from 2-(2-iodophenyl)-1H-indoles via palladium-catalyzed intramolecular aminocarbonylation. The

Full text of DOI:10.1016/j.tetlet.2016.07.108

Accepted Manuscript
Facile approaches toward the synthesis of 6H-isoindolo[2,1-α]indol-6-ones via
palladium-catalyzed carbonylation with carbon monoxide
Qingshuai Han, Shurong Fu, Xiaofeng Zhang, Shen Lin, Qiufeng Huang
PII:
S0040-4039(16)30976-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.108
TETL 47970
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 June 2016
27 July 2016
30 July 2016
Please cite this article as: Han, Q., Fu, S., Zhang, X., Lin, S., Huang, Q., Facile approaches toward the synthesis of
H-isoindolo[2,1-α]indol-6-ones via palladium-catalyzed carbonylation with carbon monoxide, Tetrahedron
6
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.108
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Graphical Abstract
Facile approaches toward the synthesis of
Leave this area blank for abstract info.
6
H-isoindolo[2,1-α]indol-6-ones via
palladium-catalyzed carbonylation with
carbon monoxide
Qingshuai Han, Shurong Fu, Xiaofeng Zhang, Shen Lin, Qiufeng Huang*

1
Tetrahedron Letters
Facile approaches toward the synthesis of 6H-isoindolo[2,1-α]indol-6-ones via
palladium-catalyzed carbonylation with carbon monoxide
Qingshuai Han, Shurong Fu, Xiaofeng Zhang, Shen Lin, Qiufeng Huang
College of Chemistry & Chemical Engineering, Fujian Normal University, Fuzhou, 350007, P. R. China and Fujian Key Laboratory of Polymer Materials,
Fuzhou, 350007, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Two facile methods for the preparation of 6H-isoindolo[2,1-α]indol-6-ones were developed. In
the first protocol, 6H-isoindolo[2,1-α]indol-6-ones were prepared from 2-(2-iodophenyl)-1H-
indoles via palladium-catalyzed intramolecular aminocarbonylation. The second involves
intermolecular carbonylation of indoles with iodobenzenes followed by intramolecular cross-
dehydrogenative-coupling.
Available online
Keywords:
6
H-isoindolo[2,1-α]indol-6-one
2
015 Elsevier Ltd. All rights reserved.
Palladium-catalyzed
carbonylation
carbon monoxide
—
——

Corresponding author. Tel.: +86-13599081672; fax: +86-591-228-67399; e-mail: qiufenghuang@fjnu.edu.cn

