Three-component domino reactions for selective formation of indeno[1,2- b ]indole derivatives

Article abstract of DOI:10.1021/ol3023038

Efficient three-component domino strategies for the synthesis of multifunctionalized tetracyclic indeno[1,2-b]indole derivatives with different substituted patterns have been established successfully. The first pathway involves a novel sequential methyl migration, aromatization, and esterification, while a second reaction in HOAc leads to compounds 6 with high syn diastereoselectivity. Both reactions showed attractive features including mild conditions, convenient one-pot operation, short reaction times of 15-32 min, and excellent regio- and/or stereoselectivity.

Full text of DOI:10.1021/ol3023038

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5210–5213
Three-Component Domino Reactions
for Selective Formation of
Indeno[1,2‑b]indole Derivatives
Bo Jiang,† Qiu-Yun Li,† Shu-Jiang Tu,*,† and Guigen Li*,‡,§
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou,
221116, Jiangsu, P. R. China, Institute of Chemistry & Biomedical Sciences,
Nanjing University, Nanjing 210093, P. R. China, and Department of Chemistry and
Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
laotu@jsnu.edu.cn; guigen.li@ttu.edu
Received August 21, 2012
ABSTRACT
Efficient three-component domino strategies for the synthesis of multifunctionalized tetracyclic indeno[1,2-b]indole derivatives with different
substituted patterns have been established successfully. The first pathway involves a novel sequential methyl migration, aromatization, and
esterification, while a second reaction in HOAc leads to compounds 6 with high syn diastereoselectivity. Both reactions showed attractive
features including mild conditions, convenient one-pot operation, short reaction times of 15À32 min, and excellent regio- and/or stereoselectivity.
Heterocycles of indole derivatives containing multiple
rings widely exist in nature; they often serve as “privileged
structures” in drug discovery and development based
on their attractive capacity of binding to many cell recep-
tors with high affinity1 and subsequent potent biological
and pharmaceutical profiles.2 Among fused indole com-
pounds, tetracyclic indeno[1,2-b]indole skeletons are par-
ticularly important because they have been widely used as
building blocks in total synthesis of many natural products
and display biological activities such as powerful lipid
peroxidation inhibitors,3 potassium channel openers,4
DNS intercalators, and topoisomerase II inhibitors.5 There-
fore, these derivatives have attracted special attention in
organic and medicinal fields. So far, many approaches to
polycyclic indeno[1,2-b]indoles have been developed; most
of these syntheses were achieved via cascade cyclization
(3) Brown, D. W.; Graupner, P. R.; Sainsbury, M.; Shertzer, H. G.
Tetrahedron 1991, 47, 4383.
(4) (a) Butera, J. A.; Antane, S. A.; Hirth, B.; Lennox, J. R.; Sheldon,
J. H.; Norton, N. W.; Warga, D.; Argentieri, T. M. Bioorg. Med. Chem.
Lett. 2001, 11, 2093. (b) Antane, S. A.; Butera, J. A.; Lennox, J. R. US
2001047026, 2001.
† Jiangsu Normal University.
‡ Nanjing University.
§ Texas Tech University.
(5) (a) Bal, Ch.; Baldeyrou, B.; Moz, F.; Lansiaux, A.; Colson, P.;
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Wierzbicki, M.; Bailly, Ch. Biochem. Pharmacol. 2004, 68, 1911. (b)
Wierzbicki, M.; Boussard, M.-F.; Rousseau, A.; Boutin, A.; Delagrange, P.
EP 1245565, 2002
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(b) Chernyak, N.; Tilly, D.; Li, Z.; Gevorgyan, V. ARKIVOC 2011, v, 76.
(c) Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V. Org. Lett. 2008, 10, 2617.
(7) (a) Shapiro, R.; Chatterjie, N. J. J. Org. Chem. 1970, 35, 447.
(b) Bullington, J. L.; Dodd, J. H. J. Org. Chem. 1993, 58, 4833. (c) Black,
D.St.C.;Bowyer,M.C.;Condie,G.C.;Craig,D.C.;Kumar,N.Tetrahedron
1994, 50, 10983. (d) Hemmerling, H.-J.; Reiss, G. Synthesis 2009, 985.
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Chem. Rev. 2003, 103, 893. (b) Shiri, M. Chem. Rev. 2012, 112, 3508.
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Chaltin, P.; Meert, E. M.K.; Cammue, B. P.A. Curr. Med. Chem. 2009, 16,
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Chem. 2007, 50, 4669. (e) Alper, P. B.; Marsilje, T. H.; Mutnick, D.; Lu, W.;
Chatterjee, A.; Roberts, M. J.; He, Y.; Karanewsky, D. S.; Chow, D.; Lao,
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10.1021/ol3023038
Published on Web 10/01/2012
2012 American Chemical Society

