Environmentally benign synthesis of indeno[1,2-b]quinolines via an intramolecular povarov reaction

Article abstract of DOI:10.1021/ol402775k

A new synthetic route to indeno[1,2-b]quinolines via reactions of o-propargylbenzaldehydes with N-aryl amines based on an intramolecular aza-Diels-Alder (Povarov) reaction has been developed. This method offers several advantages such as no requirement fo

Full text of DOI:10.1021/ol402775k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Environmentally Benign Synthesis
of Indeno[1,2‑b]quinolines via an
Intramolecular Povarov Reaction
Ming Chen, Ning Sun, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China
yhliu@mail.sioc.ac.cn
Received September 25, 2013
ABSTRACT
A new synthetic route to indeno[1,2-b]quinolines via reactions of o-propargylbenzaldehydes with N-aryl amines based on an intramolecular aza-
DielsÀAlder (Povarov) reaction has been developed. This method offers several advantages such as no requirement for an oxidant, high
efficiency, and a wide reaction scope.
Quinoline ring systems occur widely in natural products,
and manyofthemshowinteresting biological activities.1 In
particular, quinoline rings condensed with various hetero-
cycles or carbocycles are of significant interest since they
have been found to be potentially useful as anticancer
agents by acting as DNA ligands.2 For example, indeno-
quinoline A possesses cytotoxic properties with in vivo
activity in colon 38 tumors.2c Indenoquinoline B exhibits
cytotoxicities comparable to that of camptothecin against
MCF-7 cells2d (Figure 1). Owing to their biological
importance, much effort has been devoted to develop
more efficient and convenient strategies for the synthesis
of quinolines.3 Classical methods, such as Skraup,4a
Combes,4b Friedlander,4c Pfitzinger,4d and DoebnerÀvon
€
Miller4e reactions, are frequently employed. However,
usually they do not allow the formation of quinolines with
(3) For reviews, see: (a) Jones, G. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New
ꢀ
York, 1996; Vol. 5, p 167. (b) Kouznetsov, V. V.; Mendez, L. Y. V.;
(1) (a) Michael,J.P.Nat. Prod. Rep. 1997,14, 605. (b) Balasubramanian,
M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 5, p 245.
ꢀ
Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141. For recent develop-
ments in the synthesis of quinolines, see: (c) Amii, H.; Kishikawa, Y.;
Uneyama, K. Org. Lett. 2001, 3, 1109. (d) Zhang, X.; Campo, M. A.;
Larock, R. C. Org. Lett. 2005, 7, 763. (e) Luo, Y.; Li, Z.; Li, C.-J. Org.
Lett. 2005, 7, 2675. (f) Morel, A. F.; Larghi, E. L.; Selvero, M. M. Synlett
2005, 2755. (g) Tanaka, S. Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006,
71, 800. (h) Jia, C. S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol.
Chem. 2006, 4, 104. (i) Wu, J.; Xia, H. G.; Gao, K. Org. Biomol. Chem.
2006, 4, 126. (j) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.;
Plastina, P. J. Org. Chem. 2007, 72, 6873. (k) Horn, J.; Marsden, S.;
Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117 and
references cited therein. (l) Vander Mierde, H.; van der Voort, P.; De
Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625. (m) Lekhok, K. C.;
Prajapati, D.; Boruah, R. C. Synlett 2008, 655.
(2) (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.;
McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888. (b)
Werbovetz, K. A.; Bhattacharjee, A. K.; Brendle, J. J.; Scovill, J. P.
Bioorg. Med. Chem. 2000, 8, 1741. (c) Deady, L. W.; Kaye, A. J.; Finlay,
G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1997, 40, 2040. (d)
Chakrabarty, S.; Croft, M. S.; Marko, M. G.; Moyna, G. Bioorg. Med.
Chem. 2013, 21, 1143. (e) Deady, L. W.; Desneves, J.; Kaye, A. J.;
Thompson, M.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg.
