Combinatorial synthesis of fused tetracyclic heterocycles containing [1,6]naphthyridine derivatives under catalyst free conditions

Article abstract of DOI:10.1021/co400020w

A three-component reaction between an aromatic aldehyde, an amine, and tert-butyl 2,4-dioxopiperidine-1-carboxylate in EtOH at refluxing temperature gave fused tetracyclic heterocycles in high yields. The amines include 1H-indazol-5-amine, 1H-indazol-6-amine, 1H-indol-5-amine, and 1H-benzo[d]imidazol-5-amine, giving 11-aryl-3H-indazolo[5,4-b][1,6] naphthyridine, 11-aryl-1H-indazolo[6,7-b][1,6]naphthyridine, 11-aryl-3H-indolo[5,4-b][1,6]naph-thyridine, and 11-aryl-3H-imidazo[4′, 5′:3,4]benzo[1,2-b][1,6]naphthyridine derivatives, respectively.

Full text of DOI:10.1021/co400020w

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Article
A Combinatorial Synthesis of Fused Tetracyclic Heterocycles Containing
[1,6]Naphthyridine Derivatives under Catalyst Free Conditions
Chao Li, Xing-Ye Mu, Yu-Ling Li, Yun Liu, and Xiang-Shan Wang
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400020w • Publication Date (Web): 12 Apr 2013
Downloaded from http://pubs.acs.org on April 19, 2013
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A Combinatorial Synthesis of Fused Tetracyclic Heterocycles Containing
[1,6]Naphthyridine Derivatives under Catalyst Free Conditions
Chao Li, XingꢀYe Mu, YuꢀLing Li, Yun Liu, XiangꢀShan Wang*
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A threeꢀcomponent reaction between an aromatic aldehyde, an amine, and tertꢀbutyl
2,4ꢀdioxopiperidineꢀ1ꢀcarboxylate in EtOH at refluxing temperature gave fused tetracyclic
heterocycles in high yields. The amines include 1Hꢀindazolꢀ5ꢀamine, 1Hꢀindazolꢀ6ꢀamine,
1Hꢀindolꢀ5ꢀamine and 1Hꢀbenzo[d]imidazolꢀ5ꢀamine, giving 11ꢀarylꢀ3Hꢀindazolo[5,4ꢀb][1,6]
naphthyridine, 11ꢀarylꢀ1Hꢀindazolo[6,7ꢀb][1,6]naphthyridine, 11ꢀarylꢀ3Hꢀindolo[5,4ꢀb][1,6]naphꢀ
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thyridine
and
11ꢀarylꢀ3Hꢀimidazo[4',5':3,4]benzo[1,2ꢀb][1,6]naphthyridine
derivatives,
respectively.
NH Ar
O
N
BOC-t
N
N
H
H2N
N
N
H
H2N
H2N
Ar
O
N
O
O
N
HN
Ar
O
N
HN
BOC-t
N
H
N
BOC-t
H
+
ArCHO
N
O
N
N
O
H
N
H
N
N
H2N
H
N
NH Ar
O
BOC-t
N
N
H
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A Combinatorial Synthesis of Fused Tetracyclic Heterocycles Containing
[1,6]Naphthyridine Derivatives under Catalyst Free Conditions
Chao Li, XingꢀYe Mu, 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 threeꢀcomponent reaction between an aromatic aldehyde, an amine, and tertꢀbutyl
2,4ꢀdioxopiperidineꢀ1ꢀcarboxylate in EtOH at refluxing temperature gave fused tetracyclic
heterocycles in high yields. The amines include 1Hꢀindazolꢀ5ꢀamine, 1Hꢀindazolꢀ6ꢀamine,
1Hꢀindolꢀ5ꢀamine and 1Hꢀbenzo[d]imidazolꢀ5ꢀamine, giving 11ꢀarylꢀ3Hꢀindazolo[5,4ꢀb][1,6]
naphthyridine, 11ꢀarylꢀ1Hꢀindazolo[6,7ꢀb][1,6]naphthyridine, 11ꢀarylꢀ3Hꢀindolo[5,4ꢀb][1,6]naphꢀ
thyridine
and
11ꢀarylꢀ3Hꢀimidazo[4',5':3,4]benzo[1,2ꢀb][1,6]naphthyridine
derivatives,
respectively.
