Efficient synthesis of functionalized Benzo[ b ][1,8]naphthyridine derivatives via three-component reaction catalyzed by l -proline

Article abstract of DOI:10.1021/co4001524

A facile and efficient one-pot procedure for the preparation of functionalized benzo[b][1,8]naphthyridine derivatives by three-component reaction of 2-chloroquinoline-3-carbaldehyde, 1,3-dicarbonyl compounds, and enaminones catalyzed by l-proline is described. This new protocol has the advantages of environmental friendliness, good yields, and convenient operation.

Full text of DOI:10.1021/co4001524

Research Article
pubs.acs.org/acscombsci
Efficient Synthesis of Functionalized Benzo[b][1,8]naphthyridine
Derivatives via Three-Component Reaction Catalyzed by L‑Proline
Lei Fu, Wei Lin, Ming-Hua Hu, Xue-Cheng Liu, Zhi-Bin Huang,* and Da-Qing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
S
* Supporting Information
ABSTRACT: A facile and efficient one-pot procedure for the
preparation of functionalized benzo[b][1,8]naphthyridine
derivatives by three-component reaction of 2-chloroquinoline-
3-carbaldehyde, 1,3-dicarbonyl compounds, and enaminones
catalyzed by L-proline is described. This new protocol has the
advantages of environmental friendliness, good yields, and
convenient operation.
KEYWORDS: benzo[b][1,8]naphthyridine, three-component reaction, L-proline
INTRODUCTION
RESULTS AND DISCUSSION
■
■
We initially evaluated the three-component reaction of the
2-chloroquinoline-3-carbaldehyde 1{1}, 4-hydroxycoumarin
2{1}, and enamine 3{1}(Scheme 1). The reaction mixture, which
was composed of a 1:1:1 mixture of 1{1}, 2{1}, and 3{3}, was
tested under a variety of different conditions. The effects of
solvents and catalysts were evaluated for this reaction, and the
results are summarized in Table 1. It was found that when the
reaction was carried out in water without any catalyst the yield of
product was low (Table 1, entry 1). Ethanol as solvent provided
higher yields than those using other organic solvents (CH3CN,
THF, DMF, CHCl3, and toluene) (Table 1, entry 7 vs entries
2−6). To improve the yields, we examined this reaction using
different catalysts. Acid (p-toluenesulfonic acid, p-TSA) and some
bases (Cs2CO3, NaOH, and piperidine) can not catalyze this
reaction (Table 1, entries 8−11). However, L-proline was
identified as the optimal catalyst with 4{1,1,1} in 80% yield
(Table 1, entry 12). So L-proline was chosen as the catalyst for this
reaction. We also evaluated the amount of L-proline required for
this reaction. The results from Table 1 (entries 12−14) show that
10 mol % L-proline at reflux in ethanol is optimal for the reaction.
The optimized reaction conditions were then tested for library
construction with seven 2-chloroquinoline-3-carbaldehydes
1{1−7}, four 1,3-dicarbonyl compounds 2{1−4}, and 11 enamines
3{1-11} (Figure 1). The corresponding functionalized benzo[b]-
[1,8]naphthyridine derivatives 4 were obtained in good yields
at refluxing temperature in ethanol catalyzed by L-proline. The
results are summarized in Table 2. This protocol was efficient
with 1,3-dicarbonyl compounds with either 1,3-diketones or
β-ketoesters (such as 4-hydroxycoumarin, 4-hydroxy-6-methyl-
2H-pyran-2-one, 4-hydroxyquinolin-2(1H)-one). However, when
other 1,3-diketones such as 2-hydroxynaphthalene-1,4-dione,
1,8-Naphthyridine, tetrahydro-1,8-naphthyridine, and its anne-
lated derivatives are present in many natural and synthetic
compounds. 1,8-Naphthyridine derivatives show a broad range
of interesting physiological activities, such as anti-inflammatory,1
analgesic,2 antiaggressive,3 anticancer,4 antibacterial,5 antitumor,6
antihypertensive,7 and antiallergitic.8 Although many synthetic
methods for the preparation of 1,8-naphthyridines have been
reported, examination of literature reveals considerable scope for
refinement of the existing procedures.9 Thus, because of their great
biological importance and employment of these compounds as
starting material for the synthesis of various linearly tri- and
tetracyclic heterocycles of biological interest, the development of
effective ways to synthesize these compounds utilizing inexpensive
reagents continues to be an active area of research for synthetic
organic chemists.10
Multicomponent reactions (MCRs) are chemical trans-
formations in which three or more different starting materials
combine together via a one-pot procedure to give a final complex
product. Obviation of the need for isolation and purification of
the intermediates results in maximization of yields and reduction of
waste, and thus renders the protocols ecofriendly.11 These features
make multicomponent reactions well suited for the construction of
complex molecules from readily available starting materials.12
Small organic molecules like L-proline, and their derivatives are
readily available commercial catalysts and have been used in
various transformations with excellent yields.13 L-Proline has
been found to be very effective in enamine-based direct catalytic
asymmetric Aldol,14 Mannich,15 Michael,16 Diels−Alder,17
α-amination reaction,18 Knoevenagel-type reactions,19 unsym-
metric Biginelli reaction,20 and some domino reactions.21
Recently, we have reported the synthesis of a series of
heterocycles using MCRs or domino reactions catalyzed by
L-proline.22 In the current paper, we report a novel three-component
domino reaction for the synthesis of functionalized benzo[b][1,8]-
naphthyridine derivatives using L-proline as the catalyst.