Med. Chem. 1999, 7, 2801. (f) Deady, L. W.; Desneves, J.; Kaye, A. J.;
Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2001, 9,
445. (g) Chen, J.; Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.;
Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 2461. (h)
Chen, J.; Deady, L. W.; Kaye, A. J.; Finlay, G. J.; Bruce, C.; Baguley,
B. C.; Denny, W. A. Bioorg. Med. Chem. 2002, 10, 2381. (i) Mekapati,
S. B.; Denny, W. A.; Kurup, A.; Hansch, C. Bioorg. Med. Chem. 2001, 9,
2757. (j) Yamato, M.;Takeuchi, Y.; Hashigaki, K.; Ikeda, Y.; Ming-rong,
C.; Takeuchi, K.; Matsushima, M.; Tsuruo, T.; Tashiro, T.; Tsukagoshi,
S.; Yamashita, Y.; Nakano, H. J. Med. Chem. 1989, 32, 1295.
(4) (a) Skraup, H. Chem. Ber. 1880, 13, 2086. (b) Combes, A. Bull.
€
Chim. Soc. France 1888, 49, 89. (c) Friedlander, P. Chem. Ber. 1882, 15,
2572. (d) Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100. (e) Doebner, O.;
von Miller, W. Chem. Ber. 1881, 14, 2812.
(5) (a) Povarov, L. S.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Ser.
Khim. 1963, 953. (b) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656. (c)
For a review, see: Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
r
10.1021/ol402775k
XXXX American Chemical Society

Scheme 1. Synthesis of Quinolines through the Povarov
Reaction
Figure 1. Biologically active indeno[1,2-b]quinolines.
Scheme 2. Synthesis of Indeno[1,2-b]quinolines without the Use
of Oxidant
wide diversity. Recently, the Povarov reaction,5À7 an in-
verse electron-demand aza-DielsÀAlder (IED-DA) reac-
tion of N-aryl imines derived from aldehydes and anilines
with electron-rich olefins, became one of the most efficient
protocols for quinoline preparation (Scheme 1). Alkynes
could also be used as dienophiles in a Povarov reaction,
although it is much less common than that of alkenes.7 To
furnish the quinoline structure, further oxidation of the
initial formed tetrahydro/dihydroquinoline under aerobic
conditions or using an additional oxidant is often needed.
The imine substrate is also known to act as an oxidant by
accepting hydrogen in the presence of acid catalyst, and the
corresponding reduction product, the amine, would be a
byproduct.6n,o,7f,7g,7i The Povarov reaction usually re-
N-aryl amines; it is based on the intramolecular Povarov
reaction (Scheme 2).
During our studies of transition-metal-catalyzed trans-
formations of propargyl carboxylates,8 we occasionally
found that the reaction of o-propargylbenzaldehyde 1a
with 2 equiv of aniline in DCE at 80 °C for 23 h afforded,
unexpectedly, a ring-condensed product of indeno[1,2-b]-
quinoline 2a in 38% yield (Table 1, entry 1). The unique
structural features and potential bioactivity of indenoqui-
nolines prompted us to investigate this condensation reac-
tion under various conditions. The results are summarized
quires a Lewis acid or protic acid such as BF3 Et2O, SnCl4,
3
lanthanide triflates, Tf2NH, or p-trifluoroacetic acid to
activate the imine substrates, with the reactions under
catalyst-free conditions being quite rare. Nevertheless,
the development of more simple and practical methods
with wide diversity is highly desired. In this communica-
tion, we present a novel synthetic route to indeno[1,2-b]-
quinolines via reaction of o-propargylbenzaldehydes with
˚
in Table 1. To our delight, in the presence of 4 A molecular
sieves (Alfa, 3À5 mm beads, 30 grains, ca. 1.5 g for 0.3
mmol scale) as a water-removing agent, 86% of 2a was
obtained in DCE at 80 °C for 8 h (entry 2). Using 1.0 equiv
of aniline, the yield of 2a was reduced to 69% (entry 3).
