An Efficient Strategy for the Synthesis of Naphtho[2,3- b ][1,6]naphthyridines Promoted by Acetic Acid

Article abstract of DOI:10.1055/a-1479-4420

A three-component domino reaction for the synthesis of naphtho[2,3- b ][1,6]naphthyridine derivatives has been established. Such strategy exhibited excellent substrate scope including various enaminones and aldehydes that afforded a series of multifunctionalized naphtho[2,3- b ][1,6]naphthyridine derivatives with 70-86% yields. The advantages of bond-forming efficiency, accessibility of starting materials, and water as sole byproducts provide invaluable access to biological 1,6-naphthyridines.

Full text of DOI:10.1055/a-1479-4420

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–F
letter
A
en
C. Li et al.
Letter
Synlett
An Efficient Strategy for the Synthesis of Naphtho[2,3-
b][1,6]naphthyridines Promoted by Acetic Acid
Chunmei Lia,b
Furen Zhang*a
Zhenlu Shen*b
O
Ar
O
O
O
O
O
R
R
N
N
HOAc
+
NH
+
H
Ar
0
0
0
0
-
0
0
0
2
-
3
6
9
9
-
1
1
9
8
100–120 °C
N
R
OH
O
R
a School of Chemistry and Chemical Engineering, Zhejiang Key
Laboratory of Alternative Technologies for Fine Chemicals Pro-
cess, Shaoxing University, Shaoxing, Zhejiang Province
312000, P. R. of China
24 examples prepared
up to 86% yields
R = Ar, Bn, nBu
frzhang@usx.edu.cn
b College of Chemical Engineering, Zhejiang University of Tech-
nology, Hangzhou 310032, P. R. of China
zhenlushen@zjut.edu.cn
Corresponding Authors
Received: 05.03.2021
Accepted after revision: 10.04.2021
Published online: 10.04.2021
man leukaemia cancer cell line), MCF7 (human breast can-
cer cell line), Hep-G2 (human liver cancer cell line), and
HeLa (human cervical cancer cell line) by SRB method.8
Dibenzo[b,h][1,6]naphthyridines V, as the conjugated -
bridge, are designed and synthesized for dye-sensitized so-
lar cells (DSSCs).9 Thus, the development of simple and effi-
cient protocols toward synthesizing new functionalized
1,6-naphthyridine derivatives, especially for the ben-
zo[1,6]naphthyridines or naphtho[1,6]naphthyridines us-
ing readily available starting materials, is highly desirable.
DOI: 10.1055/a-1479-4420; Art ID: st-2021-k0089-l
Abstract A three-component domino reaction for the synthesis of
naphtho[2,3-b][1,6]naphthyridine derivatives has been established.
Such strategy exhibited excellent substrate scope including various
enaminones and aldehydes that afforded a series of multifunctionalized
naphtho[2,3-b][1,6]naphthyridine derivatives with 70–86% yields. The
advantages of bond-forming efficiency, accessibility of starting materi-
als, and water as sole byproducts provide invaluable access to biological
1,6-naphthyridines.
OMe
Key words aminopyridinone, 2-hydroxynaphthalene-1,4-dione, naph-
tho[2,3-b][1,6]naphthyridines, acetic acid, synthesis
Cl
R1
R2
N
N
R3
Ts
N
H
H
HN
N
O
In recent years, naphthyridine derivatives are widely
studied and have a wide range of applications in various ar-
eas, including pharmaceutical agents of treatment of vari-
ous human diseases and animal husbandry parasite control,
industrial lubricating coolants for metal processing, and li-
gands of analytical chemistry.1 Consequently, naphthyri-
dines, as bipyridine scaffold compounds, have been found
in various natural alkaloids, which have appreciable chemi-
cal and biological importance.2 Among them, 1,6-naph-
thyridines play an important role in organic and biological
chemistry due to their unique therapeutic and pharmaco-
logical properties.3 Furthermore, the introduction of an ar-
omatic ring onto them could greatly improve biological
properties of 1,6-naphthyridine derivatives.4 For example,
the compounds I are efficient 2-adrenoreceptor antagonists
for the treatment of hypertonia, depression, diabetes, and
inhibition of thrombocyte aggregation (Figure 1).5 Ben-
zo[b][1,6]naphthyridine II can be used as a potent phos-
phodiesterase 5 inhibitor for the treatment of Alzheimer’s
disease.6 Compounds III exhibit antibacterial and anti-HSV-
O
NC
N
H
R2
R1
N
O
I
III
II
N
N
CN
CO2H
R1
N
R2
Me
N
R
V
IV
Figure 1 Several representative active molecules with the ben-
zo[l,6]naphthyridine scaffold
In the past several decades, the multicomponent domi-
no reactions (MDRs), which can offer easy access to func-
tionalized heterocyclic structures with chemical and phar-
maceutical interest, have been developed in the organic and
medical chemical laboratory.10 These reactions have at-
tracted special attention because of their simplicity, effi-
ciency, convenience, and atom economy.11 Thus, the devel-
opment of a domino strategy for the synthesis of 1,6-naph-
thyridine derivatives is still an important and promising
1
activities.7 Benzo[h]naphtho[1,2-b][1,6]naphthyridines
IV can be against four cancer cell lines, such as K562 (hu-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Li et al.
