Silica gel-catalyzed one-pot syntheses in water and fluorescence properties studies of 5-amino-2-aryl-3H-chromeno[4,3,2-de]-[1,6]naphthyridine-4- carbonitriles and 5-amino-2-aryl-3H-quinolino-[4,3,2-de][1,6]naphthyridine-4- carbonitriles

Article abstract of DOI:10.1021/cc9001179

The silica gel-catalyzed synthesis of 5-amino-2-aryl-3H-chromeno[4,3,2-de] [1,6]naphthyridine-4-carbonitriles and 5-amino-2-aryl-3H-quinolino[4,3,2-de][1, 6]naphthyridine-4-carbonitriles were simply achieved upon the one-pot cascade reaction of malononitrile with substituted 2-hydroxyacetophenone (or 2-aminoacetophenone) and aromatic aldehyde in aqueous media. The mechanistic investigation results based on electrospray ionization mass spectrometry (ESI-MS) indicated that malononitrile displayed a dual role during this transformation. Thirteen bonds were cleaved and 12 new bonds were constructed in the formation of 5-amino-2-aryl-3H-chromeno[4,3,2-de][1,6]naphthyridine-4- carbonitriles, while only 2 H₂O molecules were removed. The fluorescence properties screening showed five new compounds have high fluorescence quantum yields.

Full text of DOI:10.1021/cc9001179

J. Comb. Chem. 2010, 12, 31–34
31
Silica Gel-Catalyzed One-Pot Syntheses in Water and Fluorescence
Properties Studies of 5-Amino-2-aryl-3H-chromeno[4,3,2-de]-
[1,6]naphthyridine-4-carbonitriles and 5-Amino-2-aryl-3H-quinolino-
[4,3,2-de][1,6]naphthyridine-4-carbonitriles
Hui Wu,*,† Wei Lin,† Yu Wan,† Hai-qiang Xin,† Da-qing Shi,‡ Yan-hui Shi,†
Rui Yuan,† Rong-cheng Bo,† and Wei Yin†
School of Chemistry and Chemical Engineering, Xuzhou Normal UniVersity, Xuzhou 221116, China, and
College of Chemistry, Chemical Engineering and Materials Science, Soochow UniVersity,
Suzhou 215123, China
ReceiVed August 4, 2009
The silica gel-catalyzed synthesis of 5-amino-2-aryl-3H-chromeno[4,3,2-de][1,6]naphthyridine-4-carbonitriles
and 5-amino-2-aryl-3H-quinolino[4,3,2-de][1,6]naphthyridine-4-carbonitriles were simply achieved upon the
one-pot cascade reaction of malononitrile with substituted 2-hydroxyacetophenone (or 2-aminoacetophenone)
and aromatic aldehyde in aqueous media. The mechanistic investigation results based on electrospray
ionization mass spectrometry (ESI-MS) indicated that malononitrile displayed a dual role during this
transformation. Thirteen bonds were cleaved and 12 new bonds were constructed in the formation of 5-amino-
2-aryl-3H-chromeno[4,3,2-de][1,6]naphthyridine-4-carbonitriles, while only 2 H2O molecules were removed.
The fluorescence properties screening showed five new compounds have high fluorescence quantum yields.
Introduction
unavailable starting materials were necessary, for example,
poly amino and cyano substituted 1H-benzo[f]chromen, 2-(2-
phenyl-4H-chromen-4-ylidene)-malononitrile14 and (E)-3-
(2,3-dihydro-2-phenylchromen-4-ylidene) but-1-ene-1,1,4-
tricarbonitrile.15
As a continuation of our efforts on synthesizing bioactive
heterocyclic compounds with efficient and green ap-
proaches,16 herein, we would like to report an unexpected
and efficient synthesis of 5-amino-2-aryl-3H-chromeno[4,3,2-
de][1,6]naphthyridine-4-carbonitriles and 5-amino-2-aryl-3H-
quinolino[4,3,2-de][1,6]naphthyridine-4-carbonitriles via one-
pot cascade reaction of malononitrile with aromatic aldehyde
and substituted 2-hydroxyacetophenone (or 2-aminoace-
tophenone) in aqueous media catalyzed by silica gel in good
yields.