Decreasing the amount of molecular sieves resulted in a
(6) For a Povarov reaction with alkenes as dienophiles, see: (a)
Laschat, S.; Lauterweine, J. J. Org. Chem. 1993, 58, 2856. (b) Beifuss,
U.; Herde, A.; Ledderhose, S. Chem. Commun. 1996, 1213. (c) Znang,
D.; Kiselyov, A. S. Synlett 2001, 1173. (d) Sundararajan, G.; N.
Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973. (e) Magomedov,
N. A. Org. Lett. 2003, 5, 2509. (f) Anniyappan, M.; Muralidharan, D.;
Perumal, P. T. Tetrahedron Lett. 2003, 44, 3653. (g) Hermitage, S.;
Howard, J. A. K.; Jay, D.; Pritchard, R. G.; Probert, M. R.; Whiting, A.
Org. Biomol. Chem. 2004, 2451. (h) Yadav, J. S.; Reddy, B. V. S.; Chetia,
L.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2005, 46, 1039. (i)
˚
slightly lower yield of 2a (83%, entry 5, ca. 1.0 g 4 A
molecular sieves was used). The solvent effect was also
examined. The reaction could proceed in toluene, where
79% of the desired product 2a was obtained (entry 6).
However, the use of EtOH gave only a complex reaction
mixture (entry 7). In order to understand the effect of
protecting groups, reactions were carried out with Bz (1b),
Ac (1c), and CO2Me (1d) protected substrates. The reac-
tion proceeded smoothly in these cases, with the yields of
2a ranging from 58% to 83% (entries 8À10).
ꢀ
Jimenez, O.; de la Rosa, G.; Lavilla, R. Angew. Chem., Int. Ed. 2005, 44,
6521. (j) Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589. (k)
Muhuhi, J.; Spaller, M. R. J. Org. Chem. 2006, 71, 5515. (l) Zhou, J.;
Magomedov, N. A. J. Org. Chem. 2007, 72, 3808. (m) Hirashita, T.;
Kawai, D.; Araki, S. Tetrahedron Lett. 2007, 48, 5421. (n) Shindoh, N.;
Tokuyama, H.; Takasu, K. Tetrahedron Lett. 2007, 48, 4749. (o)
Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem.
2008, 73, 7451. (p) Gaddam, V.; Nagarajan, R. Org. Lett. 2008, 10, 1975.
(q) Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728. (r)
Dagousset, G.; Zhu, J.; Masson, G. J. Am. Chem. Soc. 2011, 133, 14804.
(7) For a Povarov reaction with alkynes as dienophiles, see: (a)
Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F. J. Org.
Chem. 1992, 57, 1842. (b) Bortoloffl, B.; Leardini, R.; Nanni, D.;
Zanardi, G. Tetrahedron 1993, 49, 10157. (c) Baudelle, R.; Melnyk, P.;
With the optimized reaction conditions in hand, we next
investigated the reaction scope of this methodology.
During this process, we found that when Piv-protected
substrates were employed, in some cases, it was difficult
to obtain the desired products with high purity. However,
the use of Bz-protected substrates could circumvent
the purification problem. Thus we also used Bz-protected
ꢀ
Deprez, B.; Tartar, A. Tetrahedron 1998, 54, 4125. (d) Heather Twin, H.;
Batey, R. A. Org. Lett. 2004, 6, 4913. (e) Zhou, H.-B.; Liu, G.-S.; Yao,
Z. -J. Org. Lett. 2007, 9, 2003. (f) Zhao, Y.; Zhang, W.; Wang, S.; Liu, Q.
J. Org. Chem. 2007, 72, 4985. (g) Gaddam, V.; Ramesh, S.; Nagarajan,
R. Tetrahedron 2010, 66, 4218. (h) Suresh, R.; Muthusubramanian, S.;
Senthilkumaran, R.; Manickam, G. J. Org. Chem. 2012, 77, 1468. (i)
Pericherla, K.; Kumar, A.; Jha, A. Org. Lett. 2013, 15, 4078.