Received: December 2, 2013
Revised: March 19, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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Research Article
Scheme 1. Model Reaction
explained by the reaction sequence in Scheme 3. We suggest that
L-proline catalyze the formation of iminum 5 in a reversible
reaction with the 2-chloroquinoline-3-carbaldehyde 1. The higher
reactivity of the iminum ion compared with the carbonyl species
could faciliate Knoevenagel condensation with 4-hydroxycoumar-
in 2, via intermediate 6, and after the elimination of L-proline, 7
might be produced as an intermediate. The addition of 7 to
enaminones 3 then could funish the intermediate product 8, which
upon intermolecular cyclization would give rise to products 4.
Table 1. Optimizing the Reaction Conditions for the
Synthesis of 4{1,1,1}
a
temperature
time
(h)
yield
entry
solvent
H2O
catalyst (mol %)
no
(°C)
(%)
1
reflux
reflux
reflux
120
8
8
8
8
8
8
8
8
8
8
8
8
8
8
30
52
53
22
26
46
58
52
27
28
28
80
73
79
2
CH3CN no
3
THF
no
no
no
4
DMF
CHCl3
5
reflux
115
6
Toluene no
CONCLUSION
■
7
EtOH
EOH
no
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
In conclusion, we have developed a simple and efficient method
for the preparation of functionalized benzo[b][1,8]naphthyridine
derivatives by three-component reaction of 2-chloroquinoline-
3-carbaldehyde, 1,3-dicarbonyl compounds and enaminones
catalyzed by L-proline. This method has the advantages of good
yields and convenient procedure.
8
p-TSA (10%)
Cs2CO3 (10%)
NaOH (10%)
piperidine (10%)
L-proline (10%)
L-proline (5%)
L-proline (15%)
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
10
11
12
13
14
a
EXPERIMENTAL PROCEDURES
Yield was determined by HPLC-MS.
■
Melting points are uncorrected. IR spectra were recorded on
Varian F-1000 spectrometer in KBr with absorptions in cm−1. 1H
NMR and 13C NMR were determined on Varian Invoa-400 MHz
or Invoa-300 MHz spectrometer in DMSO-d6 solution. J values
are in Hz. Chemical shifts are expressed in ppm downfield
from internal standard TMS. HRMS analyses were carried out using
Bruker micrOTOF-Q or Accurate-Mass TOF LC/MS instrument.
General Procedure for the Synthesis of 4. A dry 50 mL
flask was charged with 2-chloroquinoline-3-carbaldehyde 1 (1 nmol),
1,3-dicarbonyl compounds 2 (1 mmol), enaminones 3 (1 mmol),
L-proline (0.1 mmol, 10 mol %), and ethanol (5 mL). The
mixture was stirred at refluxing temperature for 8 h. After
completion of the reaction (confirmed by TLC), the reaction
mixture was cooled to room temperature. The crystalline solids
were collected and purified by recrystallization from DMF and
water to give the pure products 4.
