Cascade reaction of isatins with heterocyclic ketene aminals: Synthesis of imidazopyrroloquinoline derivatives

Article abstract of DOI:10.1021/ol201783d

A concise and efficient route for the synthesis of highly substituted imidazopyrroloquinoline derivatives by simply refluxing a reaction mixture of different types of isatins and heterocyclic ketene aminals (HKAs) by acetic acid was developed. This method

Full text of DOI:10.1021/ol201783d

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4782–4785
Cascade Reaction of Isatins with
Heterocyclic Ketene Aminals: Synthesis
of Imidazopyrroloquinoline Derivatives
Fuchao Yu, Shengjiao Yan,* Ling Hu, Yongchao Wang, and Jun Lin*
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University),
Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming, 650091, P. R. China
linjun@ynu.edu.cn; yanshengjiao@126.com
Received July 4, 2011
ABSTRACT
A concise and efficient route for the synthesis of highly substituted imidazopyrroloquinoline derivatives by simply refluxing a reaction mixture of
different types of isatins and heterocyclic ketene aminals (HKAs) by acetic acid was developed. This method is suitable for combinatorial and
parallel syntheses in drug discovery; consequently, a library of highly substituted imidazopyrroloquinoline derivatives was rapidly constructed
using the present protocol.
The quinoline derivatives are an important class of
heterocyclic pharmaceuticals and bioactive natural pro-
ducts due to their significant and wide-spectrum biological
activities. Considerable efforts have been directed toward
the construction of quinoline building blocks. These meth-
ods include the classic Skraup,1 Doebnerꢀvon Miller,1b,2
diverse biological activities. These activities include
anticancer7,8 (TAS-1039 and 6-aryl-indeno[1,2-c]quinoline,10
Figure 1), antituberculosis agents,11 antifungal agents,12
(8) (a) Hranjec, M.; Pavlovi, G.; Marjanovi, M.; Kralj, M.; Karminski-
zamola, G. Eur. J. Med. Chem. 2010, 45, 2405. (b) Chen, Y.-L.; Huang,
H.-M.; Lu, C.-M.; Li, K.-C.; Tzeng, C.-C. Bioorg. Med. Chem. 2004, 12,
6539.
(9) (a) Padget, K.; Stewart, A.; Charlton, P.; Tilby, M. J.; Austin,
C. A. Biochem. Pharmacol. 2000, 60, 817. (b) Aoyagi, Y.; Kobunai, T.;
Utsugi, T.; Oh-hara, T.; Yamada, Y. Jpn. J. Cancer Res. 1999, 90, 578.
(10) Tseng, C.-H.; Chen, Y.-L.; Chung, K.-Y.; Cheng, C.-M.; Wang,
C.-H.; Tzeng, C.-C. Bioorg. Med. Chem. 2009, 17, 7465.
(11) Eswaran, S.; Adhikari, A. V.; Kumar, R. A. Eur. J. Med. Chem.
2010, 45, 957.
3
4
5
2
€
Friedlander, Pfitzinger, Conrad-Limpach, and Combes
reactions as well as more recent approaches.6 Conse-
quently, a number of compounds have been obtained with
(1) (a) Manske, R. H. F.; Kukla, M. Org. React. 1953, 7, 59. (b) Wu,
Y.-C.; Liu, L.; Li, H.-J.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2006, 71,
6592.
(2) Bergstrom, F. W. Chem. Rev. 1944, 35, 77.
(12) Kategaonkar, A. H.; Pokalwar, R. U.; Sonar, S. S.; Gawali,
V. U.; Shingate, B. B.; Shingare, M. S. Eur. J. Med. Chem. 2010, 45,
1128.
(13) Chen, Y.-L.; Chen, I.-L.; Lu, C.-M.; Tzeng, C.-C.; Tsao, L.-T.;
Wang, J.-P. Bioorg. Med. Chem. 2004, 12, 387.
(14) (a) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.;
Fruttarolo, F.; Romagnoli, R.; Zaid, N. A.; Moorman, A. R.; Varani,
K.; Borea, P. A. J. Med. Chem. 2005, 48, 5001. (b) Colottta, V.; Catarzi,
D.; Varano, F.; Cecchi, L.; Filacchioni, G.; Martini, C.; Trincavelli, L.;
Lucacchini, A. J. Med. Chem. 2000, 43, 3118.