(8) (a) Chen, Y.; Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012, 51,
6493. (b) Chen, M.; Y. Chen, Y.; Liu, Y. Chem. Commun. 2012, 48,
12189. (c) Chen, M.; Liu, J.; Wang, L.; Zhou, X.; Liu, Y. Chem.
Commun. 2013, 49, 8650.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Scope of N-Aryl Aminesa
Table 1. Optimization Studies for the Formation of
Indenoquinoline 2a
temp time yield
entry
R
MS (g) solvent
DCE
(°C)
(h)
(%)a
1
Piv (1a)
Piv (1a)
Piv (1a)
Piv (1a)
Piv (1a)
Piv (1a)
Piv (1a)
Bz (1b)
Ac (1c)
À
80
80
80
50
80
80
80
80
80
80
23
8
38
86
69
82
83
79
2
ca. 1.5 DCE
ca. 1.5 DCE
ca. 1.5 DCE
ca. 1.0 DCE
ca. 1.5 toluene
ca. 1.5 EtOH
ca. 1.5 DCE
ca. 1.5 DCE
3b
4
9
9
5
6
6
4.5
9.5
7
c
7
À
8
83
68
58
9
7
10
COOMe (1d) ca. 1.5 DCE
7
a 0.3 mmol scale. Isolated yields. b 1.0 equiv of PhNH2 was used.
c Complex reaction mixture was observed.
o-propargylbenzaldehydes as substrates in some cases to
examine the reaction scope. As shown in Schemes 3 and 4,
a wide variety of diversely substituted o-propargylbenzal-
dehydes and N-aryl amines were suitable for this reaction,
furnishing the desired indeno[1,2-b]quinolines in generally
good-to-high yields. We first examined the scope of N-aryl
amine substrates (Scheme 3). The results indicated that
both electron-poor and -rich aryl substituents were toler-
ated well, and the electronic nature on N-aryl rings did not
have a strong influence on this reaction. For example, p-F,
p-Cl, p-Br, p-CF3, and p-CO2Me substituted anilines af-
forded the corresponding products 2bÀ2d and 2gÀ2h in
68À84% yields. p-tBu and p-MeO-substituted anilines
provided the corresponding 2i and 2k also in good yields
of 67% and 77%, respectively. Ortho-substituted N-aryl
amines such as 2-fluorobenzenamine or 2-isopropylbenze-
namine afforded 2e or 2j in the same yield of 77%.
However, the use of 2-iodobenzenamine resulted in only
a 46% yield of 2f. Meta-substituted anilines, such as 3,4,5-
trimethoxybenzenamine underwent the reaction well with
1a to afford 2l in a high yield of 92%. When naphthalen-1-
amine was used, a pentacyclic compound 2m was obtained
in 75% yield. Next, we examined the substituent effect (R1)
on the alkyne terminus (Scheme 4). Substrates with weak
electron-withdrawing groups such as p-Cl on the aryl ring
afforded 2n in 76% yield, whereas with strong-electron-
withdrawing groups, such as p-CF3 or p-CO2Et, the for-
mation of 2o and 2p occurred in lower yields of 60% and
51%, respectively. The electron-rich p-MeO-substituted
a Isolated yields. Substrate 1a was used for 2a, 2c, 2i, 2j, and 2l.
Substrate 1b was used for 2b, 2dÀh, 2k, and 2m.
Scheme 4. Scope of o-Propargylbenzaldehydesa
a Isolated yields.
aryl alkyne provided 2q in 71% yield. The results indicated
that the electronic nature of the aryl rings on the alkyne
terminus has a strong influence on this reaction. The
2-thienyl group was also compatible with this reaction,
leading to 2r in 75% yield. In addition, alkyl-substituted
alkynes were also well accommodated. For example, an
nBu- or cyclopropyl-substituted alkynes afforded 2s and 2t
in 71% and 57% yields, respectively. Most of the above
indenoquinoline products are fluorescent, which could
find utility also in organic materials synthesis. It should
(9) (a) Reference 2h. (b) Malecki, N.; Carato, P.; Rigo, B.; Goossens,
ꢀ
J.; Houssin, R.; Baillyc, C.; Henicharta, J. Bioorg. Med. Chem. 2004, 12,
641. (c) Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett. 2008,
10, 2159. (d) Mohammadi, A. A.; Azizian, J.; Hadadzahmatkesh, A.;
Asghariganjeh, M. R. Heterocycles 2008, 75, 947. (e) Yang, D.; Jiang,
K.; Li, J.; Xu, F. Tetrahedron 2007, 63, 7654.