2
Tetrahedron
Introduction
Results and discussion
Development of synthetic methods for 6H-isoindolo[2,1-
α]indol-6-ones (2a) is an important research work in organic
synthesis, as such types of compounds are not only applied as
The intramolecular carbonylation of 2-(2-iodophenyl)-1H-
indole (1a) was initially chosen as a model reaction to establish
the optimum reaction conditions as summarized in Table 1.
versatile intermediates in diverse organic synthesis (Scheme
Among the palladium catalysts examined, Pd(OAc)
to PdCl and Pd(PPh )Cl (Table 1, entries 1-3). The addition of
PPh led to a much greater increase of the yield, affording 2a in
75% yield (Table 1, entry 4). Notably, bases played a crucial role
in the reaction. The employment of DBU brought about a much
decrease of product 2a (40%; Table 1, entry 5); and the best
2
was superior
1
1
A), but also exhibit various important biological activities
2
3
2
2
(Scheme 1B and C). A number of synthetic methods have been
3
3-9
established in recent years. For example, a two-step strategy
starting from o-nitrobenzaldehydes through wittig reaction and
tandem reductive cyclization-lactamization was established by
4
Tilve et al (Scheme 2, route 1). The synthesis of 2a can also be
result was obtained by addition of K
In order to further enhance the formation of 2a, various solvents,
such as DMSO, EtOH, THF, CH CN, xylene and toluene were
2 3
CO (86%; Table 1, entry 5).
carried out via an intramolecular wittig reaction from o-
5
phthalimidobenzyl bromide (Scheme 2, route 2). Griffiths et al.
3
reported a convenient route to 2a from 2-(N-phthaloyl)benzoic
acid via β-ketophosphonates (Scheme 2, route 3). Kim et al.
also tested ((Table 1, entries 7-12) and toluene was found to be
the most effective solvent, thus giving 2a in 95% yield (Table 1,
entry 12). A change of the carbon monoxide pressure to 10 atm
(85%; Table 1, entry 14) or 30 atm (88%; Table 1, entry 13)
decreased the yield slightly. However, only 6% yield of 2a was
formed under atmospheric pressure of CO (Table 1, entry 15). If
taken together, these results indicated the following as the
6
have developed the synthesis of 2a by intramolecular heck7
reaction from methylenephthalimidine (Scheme 2, route 4).
More recently, transition-metal-catalyzed intramolecular C-H
coupling from N-benzoylindole derivatives has become a
8
powerful method for the preparation of 2a (Scheme 2, route 5).
Furthermore, a Pd-catalyzed intramolecular cyclization via tert-
butyl isocyanide insertion from 2-(2-bromophenyl)-1H-indoles
was also issued by Zhu et al (Scheme 2, route 6). However,
a
9
Table 1. Optimization of reaction conditions
these methods often suffer from tedious experimental proceduces,
harsh reaction conditions, expensive starting materials, and
unsatisfactory yields. Since seminal work by Heck and co-
10
workers, carbonylation of aryl halides with carbon monoxide
(CO) is an effective approach for introducing a carbonyl group
b
Entry
Pd Cat.
PdCl
Pd(PPh
Ligand
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
THF
Yield(%)
NR
trace
16
1
2
3
4
5
6
7
8
9
2
Et
3
Et
3
Et
3
Et
3
N
N
N
N
3 2
) Cl
2
2
2
2
2
2
2
2
2
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
3
75
Scheme 1. Examples of important 6H-isoindolo[2,1-a]indol-6-ones
DBU
40
K
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
86
K
2
73
K
2
78
K
2
38
1
1
1
1
1
0
1
2
3
4
5
K
2
CH
3
CN
76
K
2
Xylene
87
Pd(OAc)
2
PPh
3
K
2
CO
3
Toluene
Toluene
Toluene
Toluene
95(90)
88
c
d
e
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
PPh
PPh
PPh
3
K
2
CO
CO
CO
3
2
3
K
2
3
3
85
1
2
3
K
2
6
a
Reaction conditions: 1a (0.2 mmol), Pd cat. (5 mol%), Ligand (10 mol%),
0
b
base (1 equiv.) solvent ( 1 mL), CO (20 atm), 100 C, 24h; Yield according
to GC analysis on the basis of the amount of 1a used, Number in parenthesis
c
d
e
Scheme 2. Strategies toward the synthesis of 6H-isoindolo[2,1-
is isolated yield, NR=No reaction; CO (10 atm); CO (30 atm), CO (1
atm).
a]indol-6-ones
1
1
into organic molecules. In view of recent advances in
Table 2. Synthesis of 6H-isoindolo[2,1-α]indol-6-ones via
palladium-catalyzed intramolecular carbonylation
carbonylation, we envisage that 2a could be readily constructed
a
starting
from
2-(2-iodophenyl)-1H-indoles
(1a)
via
intramolecular carbonylation by using CO as a C1 building
block.