2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-5-(4-methoxy-
phenyl)-3,3-dimethyl-3,4,5,12-tetrahydrodibenzo[b,g][1,8]-
naphthyridin-1(2H)-one 4{1,1,1}: Red solid; m.p. 228−230 °C;
IR (KBr, ν, cm−1) 3461, 2935, 1749, 1719, 1644, 1552, 1379,
1335, 1263, 1164, 1039, 808, 787, 744; 1H NMR (DMSO-d6, 400
MHz) δ (ppm) 12.25 (s, 1H, OH), 7.97 (d, J = 8.0 Hz, 1H, ArH),
7.94 (s, 1H, ArH), 7.68 (d, J = 8.0 Hz, 1H, ArH), 7.53 (t, J = 8.0
Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 7.34−7.29 (m, 4H,
ArH), 7.26 (d, J = 8.0 Hz, 1H, ArH), 7.22 (d, J = 8.8 Hz,
1H, ArH), 7.11−7.07 (m, 2H, ArH), 5.77 (s, 1H, CH), 3.82
(s, 3H, OCH3), 2.24 (d, J = 17.2 Hz, 2H, CH2), 2.05 (d, J = 16.4
Hz, 1H, CH), 1.94 (d, J = 16.8 Hz, 1H, CH), 0.87 (s, 3H, CH3),
0.76 (s, 3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ (ppm)
159.7, 159.3, 152.8, 151.8, 144.2, 134.5, 133.0, 132.6, 132.0,
127.8, 126.6, 124.7, 117.2, 116.7, 107.0 114.95, 107.00, 56.0,
5,5-dimethylcyclohexane-1,3-dione, cyclohexane-1,3-dione, furan-
2,4(3H,5H)-dione, cyclopentane-1,3-dione and 1H-indene-
1,3(2H)-dione were used the products were obtained in low yields
(4{2,4,7} and 4{5,4,5}) or complex mixture were obtained. It was
also found that phenyl groups bearing either electron-withdrawing
or electron-donating groups on the enaminone ring, were tolerated
under the reaction conditions, leading to the final products in
satisfactory yields (up to 87%). Because the enaminones were
prepared previously from the reaction of dimedone with arylamine,
we thought enaminones might no need prior preparation, but could
be formed in the reaction system. So the four-component reaction
of 6-tert-butyl-2-chloroquinoline-3-carbaldehyde 1{7}, 4-hydroxy-
coumarin 2{1}, dimedone, and aniline was carried out under the
optimal conditions. However, the product 4{7,1,5} was obtained
only in low yield (42% isolated yield) (Scheme 2).
The structures of all products 4 were characterized using IR,
1H NMR and 13C NMR spectroscopies, and HRMS analysis.
Compound 4{1,1,1} exhibited characteristic IR stretching
frequencies in the 3461, 1749, 1719, and 1644 cm−1 regions
for OH, CO(ester), CO(ketone), and CC, respectively.
1
In the H NMR spectrum of compound 4{1,1,1} the hydroxy
group proton show a singlet at δ 12.25 ppm. The methyl group
protons show two singlets at δ 0.87 and 0.76 ppm because of the
two methyl groups. A singlet appearing at δ 5.77 ppm was
assigned to the C-12 proton of the pyridine ring. In addition,
HRMS analyses were consistent with the structures. The
structure of compound 4{1,1,1} was further confirmed by
X-ray diffraction analysis23 (Figure 2).
Although the detailed mechanism of this reaction remains to
be fully clarified, the formation of compound 4 could be
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Figure 1. Diversity of reagents.
Scheme 2. Synthesis of Compound 4{7,1,5} via Four-Component Reaction
49.7, 42.7, 32.7, 31.4, 29.7, 27.0, 21.6; HRMS calcd for
C34H28N2O5 [M]+ 544.1998, found 544.2012.
2.31 (s, 3H, CH3), 2.18−2.11 (m, 2H, CH2), 2.04 (s, 3H, CH3),
1.96 (d, J = 16.0 Hz, 1H, CH), 1.88 (d, J = 17.6 Hz, 1H, CH), 0.86
(s, 3H, CH3), 0.80 (s, 3H, CH3); 13C NMR (DMSO-d6, 75
MHz) δ (ppm) 194.6, 164.4, 160.8, 158.9, 155.4, 151.3, 143.9,
135.2, 133.9, 132.9, 132.4, 131.5, 130.7, 127.4, 126.3, 123.5,
115.0, 114.6, 107.2, 100.6, 55.7, 50.0, 42.2, 32.3, 29.8, 21.3, 19.6;
HRMS calcd for C32H30N2O5 [M]+ 522.2155, found 522.2170.