(10) See Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

subjected to the oxidation conditions.11 It was found that
the indeno[1,2-b]quinolin-11-one 4 was formed smoothly
via oxidation of the bridged CH2 group.
Scheme 5. Formation of Polycyclic Compound and Further
Transformation
We proposed the following reaction mechanism for this
reaction(Scheme6). First, animine 5 isformedvia conden-
sation of aldehyde 1 with aniline. Then an aza-DielsÀ
Alder reaction (Povarov reaction) of the aza-diene moiety
with the alkyne occurs to give a cyclized intermediate 6.
Subsequently, elimination of the OBz group12 followed by
double bond isomerization furnishes the final indenoqui-
noline 2. In these reactions, no oxidant is required, since
aromatization can be achieved by elimination of a leaving
group and isomerization.
To understand the mechanism, the imine intermediate
5a was isolated in 84% yield under controlled reaction
conditions. 5a cyclized under similar reaction conditions to
afford 2a in 90% yield (Scheme 7). These results supported
our proposed mechanism.
Scheme 6. Possible Reaction Mechanism
Scheme 7. Control Experiments
In summary, we have successfully developed a facile
synthetic strategy for indeno[1,2-b]quinolines based on an
intramolecular Povarov reaction. Our reactions proceeded
efficiently in the absence of oxidants. Aromatization was
achieved by elimination of a leaving group and isomeriza-
tion. A wide variety of substituents could be incorporated,
which allows for a convenient structural modification of
simple indenoquinolines. Further studies to extend the
scope of the synthetic utility involving an intermolecular
Povarov reaction are in progress in our laboratory.
be noted that although indeno[1,2-b]quinolines can be
preparedbythe Pfitzingerreactionbetweenanappropriate
isatin and 1-indanone2c,eÀg or a Friedlander reaction be-
€
tween a 2-aminobenzaldehyde or 2-aminoaryl ketone and
1-indanone,9 the availability of the substrates employed in
these methods can be quite limited, which restricts the
structural elaboration of the indeno[1,2-b]quinolines, espe-
cially, on the quinoline ring moiety. The structures of 2h,
2l, and 2m were unambiguously determined by X-ray
crystallography.10
Interestingly, when benzene-1,4-diamine was employed,
a hepta-fused-heterocyclic compound 3 was obtained in
42% yield as the major product, in which the second ring
closure occurred at the C-1 position of the N-phenyl ring,
but not at the C-2 position (Scheme 5). The structure of 3
was also confirmed by X-ray crystallography.10 The re-
gioselectivity in this case can be rationalized by invoking
π-stacking of the aromatic groups during the second ring-
closing process, leading to indenoquinoline 3 with two
phenyl groups on the same side. To demonstrate the
synthetic utility of indenoquinoline 2, compound 2a was
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 21125210,
21372244, 21121062), Chinese Academy of Science and
the Major State Basic Research Development Program
(Grant No. 2011CB808700) for financial support.
Supporting Information Available. Experimental de-
tails, spectroscopic characterization of all new com-
pounds, and X-ray crystallography of compounds 2h,
2l, 2m, and 3 are given. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Cao, J.;Yang,X.;Hua, X.;Deng, Y.;Lai, G.Org. Lett. 2011, 13, 478.
(11) Nitta, M.; Ohnuma, M.; lino, Y. J. Chem. Soc., Perkin Trans. 1
1991, 1115.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX