Combinatorial synthesis of pyrrolo[3,2-f]quinoline and pyrrolo[3,2-a] acridine derivatives via a three-component reaction under catalyst-free conditions

Article abstract of DOI:10.1021/co400073m

A combinatorial synthesis of pyrrolo[3,2-f]quinoline and pyrrolo[3,2-a]acridine derivatives is described as a three-component reaction of aromatic aldehyde, 1H-indol-5-amine, and 1,3-dicarbonyl compounds under catalyst-free conditions. The 1,3-dicarbonyl compounds include 5,5-dimethylcyclohexane-1,3-dione, cyclopentane-1,3-dione, and 2H-indene-1,3-dione. It is interesting that the designed reactions gave aromatized or unaromatized products, which depend on the reaction temperature and reactants of 1,3-dicarbonyl compounds.

Full text of DOI:10.1021/co400073m

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Article
Combinatorial Synthesis of Pyrrolo[3,2-f]quinoline and Pyrrolo[3,2-a]acridine
Derivatives via Three-Component Reaction under Catalyst-Free Conditions
Yu-Jing Zhou, Dong-Sheng Chen, Yu-Ling Li, Yun Liu, and Xiang-Shan Wang
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400073m • Publication Date (Web): 05 Aug 2013
Downloaded from http://pubs.acs.org on August 11, 2013
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Combinatorial Synthesis of Pyrrolo[3,2-f]quinoline and Pyrrolo[3,2-a]acridine
Derivatives via Three-Component Reaction under Catalyst-Free Conditions
YuꢀJing Zhou, DongꢀSheng Chen, YuꢀLing Li, Yun Liu, XiangꢀShan Wang*
9
A combinatorial synthesis of pyrrolo[3,2ꢀf]quinoline and pyrrolo[3,2ꢀa]acridine derivatives is
described by a threeꢀcomponent reaction of aromatic aldehyde, 1Hꢀindolꢀ5ꢀamine and
1,3ꢀdicarbonyl compounds under catalystꢀfree conditions. The 1,3ꢀdicarbonyl compounds include
5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione, cyclopentaneꢀ1,3ꢀdione and 2Hꢀindeneꢀ1,3ꢀdione. It is
interesting that the designed reactions gave aromatized or unꢀaromatized products, which depend
on the reaction temperature and reactants of 1,3ꢀdicarbonyl compounds.
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Ar
O
NH
N
O
DMF
O
O
O
O
Ar
Ar
O
NH
NH
NH2
O
O
ArCHO +
EtOH
N
EtOH
N
H
N
H
H
O
O
DMF
Ar
N
O
NH
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Combinatorial Synthesis of Pyrrolo[3,2-f]quinoline and Pyrrolo[3,2-a]acridine
Derivatives via Three-Component Reaction under Catalyst-Free Conditions
YuꢀJing Zhou, DongꢀSheng Chen, YuꢀLing Li, Yun Liu, XiangꢀShan Wang*
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R.
China
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Eꢀmail: xswang1974@yahoo.com
Abstract—A combinatorial synthesis of pyrrolo[3,2ꢀf]quinoline and pyrrolo[3,2ꢀa]acridine
derivatives is described by a threeꢀcomponent reaction of aromatic aldehyde, 1Hꢀindolꢀ5ꢀamine
and 1,3ꢀdicarbonyl compounds with catalystꢀfree conditions. The 1,3ꢀdicarbonyl compounds
include 5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione, cyclopentaneꢀ1,3ꢀdione and 2Hꢀindeneꢀ1,3ꢀdione. It
is interesting that the designed reactions gave aromatized or unꢀaromatized products, which
depend on the reaction temperature and reactants of 1,3ꢀdicarbonyl compounds.
Keywords: pyrrolo[3,2ꢀf]quinoline, pyrrolo[3,2ꢀa]acridine, 1Hꢀindolꢀ5ꢀamine, catalystꢀfree,
synthesis
1. Introduction
Acridine occurs in a large number of natural products and attracts much attention
due to its widely biological activities. Its derivatives produce remarkable effects as
pharmaceuticals
including
antiꢀbacterial,1
antiꢀcancer,2ꢀ3
antiꢀtumour,4ꢀ5
ribonucleolytic,6 antiꢀangiogenic7 and antiꢀfungicidal activities.8 It is well known that
the threeꢀcomponent reaction of arylamine, aromatic aldehyde and cyclic
1,3ꢀdicarbonyl compound is an efficient method to synthesize these potentially active
heterocycles.9 As a member of this family, pyrroloacridine contains both pyrrole and
acridine moieties, which may afford unique biological activities for screening.