12-(4-Hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3,3-dimethyl-
5-(4-methylphenyl)-3,4,5,12-tetrahydrodibenzo[b,g][1,8]-
naphthyridin-1(2H)-one 4{1,3,7}: Red solid; m.p. 254−256 °C;
12-(4-Hydroxy-5-methyl-2-oxo-2H-pyran-3-yl)-5-(4-methoxy-
phenyl)-3,3,9-trimethyl-3,4,5,12-tetrahydrodibenzo[b,g][1,8]-
naphthyridin-1(2H)-one 4{2,2,1}: Red solid; m.p. 238−240 °C;
IR (KBr, ν, cm−1) 3462, 2972, 1738, 1720, 1644, 1639, 1562,
1369, 1345, 1226, 1165, 962, 936, 765; 1H NMR (DMSO-d6, 400
MHz) δ (ppm) 11.45 (s, 1H, OH), 7.77 (s, 1H, ArH), 7.47 (s,
1H, ArH), 7.27−7.20 (m, 4H, ArH), 7.06 (d, J = 8.0 Hz, 2H,
ArH), 5.94 (s, 1H, ArH), 5.59 (s, 1H, CH), 3.82 (s, 3H, CH3O),
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Table 2. Synthesis of Functionalized Indole Derivatives 4
entry
products
isolated yield (%)
mp (°C)
1
4{1,1,1}
4{1,1,2}
4{2,1,1}
4{2,1,3}
4{3,1,3}
4{4,1,4}
4{5,1,5}
4{6,1,1}
4{6,1,4}
4{6,1,5}
4{6,1,6}
4{6,1,9}
4{7,1,5}
4{2,2,1}
4{2,2,3}
4{2,2,4}
4{2,2,7}
4{3,2,3}
4{3,2,6}
4{4,2,5}
4{6,2,5}
4{7,2,7}
4{7,2,10}
4{7,2,11}
4{1,3,7}
4{2,3,1}
4{3,3,7}
4{5,3,5}
4{5,3,7}
4{5,3,8}
4{6,3,1}
4{2,4,7}
4{5,4,5}
80
79
83
84
85
83
86
87
82
85
84
76
84
82
76
83
84
84
82
87
85
86
78
75
82
85
84
83
82
76
82
36
35
228−230
233−234
234−236
246−248
256−258
260−262
256−257
244−246
246−248
256−258
244−246
236−237
252−254
238−240
258−259
256−257
232−234
256−257
258−260
254−256
246−248
246−248
256−258
260−262
254−256
238−240
234−236
254−256
254−256
279−280
243−245
258−259
263−265
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Figure 2. X-ray structure of compound 4{1,1,1}.
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Scheme 3. Proposed Mechanism for the Synthesis of 4
IR (KBr, ν, cm−1) 3463, 2812, 1680, 1506, 1458, 1380, 1329,
1255, 1160, 1102, 1034, 904, 859, 753, 671; 1H NMR (DMSO-
d6, 400 MHz) δ (ppm) 11.12 (s, 1H, OH), 7.97 (s, 1H, ArH),
7.88 (s, 1H, ArH), 7.69 (d, J = 8.0 Hz, 1H, ArH), 7.48
(s, 1H, ArH), 7.44 (s, 1H, ArH), 7.40 (d, J = 7.6 Hz, 3H, ArH),
7.36 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.16 (s, 3H, ArH), 5.65 (s,
1H, CH), 2.45 (s, 3H, CH3), 2.42 (s, 1H, CH), 2.29 (d, J = 16.0
Hz, 2H, 2 × CH), 2.11 (d, J = 16.0 Hz, 1H, CH), 1.95 (d, J = 17.2
Hz, 1H, CH), 0.91 (s, 3H, CH3), 0.78 (s, 3H, CH3); 13C NMR
(DMSO-d6, 75 MHz) δ (ppm) 197.0, 162.5, 152.4, 145.2, 138.2,
137.8, 135.3, 131.4, 131.3, 131.1, 130.6, 129.8, 129.4, 127.6,
127.4, 126.5, 124.8, 123.9, 121.6, 116.1, 115.1, 42.4, 36.3, 32.4,
30.3, 29.5, 26.5, 21.3; HRMS calcd for C34H28N3O3 [M − H]+
526.2131, found 526.2135.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The spectroscopic characterization for compounds 4 and crystallo-
graphic information file for compound 4{1,1,1}. This material is
available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zbhuang@suda.edu.cn.
*E-mail: dqshi@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was partially supported by the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (No. 10KJA150049), A Project of the
Natural Science Foundation of Jiangsu Province (No. BK20131160),
A Project Funded by the Priority Academic Project Development of
Jiangsu Higher Education Institutions and the Foundation of Key
Laboratory of Organic Synthesis of Jiangsu Province (No. JSK1210).
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(23) Crystallographic data for the structure of compounds 4{1,1,1}
have been deposited at the Cambridge Crystallographic Data Center,
and the deposit number is CCDC-990533. Copy of available meterial
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. (fax +44 1223 336 033; e-mail deposit@
ccdc.cam.ac.uk). Crystal data of 4{1,1,1}: molecular formula =
C34H28N2O5, formula weight = 544.58, (crystal system) monoclinic,
(space group) P21/c, a = 8.3089(11) Å, b = 16.1429(15) Å, c =
20.651(2) Å, β = 100.411(2)°, V = 2724.3(5) Å3, T = 293(2) K, Z = 4, Dc
= 1.328 Mg m−3, μ(Mo Kα) = 0.725 mm−1, 9166 reflection measured,
4722 independent reflections, R1 = 0.0691, R2 = 0.0782.
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