As an important aspect of combinatorial chemistry,
multicomponent reactions (MCRs) are among the most
proliferative reaction classes.1 Malononitrile (1) is one of
the most versatile reagents to be used in MCRs because
of the high reactivity of both the methylene and the cyano
groups.2 Traditionally, it is a very useful method to extend
carbon chains and to prepare heterocyclic and luminescent
active compounds that have medical and industrial utility.3
Silica gel has been used as catalyst in organic synthesis
because it is easily available, inexpensive, and nontoxic.
Use of such a heterogeneous catalyst benefits several
potential catalyst reuses and waste production minimiza-
tions.4
Naphthyridine derivatives were not only used as lumines-
cence materials in molecular recognition because of their
rigid planar structure,5,6 but also as new drug leaders7,8 and
anticancer active screening agents in new drug discovery.9,10
However, there is no report for the synthesis of chromeno-
[4,3,2-de][1,6]naphthyridine thus far, and only three papers
have ever reported the synthesis of some analogous frame-
works.11–13 Only one ring of the product was constructed in
these processes. Furthermore, these methods usually required
high reaction temperature (180-200 °C), long reaction time,
and toxic solvents, and the yields were low (∼50%). These
shortcomings limited the scope of appropriate substrates.
Moreover, multistep, corrosive catalysts such as KOH and
Results and Discussion
Using the conversion of malononitrile (1), 3,4-dimethoxy-
benzaldehyde (2h) and 2-hydroxyacetophenone (3) as a
model reaction, we tested different reaction conditions to
optimize the conditions first. A summary of the optimization
experiment is provided in Table 1. It was found that this
transformation could not run smoothly except in the presence
of silica gel (Entries 1-5, Table 1), and other acids or bases
such as HCl, NaHSO3, silica sulfonic acid (SSA), or NaOH
could not be employed as promoters in this reaction. The
important role of silica gel in this interesting reaction may
be attributed to its fitting acidity and ability to form H-bonds.
The H-bond formation between silica gel and the OH group
in 2-hydroxyacetophenone made it act as a phase transforma-
tion catalysis and enhance the solubility of reactant in water.
* To whom correspondence should be addressed. E-mail: wuhui72@
yahoo.com.cn. Phone: +86051683403163. Fax: +86051683403164.
† Xuzhou Normal University.
‡ Soochow University.
10.1021/cc9001179  2010 American Chemical Society
Published on Web 12/21/2009

32 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Table 1. Synthesis of 4h under Different Conditionsa
Wu et al.
Table 2. Synthesis of 5-Amino-2-aryl-3H-chromeno[4,3,2-de]-
[1,6]naphthyridine-4-carbonitrilea
entry
solvent
H2O
H2O
H2O
H2O
H2O
THF
DMF
catalyst (g)
time (h) T (°C) yield of 4h (%)b
1
2
3
4
5
6
7
8
9
HCl (0.07)
2
80
80
80
80
80
80
80
80
80
80
80
80
80
60
65
70
75
85
90
80
80
80
80
80
0
0
NaOH (0.08)
NaHSO3 (0.20)
SSA (0.50)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
2
2
0
2
0
2
2
78
0
2
0
[bmim]BF4 silica gel (0.03)
[bpy]BF4
2
2
56
50
0
14
63
76
0
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.03)
silica gel (0.01)
silica gel (0.02)
silica gel (0.04)
silica gel (0.05)
silica gel (0.06)
10 H2O
0.5
1
1.5
2.5
2
11 H2O
12 H2O
13 H2O
14 H2O
15 H2O
16 H2O
17 H2O
18 H2O
19 H2O
20 H2O
21 H2O
22 H2O
23 H2O
24 H2O
2
0
2
2
2
2
2
2
2
2
21
69
78
78
49
63
77
79
79
2
a All reactions were carried out in the scale of 2.0 mmol of
3,4-dimethoxybenzaldehyde 2h, 4.0 mmol of malononitrile 1, and 2.0 mmol
of 2-hydroxyacetophenone 3 in 10 mL of given solvent. b Isolated yield.
Classic organic solvents such as tetrahydrofuran (THF) and
N, N-dimethylformamide (DMF) can not be used as efficient
solvents in this transformation (Entries 6 and 7, Table 1).
Two classic ionic liquids can also promote this process
(Entries 8, 9, Table 1) but with lower efficiency than water.
When 0.03 g of silica gel was used, the reaction proceeded
in good yield (Entries 5, 20-21 Table 1) of 4h. Increasing
the amount of silica gel did not affect the efficiency of this
transformation (Entries 22-24, Table 1). Finally, when the
temperature was increased to 80 °C with H2O as the solvent,
the reaction proceeded smoothly (Entries 14-19, Table 1).