reactions in the presence of metal catalysts,6 ninhydrin
annulations,7 intramolecular reductive N-heteroannulation,8
and reductive cyclization of hydrazone9 or 2-nitrobenzylide
naphthalide.10 The development of alternative step-eco-
nomical methods for the assembly of these heterocyclic
cores, producing less waste and byproducts, continues to
be of considerable interest and important. However, to the
best of our knowledge, a one-pot synthesis of tetracyclic
indeno[1,2-b]indoles via a multicomponent domino strat-
egy involving sequential methyl migration/aromatization/
esterification has not been documented yet.
On the other hand, multicomponent domino reactions
(MDRs) for total synthesis of natural products or natural-like
structures are believed to be one of the key tools for assem-
bling multiring-junction frameworks that can be predicted by
controlling reaction processes.11,12 These reactions have at-
tracted special attention over the past few decades because of
their high efficiency, synthetic economy, and ecology in the
construction of complex heterocyclic frameworks.13 In
addition, multicomponent strategy often proceeds with
impressive selectivity.14 Designing multicomponent domino
processes for constructing multiring-junction architectures
provides a great challenge in modern organic synthesis.
In the past several years, we have been engaging in the
development of unique MDRs that can provide easy access
to new core structures of chemical and pharmaceutical
interest.15 During our study of this project, we now discov-
ered novel multicomponent reactions of N-heteroannulations
of enaminones, 2,2-dihydroxyindene-1,3-dione, and acid
anhydride or aromatic amines; they can selectively provide
multifunctionalized indeno[1,2-b]indoles with different
substituted patterns 4 and 6 (Scheme 1). The great features
of this multicomponent domino chemistry are shown by
the fact that new fused pyrazoles (tetracyclic 6À5À5À6
skeleton) were readily formed in domino fashions that
involved sequential nucleophilic substitution/cyclization/
methyl migration/aromatization/esterification. The latter
provided new N-arylamino substituted indeno[1,2-b]indole
derivatives with excellent stereo- and regioselectivity; two
quaternary centers including a quaternary amine function-
ality were controlled very well in a one-pot operation.
The present work sets excellent examples for synthesizing
such an important family of polysubstituted indeno-
[1,2-b]indoles.
Scheme 1. Synthesis of Indeno[1,2-b]indoles 4 and 6
(8) Janreddy, D.; Kavala, V.; Bosco, J. W. J.; Kuo, C.-W.; Yao, C.-F.
Eur. J. Org. Chem. 2011, 2360.
Recently, we established a new three-component dom-
ino reaction of enaminones for the synthesis of multifunc-
tionalized indole derivatives through allylic esterification.15e,f
During the continuation of this project, we attempted to
employ ninhydrin as a precursor to realize allylic esterifica-
tion (Table 1). In the first attempt, the reaction of enam-
inones 2a with 2,2-dihydroxyindene-1,3-dione 1 was
heated in HOAc at 100 °C under microwave irradiation
conditions (Table 1, entry 1). The reaction scarcely pro-
ceeded to give the desired product 7, even at enhanced
temperatures. When the solvent was changed to the cosol-
vent of HOAc/acetic anhydride (Table 1, entry 2), the
reaction resulted in red solids. Surprisingly, we found that
the product isnot the expected allylicesterification product
7. Instead, we found that anacetyl group was introduced in
the final product in which H chemical shift of methylene on
enaminone ring cannot be observed. Eventually, the struc-
tural elucidation was unequivocally determined by X-ray
diffraction of a single crystal 4a (Figure 1), and a novel
polysubstituted indeno[1,2-b]indole derivative 4a was pro-
duced in 35% yield (Table 1).
(9) (a) Graham, J.; Ninan, A.; Reza, K.; Sainsbury, M.; Shertzer,
H. G. Tetrahedron 1992, 48, 167. (b) Brown, D. W.; Mahon, M. F.;
Ninan, A.; Sainsbury, M.; Shertzer, H. G. Tetrahedron 1993, 49, 8919.
(c) Wang, J.-B.; Ji, Q.-G.; Xu, J.; Wu, X.-H.; Xie, Y.-Y. Synth. Commun.
2005, 35, 581. (d) Butera, J. A.; Antane, S. A.; Hirth, B.; Lennox, J. R.;
Sheldon, J. H.; Norton, N. W.; Warga, D.; Argentieri, T. M. Bioorg.
Med. Chem. Lett. 2001, 11, 2093. (e) Robinson, B. The Fischer Indole
Synthesis; John Wiley & Sons: Chichester, 1982.
(10) (a) Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron Lett.
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1993, 34, 6479. (b) Reboredo, F. J.; Treus, M.; Estevez, J. C.; Castedo,
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L.; Estevez, R. J. Synlett 2002, 999.
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(11) (a) Meijere, A. D.; Zezschwitz, P. V.; Brase, S. Acc. Chem. Res.
2005, 38, 413. (b) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res. 2008, 41,
883. (c) Sun, X. L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937. (d) Wasike,
J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105,
1001. (e) Trost, B. M.; Frontier, A. J. J. Am. Chem. Soc. 2000, 122,
11727. (f) Trost, B. M.; Gutierrez, A. C.; Livingston, R. C. Org. Lett.
2009, 11, 2539. (g) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
(h) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(12) (a) Santra, S.; Andreana, P. R. Angew. Chem., Int. Ed. 2011, 50,
€
9418. (b) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
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(c) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984. (d) Liao, L.; Jana, R.; Urkalan, K. B.;
Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 5784.
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(13) (a) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley-
VCH, 2004. (b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (c) Tietze, L. F. Chem.
Rev. 1996, 96, 115.
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(14) (a) Willy, B.; Muller, T. J. J. Curr. Org. Chem. 2009, 13, 1777. (b)
Encouraged by the above results, we set the reaction of
1 with 2a as the model reaction in acetic anhydride for
optimizing reaction conditions. Experiments were carried
out in two cosolvents of TFA/Ac2O and DMF/Ac2O. The
reaction failed to give the product 4a in TFA/Ac2O
(Table 1, entry 3); an incomplete reaction was observed
in DMF/Ac2O (Table 1, entry 4). In another case, when
Ac2O was used as the solvent, the reaction proceeded more
Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5,
2318. (c) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095.
€
(15) (a) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.
J. Org. Chem. 2010, 75, 296. (b) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.;
Li, G. J. Am. Chem. Soc. 2009, 131, 11660. (c) Li, G.; Wei, H. X.; Kim,
S. H.; Carducci, M. D. Angew. Chem., Int. Ed. 2001, 40, 4277. (d) Ma, N.;
Jiang, B.; Zhang, G.; Tu, S.-J.; Wever, W.; Li, G. Green Chem. 2010, 12,
1357. (e) Jiang, B.; Yi, M.-S.; Shi, F.; Tu, S.-J.; Pindi, S.; McDowell, P.;
Li, G. Chem. Commun. 2012, 808. (f) Jiang, B.; Feng, B.-M.; Wang
S.-L.; Tu, S.-J.; Li, G. Chem.;Eur. J. 2012, 18, 9823.
Org. Lett., Vol. 14, No. 20, 2012
5211