Keywords: [1,6]naphthyridine, 1Hꢀindazolꢀ5ꢀamine, 1Hꢀindazolꢀ6ꢀamine, 1Hꢀindolꢀ5ꢀamine,
1Hꢀbenzo[d]imidazolꢀ5ꢀamine, tertꢀbutyl 2,4ꢀdioxopiperidineꢀ1ꢀcarboxylate
Introduction
Naphthyridines are an important class of heterocycles found in a variety of
biologically active molecules. It is reported that they are used for the prevention and
treatment of angiogenic disorders and cancers.1 They are also used as various kinds of
inhibitors, such as the first clinical stage inhibitor of protein kinase CK2 for the
2
treatment of cancer, novel DNA ligase inhibitors with antiꢀstaphylococcal activity,3
novel selective inhibitors of p38 mitogen activated protein kinase,4 and the potent
inhibitors of the protein kinase C isozymes.5 In addition, there are many other
remarkable applications reported in the literature.6 Therefore, much attention has been
devoted to the synthesis of these bioꢀactive compounds.7
Indolonaphthyridine, indazolonaphthyridine and imidazobenzonaphthyridine,
which contain both indole (indazole, imidazole) and naphthyridine rings, are fused
tetracyclic heterocycles. These heterocyclic motifs are found in numerous alkaloid
natural products, such as indolo[1,7]naphthyridine,8 which is also named
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Incargranine B (Figure 1, left). It was isolated from the whole plant of Incarvillea
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mairei var. grandiflora. Another alkaloid of Canthinꢀ6ꢀone (Figure 1, right)
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containing indolonaphthyridine nucleus was obtained and identified from the
branches of Picrolemma granatensis. Some of them have been used as a selective
5ꢀHT2C/2B receptor antagonist,10 a 5ꢀHT2C/2B receptor antagonist with low 5ꢀHT2A
receptor affinity,11 and the cardiovascular agents.12 They have also been used as a
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inhibite of brain ischemia in rats for treating the brain disorder.13
H
H
RO
N
H
N
N
N
R
O
R
Incargranine B
Canthin-6-one
Figure 1. The interesting structures of natural products containing indolonaphthyridine
To the best of our knowledge, only a few references exist concerning their
synthesis.14 Although these reported reactions have developed some useful synthetic
procedures, still several limitations remained. For example, most of the procedures
involve several steps, or low yields, or metal catalysts, or organic solvents. Thus, a
simple, efficient, and green method to synthesize these fused tetracyclic heterocycles
would be attractive.
Distinguished from classical sequential twoꢀcomponent synthetic procedures,
multiꢀcomponent reactions (MCRs) use three or more chemical starting materials for
product formation. They have attracted considerable attention in organic synthesis and
medicinal chemistry owing to their convergence and productivity.15 As a continuation
of our research devoted to the preparation of heterocycles by threeꢀcomponent
reactions,16 herein, we would like to report a convenient and efficient
threeꢀcomponent synthesis of fused tetracyclic heterocycles. They include
3Hꢀindazolo[5,4ꢀb][1,6]naphthyridine, 1Hꢀindazolo[6,7ꢀb][1,6]naphthyridine, 3Hꢀ
indolo[5,4ꢀb][1,6]naphthyridine
and
3Hꢀimidazo[4',5':3,4]benzo[1,2ꢀb][1,6]
naphthyridine derivatives, respectively.
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Results and Discussions
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Treatment of 4ꢀchlorobenzaldehyde 1{1}, tertꢀbutyl 2,4ꢀdioxopiperidineꢀ
1ꢀcarboxylate 2{1} 17 and 1Hꢀindazolꢀ5ꢀamine 3{1} in refluxing EtOH under catalyst
free conditions, gave tertꢀbutyl 7,8ꢀdihydroꢀ10ꢀoxoꢀ11ꢀarylꢀ3Hꢀindazolo[5,4ꢀb][1,6]
naphthyridineꢀ9(6H,10H,11H)ꢀcarboxylate 4{1,1,1} in high yield and regioselectivity,
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rather
than
tertꢀbutyl
6,7ꢀdihydroꢀ9ꢀoxoꢀ10ꢀarylꢀ1Hꢀindazolo[5,6ꢀb]
[1,6]naphthyridineꢀ8(5H,9H,10H)ꢀcarboxylate 4' (Scheme 1).