Therefore, a simple, mild, and versatile preparation of pyrroloacridines in oneꢀpot
reaction is still highly desirable.
In addition, pyrroloquinoline is a skeleton of natural alkaloids. For example,
Marinoquinoline A (Figure 1, left) is isolated from the gliding bacterium
Ohtaekwangia kribbensis, and shows weak antibacterial and antifungal activities and
moderate cytotoxicity against four growing mammalian cell lines.10 Another
important alkaloid containing pyrroloquinoline is Ammosamide B (Figure 1, right),
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which is well known for its antiꢀtumour activity.11 Its derivatives also have attracted
much attention recently due to the other remarkable biological and pharmacological
activities, such as antiꢀoxidative,12 cytotoxic,13 antiꢀcancer,14 photochemotherapeutic15
and antiꢀviral activity.16 Therefore, a considerable effort has been made for the
synthesis of pyrroloquinoline annulated heterocyclic derivatives due to their wide
applications.17ꢀ22 As a continuation of our research devoted to the new methods for the
preparation of heterocycles via multiꢀcomponent reactions,23 we describe here the
synthesis of pyrrolo[3,2ꢀf]quinoline and pyrrolo[3,2ꢀa]acridine derivatives by a
threeꢀcomponent reaction of aromatic aldehyde, 1Hꢀindolꢀ5ꢀamine and 1,3ꢀdicarbonyl
compounds under catalystꢀfree conditions.
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O
H3C
N
H2N
Cl
NH
O
N
N
CH3
NH2
NH2
Marinoquinoline A
Ammosamide B
Figure 1. The interesting alkaloids containing pyrroloquinoline
2. Results and discussion
Treatment of 4ꢀcyanobenzaldehyde 1{1}, 1Hꢀindolꢀ5ꢀamine 2{1}, and
cyclopentaneꢀ1,3ꢀdione 3{1} in refluxing EtOH without catalysts, resulted in the
corresponding
10ꢀ(4ꢀcyanophenyl)ꢀ6,7,8,10ꢀtetrahydrocyclopenta[b]pyrrolo[3,2ꢀf]
quinolinꢀ9(3H)ꢀone derivatives 4{1,1,1} in high yield (Scheme 1).
CN
CN
CN
O
O
O
NH2
NH
NH
EtOH
+
+
+
Reflux
N
N
H
N
H
O
CHO
5{1,1,1}
4{1,1,1}
1{1}
2{1}
3{1}
Scheme 1. Reaction of 1{1}, 2{1} and 3{1}
In our lab, the screening of catalysts was carried out first, for example, KF/Al2O3,
piperidine and DBU (Table 1, entries 4ꢀ6), taking the reaction of
4ꢀcyanobenzaldehyde 1{1}, 2{1}, and 3{1} as a model. It was found that no catalyst,
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the reaction could take place and give 4{1,1,1} in high yields (93 %). The solvents,
such as CH3OH, EtOH, benzene and THF (entries 3, 7ꢀ10), were also tested to this
reaction, the EtOH gave the best result. Furthermore, the product was collected by
filtration without further purification, when the EtOH solution was cooled to room
temperature after the completion of the reaction. It was interesting that the same
reaction gave the aromatized cyclopenta[b]pyrrolo[3,2ꢀf]quinolinꢀ9(3H)ꢀone
derivatives 5{1,1,1} in 68 % yield at 80 ºC along with 11 % yield of 4{1,1,1} in DMF.
The yield of 5{1,1,1} was also gradually raised with the increase of temperature, and
it gave the highest yield of 84 % at reflux in DMF for 6 hours (entries 8ꢀ11).
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Table 1. Synthetic results of 4{1,1,1} and 5{1,1,1} under different reaction conditionsa
Entry
Catalyst(mol%)
Time(h)
Solvent
Yields (4/5, %)b
temperature (°C)
1
r.t.
ꢀ
10
16
10
10
10
10
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3OH
CH3CN
Benzene
THF
Trace/0
68/0
93/0
90/0
90/0
87/0
87/0
82/0
89/0
85/0
11/68
0/78
0/84
2
50
ꢀ
3
Reflux
Reflux
Reflux
Reflux
80
-
4
KF/Al2O3
5
Piperidine
6
DBU
7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
-
8
Reflux
Reflux
Reflux
80
14
16
14
10
10
6
9
10
11
12
13
DMF
100
DMF
Reflux
DMF
a
Reagents and conditions: 4ꢀcyanobenzaldehyde 1{1} (0.140 g, 1.0 mmol), 2{1} (0.213 g, 1.0
mmol), 3{1} (0.133 g, 1.0 mmol), solvent (10 mL). b Isolated yields.
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O
5
6
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O
Ar
NH
3{1} or 3{3}
O
8
9
EtOH, reflux
NH2
N
H
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4
+
ArCHO
O
N
H
1
2
O
Ar
3{1} or 3{2}
NH
O
DMf, reflux
N
5
Scheme 2. Reaction of 1, 2 and 3
The interesting and selective reaction depending on the reaction temperature,
inspired us to test other 1,3ꢀdicarbonyl compounds in this type of reaction.
2HꢀIndeneꢀ1,3ꢀdione 3{2} was chosen firstly for its similarity to
cyclopentaneꢀ1,3ꢀdione. It was found that the products were easily oxidized by air,
even if the designed reactions were treated at slightly lower temperature in EtOH,
they all aromatized to 12ꢀarylindeno[1,2ꢀb]pyrrolo[3,2ꢀf]quinolinꢀ11(3H)ꢀone
derivatives in high yields without catalysts (Scheme 2). Perhaps, the large conjugative
system promotes the centre 1,4ꢀdihydropyrdine (1,4ꢀDHP) ring to be easy oxidized by
air.
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Figure 2. The crystal structure of 4{8,1,1} with a molecule of DMF being deleted for clarity.
24ꢀ27
It was reported
that most of 1,4ꢀDHP rings are stable in air, so
7
8
9
aboveꢀmentioned results raised an interesting question: why were they so easily
oxidized by air? With this question, the single crystal of 4{8,1,1} was grown by slow
evaporation at room temperature, and determined by CCD diffractometer. The crystal
structure of 4{8,1,1} is shown in Figure 2. Xꢀray diffraction analysis indicates that all
the atoms (C(1)ꢀC(5)/N(2)) on the center 1,4ꢀDHP ring are coplanar, with mean
deviation being 0.0249 Å, which is obviously different from those of similar
structures.28,29 Perhaps, the planar 1,4ꢀDHP ring is oxidized more readily than the
distorted ones (boat, or halfꢀchair confirmation). It is also found in the crystal
structure of 4{8,1,1} that the adjacent fiveꢀmembered ring (C(1)/C(2)/C(12)ꢀC(14)) is
also a planar structure, with mean deviation being 0.009 Å. Therefore, we think that
the coplanar 1,4ꢀDHP is just because of the outer fiveꢀmembered planar ring.
Otherwise, the 1,4ꢀDHP would change to normal distorted confirmation, and it would
be stable in air.
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With this idea in mind, we selected the third 1,3ꢀdicarbonyl compound to instead
of fiveꢀmembered planar ring. 5,5ꢀDimethylcyclohexaneꢀ1,3ꢀdione 3{3} (dimedone is
not a planar structure) was subjected to react with 1 and 2{1} without catalysts. The
unꢀaromatized 8,9ꢀdihydroꢀ8,8ꢀdimethylꢀ11ꢀarylꢀ3Hꢀpyrrolo[3,2ꢀa]acridinꢀ10(6H,7H,
11H)ꢀone derivatives were obtained as we expected, whether they were treated in
refluxing EtOH or DMF.
In order to confirm our assumption, we also grew the single crystals of 4{23,1,3},
and its crystal structure is shown in Figure 3. Xꢀray diffraction analysis demonstrates
that the 1,4ꢀDHP is slightly distorted, adopting a skew boat confirmation as expected.
The atoms of C(1), C(2) C(4) and C(5) are coplanar, with atoms C(3) and N(1)
deviating from the defined plane by 0.222(2) and 0.106(2) Å, respectively. The outer
sixꢀmembered ring adopts a halfꢀchair confirmation as expected, and the atom C(7)
deviates from the plane (C(4)ꢀC(6)/C(8)/C(9)) by 0.640 (2) Å.