efficiently to give product 4a in 76% isolated yield by flash
chromatography (Table 1, entry 5). Subsequently, the
reaction was performed in Ac2O and repeated many times
at different temperatures in a sealed vessel under micro-
wave heating for 25 min. After a series of experiments, we
found that in acetic anhydride, 1a was converted into the
product 4a in 85% chemical yield at 120 °C. It turned out
that in this reaction acetic anhydride behaved as the
solvent at the same time as the esterification reagent.
such as methyl and methoxy groups to give the corre-
sponding N-arylindeno[1,2-b]indole derivatives 4cÀe
and 4o in good to high yields. The bulky o-substituted
N-arylenaminone 2f was converted into the corresponding
indeno[1,2-b]indole 4f in 76% yield (entry 6).
In addition to N-aryl substitutents, N-methyl and
N-cyclopropyl were also found to be suitable for the pres-
ent three-component domino reaction to afford the ex-
pected N-methyl- and N-cyclopropylindeno[1,2-b]indole
derivatives 4g and 4p in 74% and 69% yields, respectively
(entries 7 and 16). The propionic andydride was also
suitable for the reaction and smoothly gave desired prod-
ucts 4hÀj and 4qÀr in good yields of 63À81%. The results
showed the good scope and generality of the novel methyl
migration under domino condition with respect to a range
of enaminone substrates.
Table 1. Optimization for the Synthesis of 4a under MW
Table 2. Domino Synthesis of Indeno[1,2-b]indoles 4
entry
solvent
HOAc
AcOH/Ac2Oa
TFA/Ac2Oa
DMF/Ac2Oa
Ac2O
temp/°C
time (min)
yieldb (%)
1
2
3
4
5
6
100
100
100
100
100
120
25
25
25
25
25
25
no
35
trace
27
76
Ac2O
85
a Cosolvent: v/v = 1:1. b Isolated yields.
a Reagents and conditions: Ac2O, (1.5 mL), 120 °C, microwave
heating. b Time (min). c Isolated yields.
After the above reaction was achieved, we then turned
our attention to investigate the three-component reaction
of enaminones 2, 2,2-dihydroxyindene-1,3-dione 1, and
aromatic amines 5. Due to nucleophilicity of aromatic
amines which is stronger than that of carboxylic acid,
allylic amination was expected to be realized using aro-
matic aminesasa nucleophile (Table 3). Onthe basis of this
analysis, 2,2-dihydroxyindene-1,3-dione1 was subjectedto
the reaction of 2a with 4-chloroaniline 3a in different acids,
suchasformicacid(HCOOH), HOAc, and TFA, at120 °C
for24minundermicrowaveheating. Theexpectedproduct
8 was not observed in all acidic solvents that we examined.
Instead, a polysubstituted indeno[1,2-b]indole derivative
6a was generated regioselectively to give 32% yield in
HCOOH solvent, but this product cannot be formed in
another acidic solvent, TFA. The best yield (82%) of
product 6a was obtained in HOAc which was thus chosen
for the substrate scope investigation. Next, the reactions
of N-substituted 5,5-dimethyl-3-aminocyclohex-2-enones
Figure 1. X-ray structure of 4a.
With the optimized system in hand, we next explored its
scope using various readily available starting materials.
The results are presented in Table 2. As usual, the reactions
can be finished in 20À32 min. A range of valuable indeno-
[1,2-b]indoles can be synthesized in high yields. The reac-
tion is easyto perform simply by heating a mixture of cyclic
enaminones and 2,2-dihydroxyindene-1,3-dione 1 in acetic
anhydridewithmicrowave. We foundthat reactantscan be
not only N-arylenaminones 2a, 2h, and 2j, which possess
electron-withdrawing substituents such as fluoro, bromo,
and chloro groups at the para position of the benzene ring,
but also 2cÀe and 2l having electron-donating substituents
5212
Org. Lett., Vol. 14, No. 20, 2012