Cl
O
H
BOC-t
N
N
N
CHO
N
H
O
O
4'
H2N
Cl
EtOH
+
+
N
O
N
Cat. Free
N
Cl
H
O
N
O
1{1}
2{1}
3{1}
HN
BOC-t
N
N
H
4{1,1,1}
Scheme 1. Optimization for the synthesis of 4{1,1,1}
Subsequently, the reaction of 4ꢀchlorobenzaldehyde 1{1}, 2{1} and 3{1} was used as
a representative to optimize the experimental conditions. The reaction was first
carried out in EtOH at room temperature for 10 h and only trace amount of product
4{1,1,1} was observed by TLC (Table 1, entry 1). The reaction temperature is key to
product yields. At reflux, EtOH gives the best results. Furthermore, it should be noted
that the products dissolved completely in refluxing EtOH, and crystallized in cold
EtOH, therefore, the products of 4{1,1,1} were obtained directly by filtration without
further purification. In addition, the effects of different solvents, such as CH3CN,
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benzene, DMF, and THF (Table 1, entries 5−8) were also compared, and EtOH gave
the highest yield.
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Table 1. Synthetic results of 4{1,1,1} under different reaction conditionsa
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Entry
Time(h)
Solvent
Yields (%)b
temperature (°C)
1
2
3
4
5
6
7
8
r.t.
10
16
10
8
EtOH
Trace
68
50
EtOH
Reflux
80
EtOH
Toluene
CH3CN
Benzene
DMF
93
87
Reflux
Reflux
80
14
16
10
14
82
89
78
Reflux
THF
85
a
Reagents and conditions: 4ꢀchlorobenzaldehyde 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.
Based on the optimized reaction conditions, we next explored variations in the
aldehyde 1 (Scheme 1), the diversity of aldehyde 1{1ꢀ20} was shown in Figure 2.
Table 2 demonstrates that the reaction also tolerates significant functionalization of
the aromatic aldehydes; both electronꢀdonating (such as alkoxyl group) and
electronꢀwithdrawing (such as halide) groups can be accommodated, and substituents
ortho, meta, or para to the aromatic group can all be generated. All aldehydes reacted
well to provide a library of naphthyridine derivatives 4 (Table 2). Subsuquently, we
investigated the applicability of amines, and found that 1Hꢀindazolꢀ5ꢀamine 3{1},
1Hꢀindazolꢀ6ꢀamine 3{2}, 1Hꢀindolꢀ5ꢀamine 3{3} and 1Hꢀbenzo[d]imidazolꢀ5ꢀ
amine 3{4} (Figure 3) all gave satisfactory results (Table 2). It should be noted that
4{10,1,4} was tertꢀbutyl 11ꢀarylꢀ10ꢀoxoꢀ7,8,10,11ꢀtetrahydroꢀ1Hꢀimidazo[4',5':3,4]
benzo[1,2ꢀb][1,6]naphthyridineꢀ9(6H)ꢀcarboxylate rather than 3Hꢀimidazo[4',5':3,4]
benzo[1,2ꢀb][1,6]naphthyridine (Scheme 3), when 1Hꢀbenzo[d]imidazolꢀ5ꢀamine 3{4}
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was used as a reactant. The crystal structure of 4{10,1,4} is shown in Figure 4. In
order to prove this was not a special example; another single crystal of 4{12,1,4} was
grown and determined. It gave the same result as shown in Figure 5. All the products
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1
of 4 were characterized by H NMR, IR and HRMS, and the data were in good
agreement with the preconceived structures.