However, prolonging the reaction time did not enhance the
yield of the product (Entries 10-13, Table 1).
a All reactions were carried out in the scale of 0.03 g of silica gel in 10
mL water at 80 °C for 2 h, and starting materials (1:2:3 ) 4.0:2.0:2.0
mmol) were completely consumed. b Isolated yield. c Quantum yields,
were calculated based on 9,10-diphenylanthrance.
To explore the application of this method, the scope of
the substrates was evaluated with a variety of aromatic
aldehydes (Table 2). It appeared that the electronic nature
of the substituted groups in the aromatic ring had slightly
influence on the yield. It is noteworthy that no remarkable
steric hindrance on the reaction was observed, for example,
the desired products were obtained in moderate to good yields
when the ortho substitutes on the benzaldehyde were used
(Entries 5, 7, 12, 15, 19 and 28, Table 2).
To the best of our knowledge, fused poly cycle especially
the fused heterocycle has efficient luminescence. All of our
products exhibit strong fluorescence which can be distin-
guished by our eyes readily in EtOH or under UV light (360
nm) (Supporting Information, Figure 1), so their fluorescence
properties were screened (Table 2). Following three points
are clearly: (i) the emission wavelength of all products
appeared in the range of visible light, showing the potential
applications of these compounds (e.g., as fluorescent probe,
luminescence material or organic light-emitting diodes) in
the future. Because of the lower electron density of the
heteroaromatic ring, the emission wavelength of two products
derived from heteroaromatic aldehydes (entries 27, 28, Table
2) have little blue shift; (ii) the electro and steric effect of
substituted group on aromatic aldehydes have little influence
on the fluorescence properties, which clearly showed that
the fluorescence of products came from their framework
directly; (iii) from the library, four members 4a, 4j, 4x, and
4z with intensive fluorescence were selected, while the
corresponding fluorescent quantum yields17 were calculated
based on 9,10-diphenylanthrance (Table 2). The advantage

Silica Gel-Catalyzed One-Pot Syntheses in Water
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 33
Figure 1. ORTEP diagram of 4h.
Scheme 1. Possible Mechanism for the Formation of the
Product
of this kind of novel framework is that it can be transformed
into more thermostable derivatives through their amino
groups.
The products 4 were fully characterized by IR, 1H NMR,
and HRMS. The data were in agreement with their structures.
To further confirm the structure, the X-ray diffraction analysis
of the product 4h was carried out. As expected, the structure
is 5-amino-2-(3,4-dimethoxy-phenyl)-3H-chromeno[4,3,2-
de][1,6]naphthyridine-4-carbonitrile, and the crystal structure
of 4h is shown in Figure 1.
A reasonable mechanism for the formation of the products
was speculated based on the results of online ESI-MS
monitoring of the product under the optimal reaction condi-
tion. At room temperature, a clear reaction solution was
directly injected to the ESI source. The ESI-MS was operated
in the position of ion mode. Approximately 5 min after
mixing malononitrile (1), 3,4-dimethoxybenzaldehyde (2h),
and 2-hydroxyacetophenone (3), ESI-MS detected a major
ion attributed to the chalcone derived from 2h and 3. Thirty
minutes later, A (Scheme 2) which came from the condensa-
tion of chalcone and malononitrile was detected as the major
ion. Fifty minutes later, the ion of 4f+H was detected as
the base peak. When the reaction time was increased to 2 h,
the abundance of 4f+H increased and some residual ions
were detected because of the occurrence of side-reaction.
So we supposed that the reaction was via a cascade procedure
(Scheme 1): the aldol condensation of aldehyde and 2-hy-
droxyacetophenone give chalcone, then malononitrile attacks
the carbonyl of chalcone to form A. Interestingly, malono-
nitrile does not react with chalcone via Michael addition in
this step as usual. The intramolecular cyclization of A affords
B, and B condensates with another malononitrile give C.
The tandem intramolecular cyclization and aromatization of
C afford the final product.
However, with higher temperature (>80 °C) and longer
reaction times than 2 h, only low to moderate yields were
obtained. It may be due to the activity of 2-aminoacetophe-
none lower than that of 2-hydroxyacetophenone. From the
library, one compound 6a with the most intensive fluores-
cence was discovered (Table 3).
