Synthesis of dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinolines via intramolecular aza Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.033

An efficient and convenient one-pot intramolecular aza Diels-Alder approach for the synthesis of dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinolines has been reported. Particularly valuable features of this methodology include simple execution, inexpensive cat

Full text of DOI:10.1016/j.tetlet.2011.07.033

Tetrahedron Letters 52 (2011) 4857–4860
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Synthesis of dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinolines
via intramolecular aza Diels–Alder reaction
⇑
Subburethinam Ramesh, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient one-pot intramolecular aza Diels–Alder approach for the synthesis of dihy-
drochromeno[4,3-b]pyrrolo[3,2-f]quinolines has been reported. Particularly valuable features of this
methodology include simple execution, inexpensive catalyst, and good product yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 April 2011
Revised 6 July 2011
Accepted 9 July 2011
Available online 19 July 2011
Keywords:
Chromene
Dihydrochromeno[4,3-b]pyrrolo[3,2-
f]quinoline
Intramolecular aza Diels–Alder
Copper catalysis
Chromenes are an important class of heterocyclic compounds
which have attracted considerable attention, due to their diverse
biological activites.1 Their derivatives produce remarkable effects
as pharmaceuticals, including antifungal,1 antimicrobial,2a proges-
tational,2b antibiotic rhodomyrtone,2c antiallergic,2d and antiulcer
agents.2e As a member of this family, chromenoquinoline deriva-
tives have attracted much attention recently due to the biological
and pharmacological activities, (Fig. 1) such as selective progester-
one receptor modulators,3a transcriptional activity,3b and glucocor-
ticoid modulators.3c Pyrroloquinolines form the basic skeleton of
numerous alkaloids and biologically active compounds.4 It is envi-
sioned that chromeno[4,3-b]pyrrolo[3,2-f]quinolines, which con-
tain both pyrroloquinoline and chromene moieties may afford
unique biological activities and we paid attention to the develop-
ment of a methodology for their preparation.
Imino Diels–Alder reaction is the one of the most powerful syn-
thetic tools for biologically interesting heterocycles and natural
product synthesis.5 Herein we wish to report a facile one-pot copper
catalyzed aza-Diels–Alder type reaction between 5-aminoindoles
and O-propargyl salicylaldehydes to afford dihydrochromeno[4,3-
b]pyrrolo[3,2-f]quinoline derivatives in moderate to good yields.
Initially, a mixture of 2,3-dimethyl-1H-5-indolamine (1a) and
O-propargylsalicylaldehyde (2a) in CH3CN as solvent was stirred
at reflux temperature to optimize the reaction conditions (Scheme
1). When the reaction was catalyzed by CuBr (10 mol %), we ob-
Me
Me
HO
O
N
O
Me
Me
OH
N
Br
H
Estrogen receptor
Progesterone receptor
modulator
H3C CH3
O
OMe
OH
CH3
Me
N
O
N
O
Me
CH3
(-)-(R)-Geibalansine
An alkaloid
Benzosimiline
An alkaloid
Figure 1. Some of chromenoquinoline alkaloids and biologically active compounds.
served the formation of the expected product 3a in 40% yield
(Table 1, entry 1). The structure of 3a was also confirmed by single
crystal X-ray crystallography (Fig. 2).7
No desired product was obtained when the reaction was carried
out in InCl3 and La(OTf)3 for 20 h (Table 1, entries 3 and 4). Other
metal salts, such as CuI, AgOTf, Cu(OTf)2, PdCl2, Pd(OAc)2 were also
tested in the aza-Diels–Alder reaction (Table 1, entries 5–9), and
CuI was found to be the best choice (Table 1, entry 5). To improve
⇑
Corresponding author. Tel.: +91 40 23134831, fax: +91 40 23012460.
E-mail addresses: naga_indole@yahoo.co.in, rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.033

4858
S. Ramesh, R. Nagarajan / Tetrahedron Letters 52 (2011) 4857–4860
O
CH3
O
O
H2N
CH3
H
Catalyst
CH3 +
N
N
H
CH3
Solvent, reflux
N
H
2a
3a
1a
Scheme 1. 1,2-Dimethyl-3,12-dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinoline (3a).