CHO
CHO
CHO
CHO
CHO
Cl
Br
Br
Cl
OMe
3
CHO
5
1
4
2
CHO
CHO
CHO
CHO
Cl
Br
Cl
MeO
OMe
OMe
Cl
7
8
6
9
10
CHO
CHO
CHO
CHO
CHO
Cl
Cl
O
O
F
NO2
11
15
S
12
13
14
CHO
CHO
CHO
CHO
Cl
F
OMe
CHO
Cl
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20
16
17
18
Figure 2. Diversity of aldehydes 1{1ꢀ20}
H2N
H2N
H2N
N
N
N
N
N
N
H2N
N
H
H
H
H
4
3
2
1
Figure 3. Diversity of amines 3{1ꢀ4}
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Y
Z
Ar
O
X
O
O
H2N
BOC-t
Z
X
EtOH
N
N
O
+
Y
+
ArCHO
Cat. Free
N
H
O
1
2
4
3
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Scheme 2. Regioselective synthesis of naphthyridines 4
Table 2. The reaction time and yields of the products 4a
Entry
Ar
Product 4
Time /h
10
Yields /%b
1
2
3
4
5
6
7
8
4ꢀClC6H4
4ꢀBrC6H4
4ꢀMeOC6H4
3ꢀClC6H4
3ꢀBrC6H4
2ꢀClC6H4
2ꢀBrC6H4
3,4ꢀCl2C6H3
3,5ꢀ(MeO)2C6H3
3ꢀMeOC6H4
C6H5
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}
93
90
96
92
87
92
90
14
14
13
10
10
12
8
90
87
95
90
95
90
90
82
86
92
90
93
89
85
86
92
90
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90
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92
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82
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4{10,1,1} 10
4{11,1,1} 12
4{12,1,1} 10
Piperonyl
4ꢀClC6H4
4ꢀBrC6H4
3ꢀClC6H4
3ꢀBrC6H4
2ꢀClC6H4
2ꢀBrC6H4
3,4ꢀCl2C6H3
Piperonyl
4ꢀFC6H4
4{1,1,2}
4{2,1,2}
4{4,1,2}
4{5,1,2}
4{6,1,2}
4{7,1,2}
4{8,1,2}
4{12,1,2} 16
4{13,1,2} 12
4{14,1,2} 10
4{15,1,2} 10
4{20,1,2} 10
12
12
15
16
10
12
14
4ꢀNO2C6H4
2,3ꢀCl2C6H3
2ꢀThienyl
4ꢀClC6H4
4ꢀBrC6H4
4{1,1,3}
4{2,1,3}
4{3,1,3}
4{4,1,3}
4{8,1,3}
4{9,1,3}
9
12
10
10
10
12
4ꢀCH3OC6H4
3ꢀClC6H4
3,4ꢀCl2C6H3
3,5ꢀ(MeO)2C6H3
3ꢀCH3OC6H4
4ꢀFC6H4
4{10,1,3} 12
4{13,1,3} 10
2ꢀFC6H4
4{16,1,3}
6
3,4ꢀMe2C6H3
2,4ꢀCl2C6H3
2ꢀThienyl
4ꢀClC6H4
4ꢀBrC6H4
4ꢀCH3OC6H4
3ꢀClC6H4
2ꢀClC6H4
3,4ꢀCl2C6H3
3,5ꢀ(MeO)2C6H3
3ꢀCH3OC6H4
Piperonyl
4{17,1,3} 12
4{18,1,3}
4{20,1,3}
4{1,1,4}
4{2,1,4}
4{3,1,4}
4{4,1,4}
4{6,1,4}
4{8,1,4}
4{9,1,4}
8
9
12
10
13
13
9
10
14
4{10,1,4} 12
4{12,1,4} 15
2,4ꢀCl2C6H3
2ꢀCH3OC6H4
4{18,1,4}
4{19,1,4} 12
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a Reaction condition: 1 (1.0 mmol), 2 (0.213 g, 1.0 mmol), 3 (1.0 mmol), EtOH (10.0 mL), 80 °C.
b Isolated yields.
6
OCH3
7
8
O
N
HN
9
BOC-t
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11
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O
CHO
N
BOC-t H2N
H
N
EtOH
N
+
+
OCH3
O
Cat. Free
N
H
O
OCH3
NH
N
BOC-t
2{1}
3{4}
1{10}
N
H
4{10,1,4}
Scheme 3. Regioselective synthesis of product 4{10,1,4}
Figure 4. Crystal structure of 4{10,1,4} with DMF solvate
Xꢀray diffraction analysis indicates that the 1,4ꢀdihydropyridine rings in 4{10,1,4}
and 4{12,1,4} are adopt a halfꢀchair conformation. The atoms C1, C7, C9, C13 and
N4 are coplanar, with C8 deviating from the defined planes by 0.297 (3) for 4{10,1,4}
and 0.285 (4) Å for 4{12,1,4}, respectively. In 4{10,1,4}, the adjacent pyridine ring
also adopts a halfꢀchair conformation, the atom C11 deviates from the defined plane
by 0.657 (3) Å. However, it adopts a skew boat conformation in 4{12,1,4}, with C11
and N3 deviating from the defined plane by 0.749 (6) and 0.197 (5) Å, respectively.