3
palladium-catalyzed intermolecular carbonylation and
subsequent cross-dehydrogenative-coupling
a,b
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)
2 3
(5 mol%), PPh (10 mol%),
0
K
2
CO (1 equiv.), toluene( 1 mL), CO (20 atm), 100 C, 24h; Isolated yields
3
optimal reaction conditions: Pd(OAc)
2
(5 mol%), PPh
3
(10
mol%), K
C.
2
CO
3
(1 equiv.) in toluene under CO (20 atm) at 100
o
A number of substituted 6H-isoindolo[2,1-α]indol-6-ones
could be synthesized by the present catalytic procedure. The
carbonylation of 2-(2-iodophenyl)-5-methyl-1H-indole, 2-(2-
iodophenyl)-7-methyl-1H-indole and 2-(2-iodophenyl)-5,6-
dimethyl-1H-indole gave desired product in 97%, 83% and 85%
yield, respectively (Table 2, 2b-d). However, upon employing 2-
(2-iodophenyl)-4-methyl-1H-indole and 2-(2-iodophenyl)-4,5-
dimethyl-1H-indole, lower yields of carbonylation products were
obtained (2k and 2l). The same is true for chloro-substituted 2-
(2-iodophenyl)-1H-indole. The substrates with chloro group at
the 5-, 6-, or 7-position of the indole ring underwent
carbonylation successfully, affording 6H-isoindolo[2,1-α]indol-
6
2
-ones 2e, 2g and 2h in 83-88% yield. However, upon employing
-(2-iodophenyl)-4,5-dichloro-1H-indole, only trace amount of
product 2m was detected. These results suggest that a substituent
at the 4-position in the indole ring has deleterious effect in
delivering 6H-isoindolo[2,1-α]indol-6-one. It is found that the
electronic properties of the substituents on the indole ring or
a
Reaction conditions for intermolecular carbonylation: 1’ (0.2 mmol), 1’’ (0.3
mmol), Pd(OAc) (5 mol%), PPh (10 mol%), K CO (1 equiv.), toluene( 1
2
3
2
3
0
(iodo)phenyl ring have no effect on the observed reactivity. 2-(2-
mL), CO (20 atm), 100 C, 24h; Isolated yields.
b
Reaction conditions for intramolecular dehydrogenation: 3 (0.2 mmol),
Pd(OAc) (5 mol%), K CO (10 mol%), AgOAc (1 equiv), PivOH (0.2 mL),
20 C, 24 h; Isolated yields.
iodophenyl)-1H-indoles with electron-donating or electron-
withdrawing groups, such as alkyl, methoxy, chloro, bromo, and
fluoro were good substrates and afforded the desire products in
excellent yields (80-97% yield, 2b-j). It is worthy of noting that
this catalytic system can tolerate halogen. Halogen-substituted
2
2
3
0
1
8e
reported by Fagnou et al. ) conveniently generated the 6H-
isoindolo[2,1-α]indol-6-ones (2a 2i and 2n-r) in 50-79% yield.
Remarkably, the synthesis of aldehyde or ester substituted 6H-
isoindolo[2,1-α]indol-6-ones (compound 2n and 2q) can also be
accomplished.
6H-isoindolo[2,1-α]indol-6-ones could provide opportunities for
further functionalization.
During the course of our current investigations, we also found
that this catalytic system could be extended to the intermolecular
carbonylation. Under the optimized reaction conditions as
indicated in entry 12 of Table 1, the intermolecular carbonylation
between indoles and iodobenzenes proceeded smoothly to give
the corresponding N-benzoylindoles in moderate to good
yields(48-93%, 3a, 3i and 3n-r). After intermolecular
Conclusion
In summary, the palladium-catalyzed intramolecular C-I
aminocarbonylation of 2-(2-iodophenyl)-1H-indoles to form 6H-
isoindolo[2,1-α]indol-6-ones was developed. Pd(OAc)2 as
catalyst, PPh as ligand and K CO as base gave the best results
under 20 atm pressure of CO. This catalytic system and optimal
reaction conditions could be extended to the intermolecular
carbonylation of indoles with iodobenzenes affording N-
3
2
3
carbonylation,
intramolecular
dehydrogenation
of
N-
benzoylindoles (under a slight modification of the procedure
Table 3. Synthesis of 6H-isoindolo[2,1-α]indol-6-ones via