Table 1
Optimization of the reaction conditions
Entry
Catalyst
Solvent
Time (h)
Yielda (%)
1
2
3
4
CuBr (10 mol %)
CuCl (10 mol %)
InCl3 (10 mol %)
La(OTf)3 (10 mol %)
Cul (10 mol %)
CH3CN
CH3CN
CH3CN
CH3CN
5
5
20
20
5
40
55
—
—
5
CH3CN
68
50
60
25
Trace
60
68
70
65
85
75
75
85
60
65
85
85
70
6
7
8
9
AgÁOTf (10 mol %)
Cu(OTf)2 (10 mol %)
PdCl2 (10 mol %)
Pd(OAc)2 (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
CuI/La(OTf)3 (10 mol %)
Cul (10 mol %)
Cul (10 mol %)
Cul (30 mol %)
CH3CN
CH3CN
CH3CN
CH3CN
THF
DMF
Toluene
Ethanol
[Bmim][BF4]
[BmimllPFd
[Bmim][Cl]
[Bmim][BF4]
DMSO
6
8
15
10
8
10
11
12
13
14
15
16
17
18
19
20
21
22b
6
10
12
2
2
2
10
24
24
5
48
24
Xylene
[Bmim][BF4]
[Bmim][BF4]
CH3CN
Cul (10 mol %)
Cul (10 mol %)
a
Yield refers to column purified product. For the entries 1–9 reflux temperature of CH3CN were maintained. For the entries
10–13 reflux temperature of the corresponding solvents were maintained. Temperature was maintained 90–95 °C for entries
(14–21). In all entries, catalyst mol % was calculated relative to the 5-aminoindole (1a).
b
Reaction was performed with CH3CN as solvent at 120 °C in a sealed tube.
O1
O1
N3
N2
Cl1
N1
N1
Figure 2. ORTEP diagrams of 3a and 4e.
the yield, we examined various solvents in the presence of CuI as
catalyst (Table 1, entries 10–19). The best result was obtained
when [Bmim][BF4] was used. The yield of the product was not im-
proved when mixed catalytic system was used (Table 1, entry 17).
The yield of 3a (70%) was obtained, when the reaction was con-
ducted with CH3CN as solvent at 120 °C in a sealed tube (Table 1,
entry 22).
The reaction times were exceedingly long, when the reaction was
conducted at temperatures lower than 90 °C. At temperatures above
100 °C, several unidentified minor side products were formed.
With the optimized conditions in hand, that is, CuI as the suit-
able catalyst and [Bmim][BF4], we next evaluated the substrate
scope of this reaction. Different 5-aminoindoles (1a–i) were suc-
cessfully employed with O-propargyl salicylaldehyde (2a) to pro-
duce the corresponding dihydrochromeno[4,3-b]pyrrolo[3,2-
f]quinoline derivatives (3a–i) (Table 2).
Various substitution patterns at 1, 2, 3 positions as well as 7-Cl
of 5-aminoindoles were well tolerated in the reaction (Table 2, en-
tries 1–7, 9). This aza-Diels–Alder reaction was slightly affected by
the electron withdrawing group (–SO2Ph) and led to moderate
yield (Table 2, entry 8).

S. Ramesh, R. Nagarajan / Tetrahedron Letters 52 (2011) 4857–4860
4859
Table 2
Table 3
Synthesis of chromenopyrroloquinolines with various 5-aminoindoles (1a–i)
Synthesis of chromenopyrroloquinolines with various O-propargylsalicylaldehyde
(2a–j)
O
R3
O
O
H2N
R3
CH3
O
CuI (10 mol %)
[Bmim][BF4], 90-95 oC
GF
R2
H
H2N
+
N
CH3
CuI (10 mol %)
[Bmim][BF4], 90-95 oC
H
N
R1
R2
CH3 +
N
O
GF
N
R4
N
R1
CH3
O
2a
H
1a-i
3a-i
N
R4
2a-j
1a
3a, 4b-j
H
Entry Aminoindoles
Product
Time
(h)
Yield
(%)
Entry Aldehyde
Product
Time
(%)
Yield
(%)
CH3
O
N
O
O
H2N
CH3
H
CH3
N
H
CH3
1
2
2
2
85
85
1a
1b
O
N
1
2
3
4
5
6
7
2
2
3
1
2
3
3
85
85
80
88
80
85
85
CH3
CH3
N
H
2a
N
3a
3b
3c
3a
H
CH3
O
N
O
O
N
H2N
CH3
H3C
MeO
F
CH3
H
N
H3C
CH3
CH3
O
CH3
CH3
2b