Letter
Synlett
subject. In the recent years, our group has established sev-
eral multicomponent domino reactions for the synthesis of
heterocycles.12 More recently, we reported a series of 1,6-
naphthyridine derivatives with potential pharmaceutical
value via a three-component domino reaction using 4-
(arylamino)pyridin-2(1H)-ones as substrates.13 In continua-
tion of our efforts to construct these useful heterocyclic
blocks, we here report another domino strategy for the syn-
thesis of naphtho[2,3-b][1,6]naphthyridine derivatives us-
ing 4-(arylamino)pyridin-2(1H)-ones, aldehydes, and 2-hy-
droxynaphthalene-1,4-dione as starting materials. The
present approach represents a special example for the con-
struction of naphtho[1,6]naphthyridine derivatives with
70–86% yields.
Table 1 Optimization for the Synthesis of Compound 4aa
O
H
O
O
O
O
2a
N
N
O
Conditions
+
N
NH
OH
1a
4a
O
3
Entry
1
Catalyst (mg)
–
Solvent
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
EtOH
H2O
Temp (°C) Time (h)
Yield (%)b
0
100
100
100
100
100
100
100
100
100
100
100
reflux
100
reflux
reflux
100
rt
12
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
12
4
4
4
4
4
2
H2SO4 (10)
HCl (10)
33
12
41
67
45
17
25
42
70
73
51
45
35
43
37
0
In the beginning, the three-component domino reaction
of 6-methyl-1-phenyl-4-(phenylamino)pyridin-2(1H)-one
(1a), 4-methylbenzaldehyde (2a), and 2-hydroxynaphtha-
lene-1,4-dione (3) was employed as a model reaction to op-
timize the experimental conditions. Initially, no desired
product 4a was obtained when the model reaction was car-
ried out without any catalyst, even after longer reaction
times (Table 1, entry 1). Then, the model reaction was re-
peated many times in the presence of different acidic cata-
lysts, such as inorganic acids including sulfuric acid (H2SO4)
and hydrochloric acid (HCl), organic acids including trifluo-
roacetic acid (TFA), p-toluenesulfonic acid (TsOH) and acetic
acid (HOAc), and Lewis acids including Sc(OTf)3 and
Y(OTf)3. The results were summarized in Table 1 (entries 2–
8). It was noted that all the acidic catalysts could promote
the model reaction. For further details, the acetic acid ex-
hibited the best activities and gave the desired product 4a
with 67% yield. We also noted that the yields of product 4a
were increased from 42% to 73% when the catalyst loading
was increased from 5 mol% to 40 mol%. Subsequently, vari-
ous reaction media, including water (H2O), ethanol (EtOH),
tetrahydrofuran (THF), acetonitrile (MeCN), and N,N-di-
methylformamide (DMF), were explored for this transfor-
mation (entries 12–16). We found that the protic solvents,
such as water, ethanol, and glycol showed good adaptability
for the domino reaction. However, none of them proved
better than glycol. Thus, the three-component reaction was
carried out many times in glycol with different tempera-
tures. The yields of product 4a were increased from 0% to
73% as the temperature varied from room temperature to
100 °C (Table 1, entries 5 and 17–20). Further increasing the
temperature to 120 °C failed to improve the yield of the de-
sired product 4a obviously (Table 1, entry 21). To our de-
light, up to 84% yield of product 4a was obtained when the
model reaction was carried out using acetic acid as reaction
media and catalyst under the above optimized conditions
(Table 1, entry 22). Therefore, the optimal experimental
conditions for the domino reaction were heating the reac-
tion mixture at 100 °C for 4 h using acetic acid as reaction
media and catalyst.