4
Tetrahedron
benzoylindoles,
and
subsequent
palladium-catalyzed
2012, 68, 4274-4279; (c) Dev, K.; Maurya, R. RSC Adv. 2015,
, 13102-13106; (d) Nallapati, S. B.; Adepu, R.; Ashfag, M. S.;
Sreenivas, B. Y.; Mukkanti, K.; Pal, M. RSC Adv. 2015, 5,
8686-88691; (e) Huang, Q.; Campo, M. A.; Yao, T.; Tian, Q.;
Larock, R. C. J. Org. Chem. 2004, 69, 8251-8257; (f) Marion,
F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095-5097;
5
dehydrogenation of N-benzoylindoles also provided the 6H-
isoindolo[2,1-α]indol-6-ones in good yields. These methods offer
far greater generality than previous methods for the synthesis of
8
6H-isoindolo[2,1-α]indol-6-ones.
(
g) García, A.; Rodríguez, D.; Castedo, L.; Saá, C.;
Domínguez, D. Tetrahedron Lett. 2001, 42, 1903-1905; (h)
Francisco J, R.; Monica, T.; Juan C, E.; Luis, C.; Ramon J, E.
Synlett 2003, 1603-1606.
Kadam, H. K.; Tilve, S. G. Eur. J. Org. Chem. 2013, 4280-
4284.
Acknowledgments
Financial support from NSFC (Grant No. 21103022 and
4
.
61520106015), Foundation of Fujian Educational Committee
(Grant No. JK2014010) is gratefully acknowledged.
5.
Guillaumel, J.; Léonce, S.; Pierré, A.; Renard, P.; Pfeiffer, B.;
Arimondo, P. B.; Monneret, C. Eur. J. Med. Chem. 2006, 41,
3
79-386.
Supplementary Material
6
.
Duncanson, P.; Cheong, Y.-K.; Motevalli, M.; Griffiths, D. V.
Org. Biomol. Chem. 2012, 10, 4266-4279.
Supplementary material (experimental details, characterization
data, and copies of NMR spectra) associated with this article can
be found in the online version at http://dx.doi.org/
7.
Kim, G.; Kim, J. H.; Kim, W.; Kim, Y. A. Tetrahedron Lett.
2
003, 44, 8207-8209
8
.
(a) He, H.-F.; Dong, S.; Chen, Y.; Yang, Y.; Le, Y.; Bao, W.
Tetrahedron 2012, 68, 112-3116; (b) Laha, J. K.; Dayal, N.;
Singh, S.; Bhimpuria, R. Eur. J. Org. Chem. 2014, 5469-5475;
(c) Signori, A. M.; Latocheski, E.; Albuquerque, B. L.;
Faggion Jr, D.; Bisol, T. B.; Meier, L.; Domingos, J. B. New J.
Chem. 2015, 39, 1574-1578; (d) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137-
References and notes
1
.
(a) Samosorn, S.; Bremner, J. B.; Ball, A.; Lewis, K. Bioorg.
Med. Chem. 2006, 14, 857-865; (b) Komoda, T.; Shinoda, Y.;
Nakatsuka, S. Biosci. Biotechnol. Biochem. 2003, 67, 659-662;
3
139; (e) Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.;
Fagnou, K. J. Org. Chem. 2008, 73, 5022-5028; (f) Kandukuri,
S. R.; Oestreich, M. J. Org. Chem. 2012, 77, 8750-8755.
Tang, T.; Jiang, X.; Wang, J.-M.; Sun, Y.-X.; Zhu, Y.-M.
Tetrahedron 2014, 70, 2999-3004.
(c) Laha, J. K.; Dayal, N.; Jethava, K. P.; Prajapati, D. V. Org.
Lett. 2015, 17, 1296-1299; (d) Crawford, L. A.; Cle mence, N.
C.; McNab, H.; Tyas, R. G. Org. Biomol. Chem. 2008, 6, 2334-
9
1
.
2
1
339; (e) Scopton, A.; Kelly, T. R. J. Org. Chem. 2005, 70,
0004-10012.
0. (a) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96,
761-7764; (b) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J.
7
2
.
(a) Boussard, M.-F.; Truche, S.; Rousseau-Rojas, A.; Briss, S.;
Descamps, S.; Droual, M.; Wierzbicki, M.; Ferry, G.; Audinot,
V.; Delagrange, P.; Boutin, J. A. Eur. J. Med. Chem. 2006, 41,
Org. Chem. 1974, 39, 3318-3326; (c) Schoenberg, A.; Heck, R.
F. J. Org. Chem. 1974, 39, 3327-3331.
1
1. (a) Wu, L.; Fang, X.; Liu, Q.; Jackstell, R.; Beller, M.; Wu, X.-
F. ACS Catal. 2014, 4, 2977-2989; (b) Sumino, S.; Fusano, A.;
Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563-1574;
3
06-320; (b) Pegan, S. D.; Sturdy, M. ; Ferry, G.; Delagrange,
P.; Boutin, J. A.; Mesecar, A. D. Protein Sci. 2011, 20, 1182-
195; (c) Alarma-Estrany, P.; Crooke, A.; Mediero, A.; Peláez,
1
(c) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011,
T.; Pintor, J. J. Pineal. Res. 2008, 45, 468-475; (d) Jean, G.;
Stephane, L.; Alain, P.; Pierre, R.; Bruno, P.; Laure, P.; Paola
B, A.; Claude, M. Oncol. Res. 2003, 13, 537-549.
4
0, 4986-5009; (d) Brennführer, A.; Neumann, H.; Beller, M.
Angew. Chem. Int. Ed. 2009, 48, 4114-4133; (e) Quesnel, J. S.;
Arndtsen, B. A. J. Am. Chem. Soc. 2013, 135, 16841-16844; (f)
Fang, W.; Deng, Q.; Xu, M.; Tu, T. Org. Lett. 2013, 15, 3678-
3
.
(a)Marion, F.; Coulomb, J.; Servais, A.; Courillon, C.;
Fensterbank, L.; Malacria, M. Tetrahedron 2006, 62, 3856-
3
681.
3
871; (b) Hayashi, K.; Choshi, T.; Chikaraishi, K.; Oda, A.;
Yoshinaga, R.; Hatae, N.; Ishikura, M.; Hibino, S. Tetrahedron

5
Highlights

Two facile method for the preparation of 6H-
isoindolo[2,1-α]indol-6-ones
Carbon monoxide as C1 building block
One catalytic system, two discrete reactions