(3) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37. (b) Akbari, J.;
Heydari, A.; Kalhor, H. R.; Kohan, S. A. J. Comb. Chem. 2010, 12, 137.
(4) (a) Laddha, S. S.; Bhatnagar, S. P. Arkivoc 2008, 17, 212. (b) Buu-
Hoi, N. P.; Royer, R.; Xuong, N. D.; Jacquignon, P. J. Org. Chem. 1953,
18, 1209.
(5) (a) Reitsema, R. H. Chem. Rev. 1948, 43, 43. (b) Misani, F.;
Bogert, M. T. J. Org. Chem. 1945, 10, 347.
ꢀ
ꢀ
(6) Kouznetsov, V. V.; Vargas Mendez, L. Y.; Melendez Gomez,
ꢀ
C. M. Curr. Org. Chem. 2005, 9, 141.
(15) Kaila, N.; Janz, K.; Huang, A.; Moretto, A.; DeBernardo, S.;
Bedard, P. W.; Tam, S.; Clerin, V.; Keith, J. C., Jr.; Tsao, D. H. H.;
Sushkova, N.; Shaw, G. D.; Camphausen, R. T.; Schaub, R. G.; Wang,
Q. J. Med. Chem. 2007, 50, 40.
(16) Tseng, C.-H.; Chen, Y.-L.; Lu, P.-J.; Yang, C.-N.; Tzeng, C.-C.
J. Med. Chem. 2005, 48, 3680.
(7) (a) Tseng, C.-H.; Tzeng, C.-C.; Yang, C.-L.; Lu, P.-J.; Chen, H.-L.;
Li, H.-Y.; Chuang, Y.-C.; Yang, C.-N.; Chen, Y.-L. J. Med. Chem. 2010,
53, 6164. (b) Tseng, C.-H.; Chen, Y.-L.; Chung, K.-Y.; Cheng, C.-M.;
Wang, C.-H.; Tzeng, C.-C. Bioorg. Med. Chem. 2009, 17, 7465. (c) Tseng,
C.-H.; Chen, Y.-L.; Lu, P.-J.; Yang, C.-N.; Tzeng, C.-C. Bioorg. Med.
Chem. 2008, 16, 3153.
r
10.1021/ol201783d
Published on Web 08/17/2011
2011 American Chemical Society

anti-inflammatory agents,13 adenosine receptors,14 P-se-
lectin agonists,15 caspase-3 inhibitors,16 and anti-Alzhei-
mer’s drugs,17 among others.18 Among these compounds,
indenoquinoline derivatives (Figure 1) are the most im-
portant compounds, most notably because of their anti-
proliferative character.7,9,10 Although there have been
many studies on the synthesis of these molecules,7,19 these
methods require multistep syntheses or strict anhydrous
conditions.7,19 Thus, there is a need for the development of
concise and effective methods for building up the target
compound library.
purification of intermediates.21 For these reasons, the
cascade reaction has been used as a tool for building up
the diversity of the compound library.22
As a type of versatile syntheticintermediate, heterocyclic
ketene aminals (HKAs) are widely used for the synthesis
of a variety of heterocyclic and fused heterocyclic
compounds,23,24 including anticancer agents, herbicides,
pesticides, antianxious agents, antileishmanial agents and
antibacterial and antitherapeutic drugs.25
The structure of HKAs can be described as follows
(Scheme 1), with the conjugation of electro-donating amino
groups and the electron-withdrawing carbonyl group, with
a highly polarized double bond (CdC).26 This leads to the
electron density of the R-carbon (C3) being higher than
that of the secondary amino groups (N1 and N5). As a
result, they can serve as bis-nucleophiles (C3 and N1 as
nucleophilic sites) and react with bis-electronphiles to
synthesize the fused heterocyclic compounds.23,24 In addi-
tion to this, they can be reacted with 1,3-dipoles to form
1,2,3-triazoles or isoxazoles.25b,27 However, incorporation
of the two nucleophilic sites N1 and C3 and the electro-
nphile site C4 (CdO) through a one-pot protocol via the
cascade reaction to form polycyclic frame compounds has
not been reported to date (Scheme 1).