The center 1,4ꢀdihydropyridine ring is nearly parallel to the benzimidazole and
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pyridine rings, forming the dihedral angles of 6.2 (1) and 13.8 (2)° (9.4 (1) and 9.0
(1)° for 4{10,1,4}), respectively. Meanwhile, it is nearly perpendicular to the benzene
ring, forming a dihedral angle of 88.3 (1)° (87.5 (1)° for 4{10,1,4}).
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Figure 5. Crystal structure of 4{12,1,4} with DMF solvate
According to the structures of 4 and the references,18 we think the subsequent
Knoevenagel condensation, Michael addition, intraꢀmolecular nucleophilic addition
and dehydration may take place in the formation of the observed products. The key
step with high regioselectivity is the Michael addition reaction between
1Hꢀindazolꢀ6ꢀamine and α,βꢀunsaturated ketone. The activity of the 7ꢀposition is
higher than that of the 5ꢀposition in 1Hꢀindazolꢀ6ꢀamine, because it is both the αꢀsite
of an amino group and the benzyl position of a pyrazole ring at the same time. The
possible mechanism is outlined in Scheme 4 (using 1Hꢀindazolꢀ6ꢀamine as an
example).
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H
7
NH2
O
N
N
O
N
Knoevenagel
condensation
5
Ar
Ar
+
ArCHO
Michael addition
O
N
O
BOC-t
BOC-t
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N
O
N
NH
Ar
O
NH
BOC-t
BOC-t
Nucleophilic
addition
Dehydration
4
N
H
NH2
O
OH
Scheme 4. The possible mechanism for the formation of 4
Conclusion
In conclusion, we found a mild, efficient and highly regioselective method for the
synthesis of fused tetracyclic heterocycles containing [1,6]naphthyridine derivatives
via a three component reaction of an aromatic aldehyde, amine and tertꢀbutyl
2,4ꢀdioxopiperidineꢀ1ꢀcarboxylate under catalyst free conditions. The procedure
affords high regioselectivity while featuring mild reaction conditions, high yields and
operational simplicity without catalysts.
4. Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
1
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 synthesis of 4
A dry 25 mL flask was charged with aromatic aldehyde 1 (1.0 mmol), amine (1.0
mmol), tertꢀbutyl 2,4ꢀdioxopiperidineꢀ1ꢀcarboxylate (0.213 g, 1.0 mmol), and EtOH
(10.0 mL). The reaction mixture was stirred at refluxing temperature for 8ꢀ16 h until
all the reactant amine was consumed (monitored by TLC). The products were
obtained by filtration without further purification, after the reaction mixture was
cooled to room temperature.
tertꢀButyl 11ꢀ(4ꢀchlorophenyl)ꢀ10ꢀoxoꢀ7,8,10,11ꢀtetrahydroꢀ3Hꢀindazolo[5,4ꢀb][1,6]
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naphthyridineꢀ9(6H)ꢀcarboxylate 4{1,1,1}: M. p.: 221~223 °C; H NMR (DMSOꢀd6,
400 MHz): δH 1.41 (s, 9H, 3CH3), 2.59~2.64 (m, 1H, CH), 2.75~2.82 (m, 1H, CH),
3.50~3.60 (m, 1H, CH), 3.96~4.02 (m, 1H, CH), 5.52 (s, 1H, CH), 7.07 (d, J = 8.4 Hz,
9
1H, ArH), 7.23 (d, J = 8.4 Hz, 2H, ArH), 7.34~7.37 (m, 3H, ArH), 8.01 (s, 1H, ArH),
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9.67 (s, 1H, NH), 13.01 (s, 1H, NH). C NMR (DMSOꢀd6, 100 MHz):
δC 27.8, 30.7,
35.7, 38.5, 80.8, 98.6, 109.5, 113.7, 116.7, 121.5, 127.9, 128.7, 129.5, 130.3, 146.7,
148.3, 148.4, 152.6, 162.3, 164.2. IR (KBr): 3297, 3079, 2977, 2933, 2885, 1719,
ν
1681, 1605, 1543, 1492, 1401, 1369, 1331, 1253, 1213, 1142, 1092, 1049, 949, 846,
805, 775, 738, 703 cmꢀ1. HRMS (ESI, m/z): Calcd for C24H22N4O3Cl [M ꢀ H]ꢀ
449.1380, found 449.1384.
Acknowledgement:
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.
Supporting Information Available: Characterized data inclauding NMR, IR and
HRMS of 4, copies of CIFs for 4{10,1,4} and 4{12,1,4} are available free of charge
via the internet at http://pubs.acs.org.
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