CH3
N
N
H
4b
CH3
O
N
O
O
H2N
CH3
Ph
H
CH3
N
MeO
CH3
3
4
2
3
85
75
1c
O
N
CH3
Ph
CH3
2c
N
N
4c
H
H2N
O
N
O
O
N
CH3
N
H
H
F
1d
CH3
O
CH3
CH3
N
H
2d
N
3d
3e
H
4d
H2N
O
N
O
O
CH3
Cl
N
H
1e
Cl
CH3
5
3
80
O
N
CH3
CH3
N
CH3
2e
N
4e
H
CH3
O
O
N
H2N
O
N
Br
H
CH3
Br
CH3
N
CH3
O
1f
6
7
8
9
3
3
3
3
80
83
65
83
CH3
2f
CH3
CH3
CH3
N
N
CH3
H
4f
3f
O
N
O
O
CH3
O
N
H2N
H
CH3
CH3
CH3
N
CH3
CH3
1g
2g
N
N
CH3
H
4g
3g
O
O
OMe
O
H2N
O
N
H
CH3
N
1h SO2Ph
CH3
8
2
3
3
81
80
84
OMe
N
2h
CH3
N
SO2Ph
N
3h
H
4h
CH3
O
N
O
Cl
H2N
Cl
O
N
CH3
H
CH3
N
H
O
Cl
Cl
CH3
CH3
9
1i
Cl
N
2i
CH3
H
Cl
3i
N
H
4i
O
O
F
O
We next turned our attention to varying the O-propargyl sali-
cylaldehydes (2a–j) of the one-pot reaction with 5-aminoindole
(1a) (Table 3). O-Propargyl salicylaldehydes with electron donating
and electron withdrawing substituents did not show any signifi-
cant change in the yields (Table 3, entries 1–10).
H
CH3
10
N
F
2j
CH3
N
H
4j

4860
S. Ramesh, R. Nagarajan / Tetrahedron Letters 52 (2011) 4857–4860
O
O
NH2
N
N
N
CuI
H
Cu
+
1a
O
O
N
H
N
H
B
H
A
[4+2]
2a
cycloaddition
O
O
Cu
N
N
N
H
3a
N
C
H
Scheme 2. Proposed mechanism for the synthesis of 3a.
Based on reports from the literature,6 we have proposed a
mechanism for CuI catalyzed intramolecular aza Diels–Alder reac-
tion (Scheme 2). The first step is the formation of imine (A) from
the starting materials 2,3-dimethyl-1H-5-indolamine (1a) and
O-propargyl salicylaldehyde (2a), the second step is the formation
of copper-acetylide (B), obtained by the deprotonation of O-prop-
argylic group. The subsequent intramolecular[4+2]cycloadditon
between azadiene and copper activated triple bond (C), followed
by deprotonation generates dihydrochromenopyrroloquinoline
(3a).
Rahman, A.-U. Eur. J. Org. Chem. 2006, 10, 2371–2377; (d) Nikolai, M. E.; Artem,
S. K.; Andrey, A. Y.; Mikhail, Y. A.; Igor, V. M.; Alexander, K. J. Org. Chem. 2007, 72,
3443–3453; (e) María, E.; Benito, R.; Paula, G.; Juan, R.; Carlos, C.; Humberto, C.;
Jesus, A. Fitoterapia 2010, 81, 66–71.
3. (a) Zhi, L.; Tegley, C. M.; Pio, B.; Edward, J. P.; Motamedi, M.; Jones, T. D.;
Marschke, K. B.; Mais, D. E.; Risek, B.; Schrader, W. T. J. Med. Chem. 2003, 46,
4104; (b) Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly, J. R.; Wilcox,
D.; Stashko, M.; Lin, C. W.; Miner, J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane, B.
C. J. Med. Chem. 2001, 44, 2879; (c) Ku, Y. Y.; Grieme, T.; Raje, P.; Sharma, P.;
Morton, H. E.; Rozema, M.; King, S. A. J. Org. Chem. 2003, 68, 3238.
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Banerjee, B.; Cushman, M. Org. Lett. 2010, 12, 3112; (c) Chang, L. C.; Otero-
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C.; Oh, T. Tetrahedron 2001, 57, 6099–6138; (c) Jørgensen, K. A. Angew. Chem., Int.
Ed. 2000, 39, 3558; (d) Benforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259–
5288; (e) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 14; Boger, D. L.;
Weinreb, S. M. Hetero Diels–Alder Methodology in Organic Synthesis; Academic:
San Diego, CA, 1987; (f) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325;
(g) Lin, L. L.; Liu, X. H.; Feng, X. M. Synlett 2007, 2147; (h) Tietze, L. F. Chem. Rev.