1
Interestingly, in the H NMR of 6, one proton signal
disappeared. The possible reason is the strong shielding effect
of H17 which sits in the center of the quinolino[4,3,2-
de][1,6]naphthyridine core. The surrounding situation of H17
1
made the disappearance of its signal in H NMR spectra
(Figure 2).
Conclusions
In summary, we have discovered a novel and simple silica
gel-catalyzed construction of 5-amino-2-aryl-3H-chromeno
(or quinolino)[4,3,2-de][1,6]naphthyridine-4-carbonitriles from
commercially available starting materials in water. Silica gel
showed its important role in this interesting reaction. The
screening for fluorescence properties identified five new
compounds with high fluorescence quantum yields which
may have a good application as fluorescence material in the
future. Thirteen bonds were cleaved, and twelve new bonds
(two C-N single bonds, two C-N double bonds, three C-C
From the above mechanism, it seems that the ortho
substituted NH2 of the acetyl group can also act as an efficient
nucleophilic agent which attacks the cyano group of mal-
ononitrile. So we were going to research the one-pot reaction
of malononitrile with 2-aminoacetophenone and aromatic
aldehyde catalyzed by silica gel at 95 °C (eq 2, Table 3).
As expected, 5-amino-2-aryl-3H-quinolino[4,3,2-de][1,6]-
naphthyridine-4-carbonitriles were successfully obtained.

34 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Wu et al.
1H NMR, 13C NMR spectra, IR and partial MS spectra of
all compounds, and the X-ray structure determination of
compound 4h. This material is available free of charge via
the Internet at http://pubs.acs.org.
Table 3. Synthesis and Fluorescence of 5-Amino-2-aryl-3H-
quinolino[4,3,2-de][1,6]naphthyridine-4-carbonitrilesa
References and Notes
(1) (a) Weber, L. Curr. Opin. Chem. Biol. 2000, 4, 295–302. (b)
Montgomery, J. Acc. Chem. Res. 2000, 33, 467–473. (c)
Dom¨ ling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
3210. (d) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (e)
Mihovilovic, M. D.; Stanetty, P. Angew. Chem., Int. Ed. 2007,
46, 3612–3615. (f) Mironov, M. A. QSAR Comb. Sci. 2006,
25, 423–431. (g) Diego, J.; Ramo’n, M. Y. Angew.Chem., Int.
Ed. 2005, 44, 1602–1634. (h) Simon, C.; Constantieux, T.;
Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980. (i) Orru,
R. V. A.; de Greef, M. Synthesis 2003, 1471–1499. (j) Kappe,
C. O. QSAR Comb. Sci. 2003, 22, 630–645. (k) Zhu, J. Eur.
J. Org. Chem. 2003, 1133–1144. (l) Hulme, C.; Lee, Y.-S.
Mol. DiVersity 2008, 12, 1–15.
(2) (a) Freeman, F. Chem. ReV. 1969, 69, 591–624. (b) Fatiadi,
A. J. Synthesis 1978, 165–204. (c) Fatiadi, A. J. Synthesis
1978, 241–282.
(3) (a) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno, K. Org.
Lett. 2008, 10, 2741–2743. (b) Alberola, A.; Calvo, L. A.;
Ortega, A. G.; Sanudo-Ruiz, M. C.; Yustos, P.; Granda, S. G.;
Garcia-Rodriguez, E. J. Org. Chem. 1999, 64, 9493–9498.
(c) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8 (5), 899–902.
(4) (a) Banerjee, A. K.; Mimo, M. S. L.; Vegas, W. J. V. Chem.
ReV. 2001, 70, 971–990. (b) Spagnol, G.; Rajca, A.; Rajca,
S. J. Org. Chem. 2007, 72 (5), 1867–1869. (c) Matsushita,
Y.; Sugamoto, K.; Kita, Y.; Matsui, T. Tetrahedron Lett. 1997,
38 (50), 8709–8712. (d) Spagnol, G.; Rajca, A.; Rajca, S. J.
Org. Chem. 2007, 72 (5), 1867–1869.
(5) (a) Peng, T.; Murase, T.; Goto, Y.; Kobori, A.; Nakatani, K.