3
4
TFA (10)
5
HOAc (10)
TsOH (10)
Sc(OTf)3 (10)
Y(OTf)3 (10)
HOAc (5)
HOAc (20)
HOAc (40)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
–
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
THF
MeCN
DMF
glycol
glycol
glycol
glycol
glycol
HOAc
40
21
39
73
74
84
60
100
120
100
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3 (0.5 mmol), and
solvent (3.0 mL) at given temperature and reaction time.
b Isolated yields.
With the optimized reaction conditions in hand, we
then explored the generality of the domino reaction for the
synthesis of different naphtho[2,3-b][1,6]naphthyridine de-
rivatives by alternating the substituted aminopyridinones 1
and aldehydes 2 (Table 2).14 At first, different aromatic alde-
hydes were investigated using 6-methyl-1-phenyl-4-(phe-
nylamino)pyridin-2(1H)-one (1a) and 2-hydroxynaphtha-
lene-1,4-dione (3) as model substrates. To our delight, a
wide range of substituted groups bearing aromatic alde-
hydes, including methyl, methoxy, fluoro, chloro, bromo, ni-
tro, and cyano groups all tolerated the reaction and gave the
products with good to excellent yields (Table 2, 4a–n). At
the same time, we also noted steric effects, that is, the
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

C
C. Li et al.
Letter
Synlett
benzaldehydes with the substituent at para position exhib-
ited higher reaction activities than those bearing groups at
meta/ortho positions and afforded the corresponding prod-
ucts with higher yields. Among them, the 2,6-dichlorobenz-
aldehyde (2n) with high steric hindrance only gave the
product 4n with 70% yield. Thus, the steric effect of aromat-
ic aldehydes influenced the transformation of the reaction
obviously. In addition, the aliphatic aldehydes including n-
heptanal and 3-methyl butanal have been used to replace
benzaldehyde for the model reaction, respectively. Unlucki-
ly, no corresponding product was obtained, which may be
attributed to the low stability of the condensed intermedi-
ate between aliphatic aldehyde and 2-hydroxynaphtha-
lene-1,4-dione (3).
To further expand the scope of the reaction, various 4-
(arylamino)pyridin-2(1H)-ones (1) were prepared and sub-
jected to the domino cyclization reaction (Table 2, 4o–v). A
wide range of functional groups on the phenyl substituent
of the substrates 1, such as methyl, methoxyl, fluoro, chloro,
and trifluoromethyl, were investigated. Fortunately, all the
4-(arylamino)pyridin-2(1H)-one substrates were well toler-
ated in the domino reaction with different aromatic alde-
hydes (2) and 2-hydroxynaphthalene-1,4-dione (3) and
gave the corresponding products 4 with 75–84% yields. The
electron effect of the aryl ring of 4-(arylamino)pyridin-
2(1H)-ones is not obvious in the reaction. It was worth
mentioning that the substrate 4-(arylamino)pyridin-2(1H)-
one bearing aliphatic substituents including benzyl and n-
butyl also exhibited good reaction activities and gave the
corresponding products with 75% and 78% yields, respec-
tively. Additionally, when the aromatic aldehydes, such as
2-nitrobenzaldehyde (2o) and fused aldehyde 1-naphthal-
dehyde (2p) were used, the ring-opening compounds (4′a
and 4′b) were obtained with 68% and 71% yields at the same
conditions, respectively (Scheme 1).
To our delight, the desired products 4w and 4x were giv-
en with 47–53% yields when the reaction temperature was
increased to 120 °C for 8 h, respectively. We attributed it to
the steric hindrance of substrate aldehydes which influ-
enced the formation of a new pyridine ring.
To further expand the scope of substrates, we were ea-
ger to see the result of the reactions when 3-(arylamino)cy-
clohex-2-en-1-ones 5 were employed as three-component
partners with benzaldehydes 2 and 2-hydroxynaphthalene-
1,4-dione (3) (Scheme 2).15 Unfortunately, the desired prod-
ucts were not obtained. Instead, the products 616 were
formed with good to excellent yields. The probable reason
for these results was the poor stability of enaminone 3 in
acetic acid at 100 °C, which hampered the formation of the
desired product. The electronic effect of the aldehydes had
little influence on the efficiency of the reaction. Other
enaminones, that is, 5,5-dimethyl-3-(p-tolylamino)cyclo-
hex-2-en-1-one and 3-[(4-chlorophenyl)amino]-5,5-di-
methylcyclohex-2-en-1-one, were selected for our study.