Figure 1. Structures of indenoquinolines derivatives and tar-
geted compounds.
Nowadays, the development of concise and effective
one-pot transformations for building up the target com-
pound library is a major change in organic synthesis.20
A
number of strategies have been developed to meet this
challenge. In particular, the cascade reaction has received
much attention because the ability to undertake more than
one synthetic step in the same reaction vessel represents a
useful tool for saving time and energy, as well as for
reducing the use of organic solvents in the isolation and
Scheme 1. Routes Based on the Cascade Reaction of HKAs
through the Three Reaction Sites (N1, C3 and C4) to Give
Polycyclic Compounds
(17) (a) Ronco, C.; Jean, L.; Outtaabout, H.; Renard, P.-Y. Eur. J.
Org. Chem. 2011, 302. (b) Camps, P.; Formosa, X.; Galdeano, C.;
~
ꢀ
´
rez, L.; Gomez, E.; Isambert, N.; Lavilla,
Munoz-Torrero, D.; Ramı
R.; Badia, A.; Clos, M. V.; Bartooini, M.; Mancini, F.; Andrisano, V.;
Arce, M. P.; Rodıguez-Franco, M. I.; Huertas, O.; Dafni, T.; Luque,
´
F. J. J. Med. Chem. 2009, 52, 5365.
(18) Milbank, J. B. J.; Stevenson, R. J.; Ware, D. C.; Chang, J. Y. C.;
Tercel, M.; Ahn, G. O.; Wilson, W. R.; Denny, W. A. J. Med. Chem.
2009, 52, 6822.
To explore the cascade reaction of HKAs through the
three reaction sites (N1, C3 and C4), we designed and
synthesized the target compounds based on the scaffold of
compound 1. We hypothesized that modifying the indeno
ring of 1 by incorporating heteroatoms and the HKA rings
(n = 1, 2, 3) could lead to analogs with improved
(19) (a) Ren, J.-S.; Qu, X.-G.; Dattagupta, N.; Chaires, J. B. J. Am.
Chem. Soc. 2001, 123, 6742. (b) Fush, R. C.; Miller, J. J. J. Am. Chem.
Soc. 1957, 79, 3477. (c) Borsche, W.; Sinn, F. Justus Liebigs Ann. Chem.
1937, 532, 146. (d) Degani, Y.; Willner, I. J. Chem. Soc., Chem. Commun.
1985, 648. (e) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem.
Soc. 2007, 129, 10096. (f) Ryckebusch, A.; Garcin, D.; Lansiaux, A.;
ꢀ
Goossens, J.-F.; Baldeyrou, B.; Houssin, R.; Bailly, C.; Henichart, J.-P.
J. Med. Chem. 2008, 51, 3617.
(20) Wang, F.; Liu, H.-X.; Jiang, Y.-Y.; Zhao, Y.-F. Org. Lett. 2009,
11, 2469.
(21) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J. N. Org.
Lett. 2008, 10, 3543.
(22) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987.
(23) For reviews, see: (a) Huang, Z.-T.; Wang, M.-X. Heterocycles
1994, 37, 1233. (b) Huang, Z.-T.; Wang, M.-X. Prog. Natural Sci. 1999,
11, 971.
(24) For recent studies, see: (a) Yan, S.-J.; Chen, Y.-L.; Liu, L.; He,
N.-Q.; Lin, J. Green Chem. 2010, 12, 2043. (b) Yan, S.-J.; Huang, C.; Su,
C.-X.; Ni, Y.-F.; Lin, J. J. Comb. Chem. 2010, 12, 91. (c) Yan, S.-J.;
Chen, Y.-L.; Liu, L.; Tang, Y.-J.; Lin, J. Tetrahedron Lett. 2011, 52, 465.
(d) Yan, S.-J.; Niu, Y.-F.; Huang, R.; Lin, J. Synlett. 2009, 17, 2821. (e)
Xu, W.-Y.; Jia, Y.-M.; Yang, J.-K.; Huang, Z.-T.; Yu, C.-Y. Synlett
2010, 11, 1682. (f) Muhammd, Y.; Yu, C.-Y.; Jia, Y.-M.; Huang, Z.-T.