Bioorg. Med. Chem. Lett. 2005, 15, 259–262. (b) Lu, W. B.;
Zhang, L. H.; Ye, X. S.; Su, J. C.; Yu, Z. X. Tetrahedron
2006, 62, 1806–1816.
entry product
Ar
yield (%)b λem (nm)
Φc
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
C6H5
39
35
37
39
38
40
37
38
34
40
42
41
32
42
38
34
36
27
35
22
33
482
506
482
476
488
478
487
478
491
488
485
490
455
486
491
492
490
490
497
434
397
0.780
0.110
0.523
0.488
0.514
0.612
0.572
0.370
0.131
0.452
0.610
0.106
0.168
0.485
0.167
0.485
0.364
0.351
0.320
0.389
0.289
4-CNC6H4
4-CH3C6H4
4-OHC6H4
2-MeOC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-IC6H4
2,4-Cl2C6H3
pyridine-4-yl
thiophene-2-yl
7
8
9
6g
6h
6i
10
11
12
13
14
15
16
17
18
19
20
21
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
a All reactions were carried out in the scale of 0.03 g of silica gel in 10
mL of water at 95 °C for 6 h, and starting materials (1:2:3 ) 4.0:2.0:2.0
mmol) were completely consumed. b Isolated yield. c Quantum yields,
were calculated based on 9,10-diphenylanthrance.
(6) Van, D.; Joost, T. M. J. Org. Chem. 1996, 61 (3), 1136–1139.
(7) Chan, L.; Jin, H.; Stefanac, T.; Lavallee, J. F.; Falardeau, G.;
Wang, W.; Be`dard, J.; May, S.; Yuen, L. J. Med. Chem. 1999,
42, 3023.
(8) Falardeau, G.; Chan, L.; Stefanac, T.; May, S.; Jin, H.; Lavllee,
J. F. Bioorg. Med. Chem. Lett. 2002, 18, 2769.
Figure 2
double bonds, two C-C single bonds, two N-H single
bonds, and one C-O single bond) were constructed in the
formation of 4, while only two H2O molecules were removed.
Three rings of the fused-ring framework were constructed
in one-pot. In addition, there are several modifiable and
coordinate sites in these two new interesting types of
framework, so the subsequent step of the combinatorial
development process, namely, structural optimization, should
be possible. Future efforts to explore the coordination effect
of products and the synthetic utility of the reaction are
underway.
(9) Bedard, J.; May, S.; L’ Heureux, L.; Stamminger, T.; Copsey,
A.; Drach, J.; Huffman, J.; Chan, L.; Jin, H.; Rando, R. F.
Antimicrob. Agents Chemother. 2000, 44, 929.
(10) Ruchelamn, A. L.; Singh, S. K.; Ray, A.; Wu, X. H.; Yang,
J. M.; Liu, A.; Liu, L. F.; Lavoie, E. J. Bioorg. Med. Chem.
2003, 11, 2061.
(11) Raafat, M. S. S. ArkiVoc 2006, 59–67.
(12) Jan, S. J. Chem. Soc., Perkin Trans I. 1988, 2053–2058.
(13) VanAllan, J. A.; Petropoulos, C. C.; Reynolds, G. A.; Maier,
D. P. J. Heterocycl. Chem. 1970, 7 (6), 1363–1368.
(14) Schiedel, M. S.; Briehn, C. A.; Ba¨uerle, P. Angew. Chem.,
Int. Ed. 2001, 40, 4677–4680.
(15) Chandrasekhar, S.; Vijeender, K.; Sridhar, C. Tetrahedron Lett.
2007, 48, 4935–4937.
Acknowledgment. We thank the “National Natural Sci-
ences Foundation of China” (No. 20772103), the “Natural
Science Foundation in Jiangsu Province” (No. BK2007028)
and “Qin Lan Project in Jiangsu Province” (No. QL200607
and No. 08QLT001) for financial support.
(16) Wu, H.; Zhang, P.; Shen, Y.; Zhang, F. R.; Wan, Y.; Shi,
D. Q. Synlett 2007, 336–338.
(17) Measurements referenced to 9, 10-diphenylanthrance (Φf )
0.66);(a) Principles of Fluorescence Spectroscopy, 2nd ed.;
Lakowicz, J. R., Ed.; Kluwer Academic/Plenum Publishers:
New York, 1999. (b) Demas, J. N.; Grosby, G. A. J. Phys.
Chem. 1971, 75, 991–1024.
Supporting Information Available. Details of experi-
mental procedures and analytical data were given. It includes
CC9001179