Again, we obtained the product 6a with similar yield for the
same reason.
O
Ar
H
O
O
Ar
O
O
O
2
O
+
HOAc
100°C
R
R
R
R
NH
OH
6
O
5
3
OMe
O
O
O
O
O
O
O
O
O
O
O
O
6a, 76%
6b, 83%
6c, 80%
Cl
Br
O
O
O
O
O
O
O
Ar
O
O
O
O
N
O
O
O
O
O
Ar
H
O
2
N
NH
HO
6d, 85%
6e, 84%
6f, 75%
HOAc, 100 °C, 4 h
NH
Ar = 2-O2NC6H5, 4'a, 68%
1-naphthyl, 4'b, 71%
1a
O
O
O
+
Ar
O
O
O
O
N
O
Ar
H
N
OH
2
6g, 81%
O
O
3
HOAc, 120 °C, 8 h
Scheme 2 Synthesis of 2-aryl-2,3,4,12-tetrahydro-1H-benzo[b]xan-
thene-1,6,11-triones. Reagents and conditions: 5 (0.5 mmol), 2 (0.5
mmol), 3 (0.5 mmol), and acetic acid (3.0 mL) at 100 °C for about 4 h.
Isolated yields are given.
Ar = 2-O2NC6H5, 4w, 53%
1-naphthyl, 4x, 47%
Scheme 1 Substrate scope for synthesis of 4
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

D
C. Li et al.
Letter
Synlett
Table 2 Synthesis of Naphtho[2,3-b][1,6]naphthyridine-2,5-dione Derivatives 4a,b
O
O
O
Ar
O
O
O
R
R
N
HOAc
N
+
+
Ar
H
100 °C
OH
NH
R
N
R
2
1
O
3
4
F
Br
N
OMe
Cl
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
O
4a, 84%
4b, 78%
4c, 82%
4d, 86%
4e, 85%
F
Br
O
CN
O
NO2
O
NO2
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
O
O
O
O
N
4f, 86%
4g, 78%
4h, 83%
4i, 81%
4j, 80%
Cl
N
Br
Cl
Cl
O
Cl
O
O
O
O
O
O
O
O
Cl
O
O
N
N
N
N
N
N
N
N
N
O
O
O
O
4k, 74%
4l, 75%
4m, 73%
4n, 70%
4o, 78%
Cl
N
MeO
F3C
O
O
O
O
O
O
O
F
O
O
O
O
O
O
Cl
N
N
N
N
N
N
N
N
O
N
F
O
Cl
OMe
CF3
4p, 84%
4q, 80%
4r, 81%
4s, 76%
4t, 79%
O
O
O
O
O
O
N
N
N
N
4u, 75%
4v, 77%
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), and acetic acid (3.0 mL) at 100 °C for about 4 h.
b Isolated yields.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

E
C. Li et al.
Letter
Synlett
Similar to our previous domino reaction processes, the
present reactions showed the following attractive charac-
teristics: (1) easily available starting materials, (2) simple
and efficient one-pot procedure, (3) water as the sole by-
product. In addition, the structures of synthetic new com-
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
1
pounds were all confirmed by their H NMR, 13C NMR, and
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (21776260) and the Key Research and De-
velopment Project of Zhejiang Province (2021C01079) for this
HRMS spectra.
On the basis of the experimental results, a reasonable
mechanism for this three-component domino reaction is
represented in Scheme 3. Firstly, the intermediate A was
generated from the Knoevenagel reaction between 2-hy-
droxynaphthalene-1,4-dione 3 and aldehyde 2a and further
underwent the Michael addition with aminopyridinones 1a
to afford intermediate B. After an intramolecular cyclization
of intermediate B in the presence of acetic acid, the inter-
mediate C was formed, which was further converted into
the expected product 4a after elimination of H2O.
research work.
N
ati
o
na
l
N
a
t
ura
l
Sc
i
e
n
c
e
F
o
u
n
dati
o
n
o
f
C
h
i
na(2
1
7
7
6
2
6
0)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1479-4420.