Synlett 2008, 12, 1357. (g) Li, M.; Zhou, Z.-M.; Wen, L.-R.; Qiu, Z.-X.
J. Org. Chem. 2011, 76, 3054. (h) Wen, L.-R.; Liu, C.; Li, M.; Wang, L.-J.
J. Org. Chem. 2010, 75, 7605.
(25) (a) Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.;
Qing, C.; Lin, J. Eur. J. Med. Chem. 2011, 46, 1172. (b) Yan, S.-J.; Liu,
Y.-J.; Chen, Y.-L.; Liu, L.; Lin, J. Bioorg. Med. Chem. Lett. 2010, 20,
5225. (c) Yan, S.-J.; Huang, C.; Zeng, X.-H.; Huang, R.; Lin, J. Bioorg.
Med. Chem. Lett. 2010, 20, 48. (d) Tieman, C. H.; Kollmeyer, W. D. US.
Pat. 3,948,934, 1976. (e) Maryanoff, B. E.; Nortey, S. O.; McNally, J. J.;
Sanfilippo, P. J.; McComsey, D. F.; Dubinsky, B.; Shank, R. P.; Reitz, A. B.
Biomed. Chem. Lett. 1999, 9, 1547. (f) Kondo, H.; Taguchi, M.; Inoue,
Y.; Sakamoto, F.; Tsukamoto, G. J. Med. Chem. 1990, 33, 2012. (g)
Suryawanshi, S. N.; Pandey, S.; Rashmirathi; Bhatt, B. A.; Gupta, S.
Eur. J. Med. Chem. 2007, 42, 511. (h) Abdelhalim, M. M.; El-Saidi, M.
M.T.; Rabie, S. T.; Elmegeed, G. A. Steroids 2007, 72, 459.
(26) Baum, K.; Bigelow, S. S.; Nauyen, N. V.; Archibald, T. G.;
Gilardi, R.; Flippen-Anderson, J. L.; Georeg, C. J. Org. Chem. 1992, 57,
235.
(27) (a) Viswanathan, N. I.; Balakrishnan, V. J. Chem. Soc., Perkin
Trans. 1 1979, 2361. (b) Huang, Z.-T.; Wang, M.-X. Synth. Commun.
1991, 21, 1167.
Org. Lett., Vol. 13, No. 18, 2011
4783

properties such as antiproliferative characteristics and
better log P values (Scheme 2).
a low yield (52%). The catalyst AcOH promoted the
reactions in different solvents (Table 1, entries 5, 9, 13
and 17). The results indicated that the best reaction con-
ditions for the synthesis of imidazopyrroloquinolines were
toluene as the solvent and acetic acid as the catalyst under
reflux for 4 h with an isolated product with a good yield
(78%) (Table 1, entry 13).
Scheme 2. Routes Based on the Cascade Reaction of HKAs to
Produce Imidazopyrroloquinolines
Under optimized conditions, other five-member HKAs
served as substrates to react with different isatins (3aꢀ3d).
As a result, we obtained polycyclic quinolines (5aꢀ5i),
including a 2,3-dihydropyrrolo[1,2-a]imidazol-5-one ske-
leton, with good yields (78ꢀ85%) (Table 2, entries 1ꢀ9).
To explore the feasibility of substrates, the six-member
HKAs were reacted with different isatins (3aꢀ3d) under
the same conditions. The target compounds (5jꢀ5y),
including a 3,4-dihydropyrrolo[1,2-a]pyri-midin-6(2H)-
one skeleton, were formed with excellent yields (82ꢀ
94%) (Table 2, entries 10ꢀ25). We believe that the ring
size can influence the yields of the reaction. Consequently,
the seven-member HKAs were able to react with isatins
3 in toluene, catalyzed by AcOH, to produce poly-
cyclicquinolines(5zꢀ5a0) with good yields (Table 2, entries
26ꢀ27).
In this communication, we report a novel synthetic
method to produce imidazopyrroloquinoline derivatives
5 by refluxing isatins 3 and HKAs 4 catalyzed by acetic
acid, forming the target compounds with good to excellent
yields (78ꢀ94%).