1996, 96, 115–136; (i) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007.
6. (a) Furstner, A.; Stimson, C. C. Angew. Chem., Int. Ed. 2007, 46, 8845–8849; (b)
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216; (c) Malihe, J. K.; Saeed, B.;
Hamid, R. B.; Jurgen, H. G. Synlett 2009, 1, 55–58; (d) Yoo, E. J.; Ahlquist, M.; Bae,
I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. J. Org. Chem. 2008, 73, 5520–5528.
7. The CCDC deposition number of 3a is 796986; molecular formula: C20H16N2O,
orthorhombic, Unit cell parameters: a = 9.3913(6), b = 25.0587(18),
c = 16.0101(11), Space group Pccn. The CCDC deposition number for
In conclusion, we have developed a simple and efficient one-pot
method for the synthesis of new dihydrochromeno[4,3-b]pyrrol-
o[3,2-f]quinoline derivatives8 by utilizing intramolecular aza
Diels–Alder reaction between 5-aminoindoles and O-propargyl sal-
icylaldehydes with CuI as the catalyst and ionic liquid as the sol-
vent in good yields.
Acknowledgments
We greatfully acknowledge DST for financial assistance (Project
Number: SR/S1/OC–70/2008) and for providing single-crystal
X-ray diffractometer facility in our school. S.R. thanks CSIR for
Senior Research Fellowship.
compound 4e is 796987. Formula:
C22H15Cl1N2O2S1. Unit cell parameters:
a = 15.9100(12), b = 9.0681(7), c = 16.2656(18), b = 117.7960(10), space group
P21/c.
Supplementary data
8.
A
typical procedure for the preparation of 3a: In a round bottomed flask
equipped with magnetic stirring bar, 1.0 mmol of 2,3-dimethyl-1H-5-
a
indlamine (1a) and 1.0 mmol of O-propargyl salicylaldehyde (2a) in 5 mL of
ionic liquid [Bmim][BF4] as solvent, was added 10 mol % of CuI. Reaction mixture
was stirred at 90–95 °C for 2 h. After completion of the reaction, as indicated by
the TLC, water (20 mL) was added to the crude reaction mass. Then aqueous
layer was extracted with dichloromethane (3 Â 20 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under the reduced
pressure. Product was purified by column chromatography on silica gel (eluent:
hexane/ethyl acetate) afforded 85%, Rf = 0.71 (10% of ethylacetate in hexanes).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.033.
References and notes
1. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.;
Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939–9953; (b) Nicolaou, K. C.;
Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao, G.-Q.; Affleck, R.
L.; Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954–9967; (c) Tangmouo, J. G.; Meli, A.
L.; Komguem, J.; Kuete, V.; Ngounou, F. N.; Lontsi, D.; Beng, V. P.; Choudhary, M.
I.; Sondengam, B. L. Tetrahedron Lett. 2006, 47, 3067.
2. (a) Kraus, G. A.; Kim, I. J. Org. Chem. 2003, 68, 4517; (b) Tegley, C. M.; Zhi, L.;
Marschke, K. B.; Gottardis, M. M.; Yang, Q.; Jones, T. K. J. Med. Chem. 1998, 41,
4354; (c) Shaheen, F.; Ahmad, M.; Khan, S. N.; Hussain, S. S.; Anjum, S.;
Tashkhodjaev, B.; Turgunov, K.; Sultankhodzhaev, M. N.; Choudhary, M. I.;
mp 243–245 °C; IR (KBr): 3366, 2852, 1388, 1298, 898, 580 cmÀ1 1H NMR
;
(400 MHz, DMSO + CDCl3, TMS) d: 9.79 (1H, s); 8.35 (2H, s); 7.67 (1H, d,
J = 8.6 Hz); 7.58 (1H, d, J = 8.8 Hz); 7.22 (1H, t, J = 7.2 Hz); 7.04 (1H, t, J = 7.2 Hz)
6.90 (1H, d, J = 8.2 Hz); 5.33 (2H, s); 2.45 (3H, s); 2.36 (3H, s); 13C NMR
(100 MHz, DMSO + CDCl3, TMS) d: 156.7, 145.5, 144.4, 131.3, 130.9, 130.7, 126.3,
124.7, 123.9, 123.4, 123.2, 122.3, 122.1, 120.9, 117.0, 116.2, 109.5 (aromatic C);
68.9, 12.2, 11.4 (aliphatic C); m/z = 301 (M+H) positive mode; Anal. Calcd for
C
20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.85; H, 5.41; N, 9.45.