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
nS
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p
p
orti
n
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n
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a
ti
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References and Notes
(1) (a) Clark, R. D.; Repke, D. P.; Klipatrick, A. T.; MacKinnon, A. C.;
Clauge, R. U.; Spedding, M. J. Med. Chem. 1989, 32, 2034.
(b) Clark, R. D.; Repke, D. P.; Berger, J.; Nelson, J. T.; Kilpatrick, A.
T.; Brown, C. M.; MacKinnon, A. C.; Clauge, R. U.; Spedding, M.
J. Med. Chem. 1991, 34, 705.
(2) (a) Gross, H.; Goeger, D. E.; Hills, P.; Mooberry, S. L.; Ballantine,
D. L.; Murray, T. F.; Valeriote, F. A.; Gerwick, W. H. J. Nat. Prod.
2006, 69, 640. (b) Zhang, A.; Ding, C.; Cheng, C.; Yao, Q. J. Comb.
Chem. 2007, 9, 916. (c) Turner, J. A. J. Org. Chem. 1990, 55, 4744.
(d) Baldwin, J. J.; Mender, K.; Panticello, G. S. J. Org. Chem. 1978,
43, 4878. (e) Jiang, B.; Fan, W.; Sun, M.-Y.; Ye, Q.; Wang, S.-L.; Tu,
S.-J.; Li, G. J. Org. Chem. 2014, 79, 5258.
O
HN
O
O
O
H
N
2a
HOAc, – H2O
O
OH
1a
O
O
3
A
O
O
O
O
N
(3) (a) Egbertson, M. S. Curr. Top. Med. Chem. 2007, 7, 1251.
(b) Frasson, I.; Spanò, V.; S. Martino, D.; Nadai, M.; Doria, F.;
Parrino, B.; Carbone, A.; Cascioferro, S. M.; Diana, P.;
Cirrincione, G.; Freccero, M.; Barraja, P.; Richter, S. N.;
Montalbano, A. Eur. J. Med. Chem. 2019, 162, 176. (c) Wang, M.-
S.; Zhuo, L.-S.; Yang, F.-P.; Wang, W.-J.; Huang, W.; Yang, G.-F.
Eur. J. Med. Chem. 2020, 185, 111803. (d) Chen, D.-M.; Liu, J.-Y.;
Wei, M.; Wang, B.-W.; Chu, R.-H.; Chen, D.-S. Heterocycl.
Commun. 2019, 25, 15. (e) Wortmann, L.; Lindenthal, B.; Muhn,
P.; Walter, A.; Nubbemeyer, R.; Heldmann, D.; Sobek, L.;
Morandi, F.; Schrey, A. K.; Moosmayer, D.; Günther, J.; Kuhnke,
J.; Koppitz, M.; Luecking, U.; Roehn, U.; Schäfer, M.; Nowak-
Reppel, K.; Kuehne, R.; Weinmann, H.; Langer, G. J. Med. Chem.
2019, 62, 10321. (f) Wang, P.; Huang, J.; Kurtán, T.; Mándi, A.;
Jia, H.; Cheng, W.; Lin, W. Org. Lett. 2020, 22, 8215. (g) Dong, W.;
Yuan, Y.; Gao, X.; Hu, B.; Xie, X.; Zhang, Z. ChemCatChem 2018,
10, 2878.
(4) (a) Tsuruoka, R.; Yoshikawa, N.; Konishi, T.; Yamano, M. J. Org.
Chem. 2020, 85, 10797. (b) Mohammadi, H.; Reza Shaterian, H.
Monatsh. Chem. 2019, 150, 327. (c) Utkina, N. K.; Denisenko, V.
A. Nat. Prod. Commun. 2016, 11, 1259. (d) Vennila, K. N.;
Selvakumar, B.; Satish, V.; Sunny, D.; Madhuri, S.; Elango, K. P.
Med. Chem. Res. 2021, 30, 133.
(5) Litvinov, V. P. Adv. Heterocycl. Chem. 2006, 91, 189.
(6) Fiorito, J.; Vendome, J.; Saeed, F.; Staniszewski, A.; Zhang, H.;
Yan, S.; Deng, S.-X.; Arancio, O.; Landry, D. W. J. Med. Chem.