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Figure 3. The crystal structure of 4{19,1,3}
CHO
CHO
CHO
CHO
CHO
Cl
OMe
OMe
F
2
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1
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5
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CHO
CHO
CHO
CHO
CHO
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Cl
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CHO
CHO
OMe
Cl
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OMe
OMe
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CHO
CHO
CHO
Cl
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OMe
MeO
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Figure 4. Diversity of aldehydes 1{1ꢀ23}
4
5
O
O
O
6
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9
O
O
O
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2
3
1
Figure 5. Diversity of 1,3ꢀdicarbonyl compounds 3{1ꢀ3}
Table 2. The reaction time and yields of the products 4a
entry Ar
time (h)
products
4{1,1,1}
4{2,1,1}
4{3,1,1}
4{4,1,1}
4{5,1,1}
4{6,1,1}
4{7,1,1}
4{8,1,1}
4{9,1,1}
4{10,1,1}
4{6,1,3}
4{7,1,3}
4{9,1,3}
4{11,1,3}
4{12,1,3}
4{13,1,3}
4{14,1,3}
4{15,1,3}
4{16,1,3}
4{17,1,3}
4{18,1,3}
4{19,1,3}
Isolated yields (%)
1
4ꢀCNC6H4
6
87
90
92
86
90
84
88
90
94
92
92
95
90
90
91
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90
95
96
96
95
87
2
4ꢀFC6H4
6
3
C6H5
7
4
2,3ꢀ(MeO)2C6H3
2,4ꢀCl2C6H3
4ꢀBrC6H4
8
5
5
6
6
7
Piperonyl
8
8
4ꢀMeOC6H4
3ꢀMeOC6H4
4ꢀNO2C6H4
4ꢀBrC6H4
9
9
6
10
11
12
13
14
15
16
17
18
19
20
21
22
5
6
Piperonyl
10
8
3ꢀMeOC6H4
3,4ꢀCl2C6H3
4ꢀMeC6H4
2ꢀMeOC6H4
4ꢀClC6H4
6
6
8
5
3ꢀClC6H4
6
3,4ꢀ(CH3)2C6H3
3,4ꢀ(MeO)2C6H3
2ꢀThienyl
10
10
6
2ꢀFC6H4
8
a
Reaction condition: EtOH (10 mL), 1 (1.0 mmol), 2{1} (0.132 g, 1.0 mmol) and 3 (1.0 mmol),
reflux.
Table 3. The reaction time and yields of the products 5a
entry Ar
time (h)
10
products
5{1,1,1}
5{3,1,1}
5{5,1,1}
5{11,1,1}
5{12,1,1}
5{13,1,1}
5{15,1,1}
5{20,1,1}
Isolated yields (%)
1
2
3
4
5
6
7
8
4ꢀCNC6H4
84
84
92
87
90
83
88
90
C6H5
16
2,4ꢀCl2C6H3
3,4ꢀCl2C6H3
4ꢀMeC6H4
2ꢀMeOC6H4
3ꢀClC6H4
2ꢀClC6H4
12
15
16
18
10
10
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4ꢀMe2NC6H4
2,3ꢀCl2C6H3
3,5ꢀ(MeO)2C6H3
2,4ꢀCl2C6H3
4ꢀBrC6H4
12
12
18
10
10
10
10
10
9
5{21,1,1}
5{22,1,1}
5{23,1,1}
5{5,1,2}
90
89
92
87
90
90
95
88
87
96
92
90
85
94
92
10
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19
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21
22
23
5{6,1,2}
Piperonyl
5{7,1,2}
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3ꢀMeOC6H4
3,4ꢀCl2C6H3
4ꢀMeC6H4
5{9,1,2}
5{11,1,2}
5{12,1,2}
5{13,1,2}
5{14,1,2}
5{15,1,2}
5{16,1,2}
5{20,1,2}
5{23,1,2}
2ꢀMeOC6H4
4ꢀClC6H4
8
7
3ꢀClC6H4
7
3,4ꢀ(CH3)2C6H3
2ꢀClC6H4
12
8
3,5ꢀ(MeO)2C6H3
12
a Reaction condition: DMF (10 mL), 1 (1.0 mmol), 2{1} (0.132 g, 1.0 mmol) and 3 (1.0 mmol),
reflux.
3. Conclusion
In summary, a threeꢀcomponent reaction of aromatic aldehyde, 1Hꢀindolꢀ5ꢀamine
and 1,3ꢀdicarbonyl compounds including 5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione, cycloꢀ
pentaneꢀ1,3ꢀdione and 2Hꢀindeneꢀ1,3ꢀdione was studied under catalystꢀfree
conditions, with pyrrolo[3,2ꢀf]quinoline and pyrrolo[3,2ꢀa]acridine derivatives being
obtained in high yields. The advantages of this procedure include mild reaction
conditions, high yields, oneꢀpot operational simplicity, and with catalystꢀfree
conditions.
4. Experimental
Melting points were determined in open capillaries and are uncorrected. IR
1
spectra were recorded on a Tensor 27 spectrometer in KBr pellet. H NMR spectra
was obtained from a solution in DMSOꢀd6 with Me4Si as internal standard using a
Brukerꢀ400 spectrometer. HRMS analyses were carried out using
BrukerꢀmicroꢀTOFꢀQꢀMS analyzer.
a
General procedure for the syntheses of 4.