First, we evaluated the cascade reaction of isatins 3 and
the HKAs 4. The mixture, which was composed of a 1.1:1
ratio of 3a to 4a, was treated under various conditions
(Table 1, entries 1ꢀ20). This demonstrated that the reac-
tions could not proceed in some solvents such as aceto-
The cascade reaction has very high regional selectivity
(Table 2, entries 4ꢀ7), and the positionofthe methyl group
of compounds 5dꢀ5g can be tested by 15NꢀH HMBC
correlation data of compound 5d (See Supporting Infor-
mation). As a result, we only obtained the target product 5
in the form of compounds 5dꢀ5g (Scheme 2) (Table 2,
entries 4ꢀ7).
Table 1. Optimizing the Reaction Conditions for the Synthesis
of 5a
To verify the structure of the imidazopyrroloquinoline
derivatives, 5l was selected as a representative compound
and characterized by X-ray crystallography (CCDC
829402, Figure 2).
entry
solvent
catalyst
t [°C] time [h] yield [%]a
1
acetonitrile
THF
ꢀ
reflux
reflux
reflux
reflux
reflux
reflux
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
n.r.
n.r.
52
2
ꢀ
ꢀ
ꢀ
3
toluene
dioxane
4
n.r.
67
5
acetonitrile AcOH
acetonitrile ZnCl2
6
69
7
acetonitrile H3PW14O4 reflux
n.r.
15
8
acetonitrile TFA
reflux
reflux
reflux
9
THF
AcOH
ZnCl2
28
10
11
12
13
14
15
16
17
18
19
20
THF
n.r.
n.r.
5
THF
H3PW14O4 reflux
THF
TFA
reflux
reflux
reflux
toluene
toluene
toluene
toluene
dioxane
dioxane
dioxane
dioxane
AcOH
ZnCl2
78
n.r.
n.r.
45
H3PW14O4 reflux
TFA
reflux
reflux
reflux
Figure 2. Molecular structure of 5l. Ellipsoids set at 30%
probability.
AcOH
ZnCl2
70
12
H3PW14O4 reflux
TFA reflux
n.r.
6
A proposed mechanism of the acetic acid-catalyzed
cascade reaction is depicted in Scheme 3. First, the R-C
of the ketene N,N-acetals 4 added to the carbonyl group of
compound 3 to afford 6. The intermediate 6 was followed
by imine-enamine tautomerization to produce 7. Inter-
mediate 7 seized one proton of AcOH to form 8. Inter-
mediate 8, through intramolecular cyclization, dehydration,
a Isolated yield based on HKA 4a. n.r. = no reaction.
nitrile, THF or 1,4-dioxane under catalyst-free conditions
(Table 1, entries 1, 2 and 4). We obtained the target
compound 5a in the absence of catalysts in toluene with
4784
Org. Lett., Vol. 13, No. 18, 2011

and ring-opening reactions formed 10. Protonation of
compound 10 produced 11. Subsequently, the NH2
attacked the intramolecular carbonyl group to form
intermediate 12, which, through losing H2O and proton
transfer, produced 13. Finally, 13 lost a proton and a
molecule of H2O to result in the target product 5.
Table 2. Preparation of Imidazopyrroloquinoline Derivative 5a
Scheme 3. Proposed Mechanism of the Cascade Reaction
In conclusion, we developed a procedure for the simple
synthesis of a variety of potential, biologically active
imidazopyrroloquinoline based on the cascade reaction.
Using this method, a molecularly diverse imidazopyrrolo-
quinoline derivatives library was rapidly constructed with
good yields by simply refluxing a reaction mixture of
isatins and HKAs in toluene, catalyzed by AcOH.
Acknowledgment. We gratefully acknowledge the fi-
nancial support from the Natural Science Foundation of
China (grant numbers 30860342, 21162037 and 81160384)
and the Natural Science Foundation of Yunnan Province
(2009CC017, 2008CD063).
Note Added after ASAP Publication. The acknowledg-
ment was corrected and reposted August 25, 2011.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds
and X-ray structural data of 5l. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: Isatin 3 (2.2 mmol), HKA 4 (2 mmol), acetic
acid (0.4 mL) and toluene (15 mL), at refluxed temperature, and reaction
time of 4 h. b Isolated yield based on HKA 4.
Org. Lett., Vol. 13, No. 18, 2011
4785