(2b, 2c, 2e, 2h and 4-chlorophenyl 2n) with various aro-
matic amines 5 and 1 in acetic acid were performed for
short periods (15À28 min), leading to formation of a series
of new polysubstituted indeno[1,2-b]indoles with excellent
regio- and stereoselectivity as listed in Table 3. Both
electron-deficient and electron-rich aromatic groups on
the N-substituted 5,5-dimethyl-3-aminocyclohex-2-enones
showed very good chemical yields of 6aÀm (entries 1À13).
N-Phenyl-3-aminocyclohex-2-enone 2o was converted
into the corresponding arylamino-substituted indeno[1,2-
b]indoles 6n and 6o in 65% and 80% yields, respectively.
The tolerance of functionalities, such as chloro, bromo in
this protocol provides the opportunity of their various further
chemical manipulations in products. The structural elucida-
tion and attribution of relative regio- and stereoselectivity
were determined by NMR analysis and X-ray diffraction of
single crystal 6d (see the Supporting Information).
nucleophilic substitution (1 to A), intramolecular cycliza-
tion (A to B), dehydration (B to C), isomerization of the
carbocation (C to D), methyl (H) migration (D to E),
deprotonation (E to F), and final aromatization/esterifica-
tion (F to 4). The reason of methyl (H) migration is
attributed to the stability of the resulting positive cations.
The stability of tertiary carbocation is higher than that of
secondary one. Similar to the former, the latter involves
nucleophilic substitution and intramolecular cyclization
(1 to B), which underwent SN 1 type reaction with aromatic
amines to regioselectively yield thermodynamically stable
N-arylamino-substituted indeno[1,2-b]indoles due to its
intramolecular hydrogen bonding (G and H).
Scheme 2. Possible Mechanism for Products 4 and 6
Table 3. Domino Synthesis of Indeno[1,2-b]indoles 6a
In conclusion, we have successfully established new three-
component domino reactions for the synthesis of polyfunc-
tionalized indeno[1,2-b]indoles with different substituted
patterns. The reaction mechanism involves novel methyl
(H) migration and esterification. The reactionswereshown
to have attractive features of mild conditions, convenient
one-pot operation, short reaction reaction times of 15À32
min, and excellent regio- and stereoselectivity.
a Reagents and conditions: HOAc (1.5 mL), 120 °C, microwave
heating. b Time (min). c Isolated yield.
Ingeneral, the reaction can be finished efficiently withall
cases within 15À32 min. Water is nearly a sole byproduct,
which makes the workup convenient. In most cases, the
products precipitated out after cold water was poured into
the reaction mixture. During these two domino reaction
processes, the construction of fused indole skeleton,
methyl (H) migration, and esterification were readily
achieved via regioselective three-component domino reac-
tion in a one-pot operation, and two stereogenetic centers
have been completely controlled including a quaternary
amine center attached on the indene ring in the latter.
The mechanism hypothesis for these reactions was
proposed and is shown in Scheme 2. The former involves
the ring closure cascade reactions that consist of initial
Acknowledgment. We are grateful for financial support
from the NSFC (Nos. 20928001, 21232004, 21072163,
21002083, and 21102124) and PAPD of Jiangsu Higher
Education Institutions and the Robert A. Welch Founda-
tion (D-1361) and NIH (R21DA031860-01).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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