2017, 60, 8858.
N
NHO
N
O
O
HO
B
C
O
O
O
N
– H2O
N
4a
Scheme 3 The plausible mechanism for the formation of 4a
In conclusion, a simple and efficient strategy for the
preparation of polysubstituted naphtho[2,3-b][1,6]naph-
thyridine derivatives via domino reaction processes has
been developed, which could provide a series of potential
biological molecules. Undoubtedly, the operational simplic-
ity and environmentally friendly nature make the strategy
highly attractive. Other features of this method include
bond-forming efficiency, inexpensive and easily available
starting
materials
(6-methyl-1-phenyl-4-(phenylami-
no)pyridin-2(1H)-ones, aldehydes, and 2-hydroxynaphtha-
lene-1,4-dione), and the acquisition of activating products
with good to excellent yields.
(7) (a) Muthukrishnan, I.; Vachan, B. S.; Karuppasamy, M.; Eniyaval,
A.; Uma, Maheswari. C.; Nagarajan, S.; Menéndez, J. C.;
Sridharan, V. Org. Biomol. Chem. 2019, 17, 6872. (b) Khakwani,
S.; Aslam, S.; Shahi, M. N.; Mussadiq, S.; Bernaedino, A. M. R.;
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

F
C. Li et al.
Letter
Synlett
Khan, M. A. Asian J. Chem. 2017, 29, 27. (c) Bernardino, A. M. R.;
Castro, H. C.; Frugulhetti, I. C. P. P.; Loureiro, N. I. V.; Azevedo, A.
R.; Pinheiro, L. C. S.; Souza, T. M. L.; Giongo, V.; Passamani, F.;
Magalhães, U. O.; Albuquerque, M. G.; Cabral, L. M.; Rodrigues,
C. R. Bioorg. Med. Chem. 2008, 16, 313.
tho[2,3-b][1,6]naphthyridine-1,6,11(2H)-trione (4a)
Red brown solid; mp 290–292 °C. 1H NMR (400 MHz, CDCl3,
TMS):  = 8.03 (d, J = 8.0, 1.2 Hz, 1 H, ArH), 7.82 (d, J = 7.6, 0.8
Hz, 1 H, ArH), 7.63–7.66 (m, 5 H, ArH), 7.42–7.49 (m, 4 H, ArH),
7.51–7.53 (m, 3 H, ArH), 7.19 (d, J = 7.2 Hz, 1 H, ArH), 7.12 (d, J =
8.0 Hz, 2 H, ArH), 7.04–7.08 (m, 1 H, ArH), 5.77 (s, 1 H, CH), 5.58
(s, 1 H, CH), 2.30 (s, 3 H, CH3), 1.82 (s, 3 H, CH3). 13C NMR (100
MHz, CDCl3, TMS):  = 187.8, 182.1, 165.0, 161.6, 153.6, 145.5,
139.7, 138.1, 135.3, 134.2, 133.9, 133.1, 132.6, 131.2, 129.7,
129.6, 129.5, 129.1, 128.9, 128.3, 127.8, 126.6, 126.4, 124.6,
123.1, 99.5, 35.5, 21.6, 21.0. HRMS (ESI): m/z calcd for
(8) (a) Prabha, K.; Rajendra, Prasad. K. J. MedChemComm 2013, 4,
340. (b) Vichai, V.; Kirtikara, K. Nat. Protoc. 2006, 1, 1112.
(9) Arslan, B. S.; Güzel, E.; Kaya, T.; Durmaz, V.; Keskin, M.; Avc, D.;
Nebioğlu, M.; Şişman, İ. Dyes Pigm. 2019, 164, 188.
(10) (a) Wang, Q.; Zhu, J. Domino Reactions; Tietze, L. F., Ed.; Wiley-
VCH: Weinheim, 2014, 57. (b) Pellissier, H. Chem. Rev. 2013,
113, 442. (c) Clavier, H.; Pellissier, H. Adv. Synth. Catal. 2012,
354, 3347. (d) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G.
Chem. Asian J. 2010, 5, 2318. (e) Tietze, L. F.; Modi, A. Med. Res.
Rev. 2000, 20, 304. (f) Enders, D.; Grondal, C.; Huttl, M. R. M.
Angew. Chem. Int. Ed. 2007, 46, 1570.