A dry 50 mL flask was charged with aromatic aldehyde 1 (1.0 mmol),
1Hꢀindolꢀ5ꢀamine 2 (0.132 g, 1.0 mmol), 1,3ꢀdicarbonyl compounds 3 (1.0 mmol) and
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EtOH (10 mL). The reaction mixture was stirred at reflux for 5ꢀ10 h. After the
completion of the reaction, as indicated by TLC, the products 4 were obtained as pale
yellow power or crystals, when the mixture was allowed to down to room
temperature.
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10ꢀ(4ꢀMethoxyphenyl)ꢀ6,7,8,10ꢀtetrahydrocyclopenta[b]pyrrolo[3,2ꢀf]quinolinꢀ9(3H)ꢀ
1
one 4{8,1,1}: M. p. 289~291 °C; H NMR (DMSOꢀd6, 400 MHz): δH 2.18~2.28 (m,
2H, CH2), 2.62~2.67 (m, 2H, CH2), 3.63 (s, 3H, OCH3), 5.18 (s, 1H, CH), 6.19 (s, 1H,
ArH), 6.70 (d, J = 8.0 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 1H, ArH), 7.08 (d, J = 8.0
Hz, 2H, ArH), 7.16 (s, 1H, ArH), 7.24 (d, J = 8.0 Hz, 1H, ArH), 9.92 (s, 1H, NH),
10.98 (s, 1H, NH). 13C NMR (DMSOꢀd6, 100 MHz): 23.9, 33.2, 37.9, 54.8, 99.8,
110.6, 111.2, 111.6, 113.1, 114.8, 125.3, 126.9, 128.6, 129.1, 132.7, 139.5, 157.0,
164.9, 199.4. IR (KBr): 3247, 3076, 3036, 2922, 2837, 2805, 2717, 2576, 1689, 1613,
1561, 1510, 1453, 1436, 1354, 1341, 1293, 1253, 1191, 1175, 1161, 1125, 1033, 989,
892, 836, 749, 725, 697 cmꢀ1. HRMS (ESI, m/z): Calcd for C21H19N2O2 [M + H]+
331.1447, found 331.1442.
General procedure for the syntheses of 5.
A dry 50 mL flask was charged with aldehyde 1 (1.0 mmol), 1Hꢀindolꢀ5ꢀamine 2
(0.132 g, 1.0 mmol), 1,3ꢀdicarbonyl compounds 3 (1.0 mmol) and DMF (10 mL). The
reaction mixture was stirred at reflux for 8ꢀ18 h. After the completion of the reaction,
as indicated by TLC, a little water was added to the mixture at reflux. The products 5
were obtained as pale yellow power or crystals, when the mixture was allowed to
down to room temperature.
10ꢀ(2,3ꢀDichlorophenyl)ꢀ7,8ꢀdihydrocyclopenta[b]pyrrolo[3,2ꢀf]quinolinꢀ9(3H)ꢀone
1
5{22,1,1}: M. p. > 300 °C; H NMR (DMSOꢀd6, 400 MHz): δH 2.73~2.79 (m, 2H,
CH2), 3.31~3.36 (m, 2H, CH2), 5.15 (s, 1H, ArH), 7.32~7.35 (m, 2H, ArH), 7.55~7.59
(m, 1H, ArH), 7.82 (d, J = 9.2 Hz, 1H, ArH), 7.89 (d, J = 8.0 Hz, 1H, ArH), 8.05 (d, J
13
= 8.8 Hz, 1H, ArH), 11.92 (s, 1H, NH). C NMR (DMSOꢀd6, 100 MHz): 27.7, 36.2,
103.3, 119.7, 120.7, 121.3, 122.5, 123.0, 125.1, 128.6, 129.0, 129.9, 130.6, 132.0,
132.5, 138.4, 140.9, 149.5, 167.9, 203.6. IR (KBr): 3449, 3034, 2927, 1704, 1570,
1538, 1488, 1456, 1429, 1414, 1368, 1341, 1311, 1275, 1185, 1166, 1149, 1099, 1044,
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892, 797, 742 cmꢀ1. HRMS (ESI, m/z): Calcd for C20H13N2OCl2 [M + H]+ 367.0405,
found 367.0391.
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Acknowledgement:
9
We are grateful to the National Natural Science foundation of China (20802061,
21104064), a project funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions, Qing Lan Project (10QLD008, GSFM2011003)
and College Industrialization Project (JHB2012ꢀ31) of Jiangsu Province for financial
support.
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Supporting Information Available. Characterized data including NMR, IR and
HRMS of 4 and 5, and crystallographic information files (CIF) of 4{8,1,1} and
4{19,1,3}, this material is available free of charge via the Internet at http:
//pubs.acs.org.
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