(11) (a) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2004. (b) Anastas, P. T.; Warner, J. C. Green
Chemistry Theory and Practice; Oxford University Press: New
York, 1998. (c) Indumathi, S.; Menendez, J. C.; Perumal, S. Curr.
Org. Chem. 2013, 17, 2038. (d) Ma, G.-H.; Tu, X.-J.; Ning, Y.; Jiang,
B.; Tu, S.-J. ACS Comb. Sci. 2014, 16, 281.
(12) (a) Li, C. M.; Zhang, F. R.; Qi, C. Z. Green Chem. 2019, 21, 3109.
(b) Zhang, F. R.; Li, C. M.; Qi, C. Z. Org. Chem. Front. 2020, 7, 2456.
(13) (a) Li, C. M.; Qi, C. Z.; Zhang, F. R. Synlett 2020, 31, 1313. (b) Li, C.
M.; Fan, W. M.; Qi, C. Z.; Zhang, F. R. Tetrahedron Lett. 2020, 61,
152144.
(14) General Procedure for the Synthesis of 5,12-Dihydronaph-
tho[2,3-b][1,6]naphthyridine-1,6,11(2H)-triones 4a–v
A mixture of aminopyridinone 1 (0.5 mmol), aldehyde 2 (0.5
mmol), 2-hydroxynaphthalene-1,4-dione 3 (0.5 mmol), and
HOAc (3.0 mL) was stirred and heated at 100 °C for about 4 h.
After completion of the reaction as indicated by TLC, the reac-
tion mixture was diluted with cold water (10 mL). The crude
products were filtered by Büchner funnel and further purified
by recrystallization from hot 95% ethanol to afford the desired
pure products 4 as red to red brown solid.
C
36H27N2O3 [M + H]+: 535.2022; found: 535.2021
(15) General Procedure for the Synthesis of 12-Aryl-2,3,4,12-tet-
rahydro-1H-benzo[b]xanthene-1,6,11-triones 6
Similarly, the mixture of 3-(arylamino)cyclohex-2-en-1-one 1
(0.5 mmol), aldehyde 2 (0.5 mmol), 2-hydroxynaphthalene-1,4-
dione (3, 0.5 mmol), and HOAc (3.0 mL) was stirred and heated
at 100 °C for about 4 h. After completion of the reaction as indi-
cated by TLC, the reaction mixture was diluted with cold water
(10 mL). The crude products were filtered by Büchner funnel
and further purified by recrystallization from hot 95% ethanol
to afford the desired pure products 6 as red to red-brown solid.
3,3-Dimethyl-12-phenyl-2,3,4,12-tetrahydro-1H-
benzo[b]xanthene-1,6,11-trione (6a)
Red solid; mp 232–234 °C. 1H NMR (400 MHz, CDCl3, TMS):  =
8.14 (t, J = 5.6 Hz, 1 H, ArH), 8.00–8.02 (m, 1 H, ArH), 7.71–7.73
(m, 2 H, ArH), 7.41 (d, J = 7.6 Hz, 2 H, ArH), 7.28 (t, J = 7.6 Hz, 2
H, ArH), 7.18 (t, J = 7.2 Hz, 1 H, ArH), 5.16 (s, 1 H, CH), 2.65–2.78
(m, 2 H, CH2), 2.25–2.35 (m, 2 H, CH2), 1.17 (s, 3 H, CH3), 1.08 (s,
3 H, CH3). 13C NMR (100 MHz, CDCl3, TMS):  = 196.2, 182.9,
178.0, 162.8, 149.0, 142.5, 134.5, 133.7, 131.6, 130.6, 128.7,
128.5, 127.2, 126.6, 126.5, 125.3, 114.3, 50.7, 40.7, 32.8, 32.4,
29.1, 27.4. HRMS (ESI): m/z calcd for C25H21O4 [M + H]+:
385.1440; found: 385.1449
(16) (a) Dabiri, M.; Noroozi, Tisseh. Z.; Bazgir, A. J. Heterocycl. Chem.
2010, 47, 1062. (b) Maleki, B.; Akbarzadeh, E.; Babaee, S. Dyes
Pigm. 2015, 123, 222. (c) Khurana, J. M.; Lumb, A.; Chaudhary,
A.; Nand, B. Synth. Commun. 2013, 43, 2147.
3-Methyl-2,5-diphenyl-12-(p-tolyl)-5,12-dihydronaph-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F