An efficient synthesis of 9-anthrone lactone derivatives via the Knoevenagel condensation and intramolecular cyclization

Article abstract of DOI:10.1002/jhet.3785

One-step synthesis of 9-anthrone lactone derivatives from 1-acetyloxyanthraquinone with a variety of dicarbonyl substrates in the presence of K₂CO₃ by Knovenagel condensation and intramolecular cyclization is developed. Possible reaction mechanisms have been investigated using the density functional theory (DFT), which has been widely used in the study of reaction mechanism. The strategy could be useful for the synthesis of the core structure of marine natural product aspergiolide.

Full text of DOI:10.1002/jhet.3785

Received: 26 July 2019
DOI: 10.1002/jhet.3785
Revised: 16 September 2019
Accepted: 7 October 2019
A R T I C L E
An efficient synthesis of 9-anthrone lactone derivatives via
the Knoevenagel condensation and intramolecular
cyclization
Weiqiang Tan1
| Jifang Zheng1 | Jing Guan1 | Xiuzhi Zhan1 | Liming Gao1
|
Lili Lyu1 | Bin Shan1 | Qipeng Yang1 | Mingliang Ma2 | Yan Xia1,3
1School of Environmental and Municipal Engineering, Qingdao University of Technology, Qingdao, China
2Research Institute of Functional Materials, School of Civil Engineering, Qingdao University of Technology, Qingdao, China
3Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's
Republic of China
Correspondence
Weiqiang Tan and Qipeng Yang, School of
Abstract
Environmental and Municipal
Engineering, Qingdao University of
Technology, Qingdao 266033, People's
Republic of China.
One-step synthesis of 9-anthrone lactone derivatives from 1-acetyloxyanthra-
quinone with a variety of dicarbonyl substrates in the presence of K2CO3 by
Knovenagel condensation and intramolecular cyclization is developed. Possible
reaction mechanisms have been investigated using the density functional theory
(DFT), which has been widely used in the study of reaction mechanism. The
strategy could be useful for the synthesis of the core structure of marine natural
product aspergiolide.
Email: tanweiqiang@qut.edu.cn (W. T.);
yangqipeng@qut.edu.cn (Q. Y.)
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21102079,
21506109, 51503116, 21808118
The tandem Knoevenagel condensation and intramolecu-
lar cyclization with ethyl cyanoacetate, ethyl acetoacetate,
1 | INTRODUCTION
and dialkyl malonates that contain an active methylene
group in the presence of a catalytic amount of piperidine
is perhaps the most direct and simple method known for
the preparation of substituted coumarins (Scheme 1A).[4]
While this procedure is a suitable method, it suffers from
drawbacks such as limited substrate scope. It was difficult
to prepare the naphtho[1,2,3-de]chromene-2,7-dione deriv-
atives bearing a coumarin unit from 1-hydroxyanthracene-
9,10-dione by the classical methods.[9] In an attempt to
improve on these procedures, Klimenko described a
convenient and single-step alternative to the condensation
to provide a π-expanded furan derivative and a compound
bearing a coumarin unit by the reaction of 1-aceto-
xyanthraquinone with phenylacetonitrile under different
conditions.[10] Subsequently, the method of the synthesis
of π-expanded coumarins has been developed by Gryko
and coworkers.[11]
Coumarins and their derivatives are useful and fundamen-
tal structural motifs that occur widely in biologically active
natural products.[1] Much attention has been paid to the
development of efficient synthetic protocols for the prepara-
tion of coumarin derivatives for many years as members of
this family have wide applications in medicinal chemistry[2]
and organic photonic-oriented materials.[3] For example,
the aspergiolide derivatives (Scheme 1B), an 9-anthrone lac-
tone compound, which has a novel 1-benzoylnaphtho[1,2,3-
de]chromene-2,7-dione structural core, was prepared from
Aspergillosis glaucus HB1-19 extracted from marine-derived
filamentous fungus.[5] It exhibited cytotoxicity against sev-
eral cancer cell lines and played an important role for drug
discovery and structure modifications.[6,7]
Coumarins can be synthesized by one of several
methods such as the Witting reaction, Perkin reaction,
Pechmann reaction, and the Knoevenagel condensation.[8]
J Heterocyclic Chem. 2020;1–8.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
TAN ET AL.
For further pharmacology and pharmacokinetics stud-
ratio was nearly 75% during the complicated purifica-
tion procedure.[5] In spite of what Zhou et al have
reported that the experimental production of biosynthe-
sis reached 150 mg/L under the proposed optimized
conditions, it has not met the needs of clinical tri-
als.[6,12] Moreover, so far, there is only a literature that
described the synthesis of the core structure of
aspergiolides by two-step reaction with satisfied yield.[7]
Herein, we disclose further optimizations leading to
practical methods for the total synthesis of 9-anthrone
lactone derivatives (Scheme 1B).
ies, a large amount of aspergiolide is necessary. However,
the original production yield of aspergiolide by marine
microorganisms is very low (<15 mg/L), and the loss
2 | RESULTS AND DISCUSSION
Initially, the starting point of screening the conditions was
the reaction of 1,4-dihydroxyanthraquinone 1aa and diethyl
malonate 2a as a model reaction in the presence of potas-
sium carbonate as base in DMSO at 100ꢀC under a nitrogen
atmosphere for 12 hours (Table S1, entry 1). Unfortunately,
no desired product was detected even with use of strong
SCHEME 1 Synthesis of coumarins and their derivatives. A,
General synthesis strategy of coumarin analogues.[4] B, This work
[Color figure can be viewed at wileyonlinelibrary.com]
TABLE 1 Screening conditions for the synthesis of 3a
Entry
Substrate
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yieldsa
nd
1
R1 = R2 = OH (1aa)
K2CO3
NaH
2
R1 = R2 = OH (1aa)
nd
3
R1 = R2 = OH (1aa)
DBU
nd
4
R1 = R2 = OH (1aa)
tBuOK
K2CO3
NaH
nd
5
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = OH (1ab)
R1 = OMe, R2 = acetoxyl (1ac)
R1 = OMe, R2 = acetoxyl (1ac)
R1 = OMe, R2 = acetoxyl (1ac)
nd
6
nd
7
DBU
nd
8
tBuOK
K2CO3
K2CO3
Et3N
nd
9b
10
11b
12
13b
nd
nd
DMSO
DMSO
DMSO
nd
Et3N
nd
35%c
K2CO3
Note: General reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), base (1.0 mmol), solvent (5.0 mL), 100ꢀC, 12 hours, nitrogen atmosphere.
Abbreviation: nd, no detection.
aIsolated yields.
bReaction temperature: 25ꢀC.
cReaction time: 24 hours.

TAN ET AL.
3
TABLE 2 Optimization of reaction conditions for the synthesis of 3a
Entry
Substrate
Temperature, ꢀC
Yields, %a
1
2
3
4b
5
6
7
8
9
R = Acetyl (1ac)
70
40
25
25
40
25
40
40
40
15
85
35
55
70
37
78
53
72
R = Acetyl (1ac)
R = Acetyl (1ac)
R = Acetyl (1ac)
R = Benzoyl (1ad)
R = Benzoyl (1ad)
R = 4-Methoxylbenzoyl
R = 3,5-Dimethylbenzoyl
R = 4-(trifluoromethyl)benzoyl
Note: General reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), K2CO3 (1.0 mmol), DMSO (5.0 mL), 12 hours, nitrogen atmosphere.
aIsolated yields.
bReaction time: 72 hours.
bases including NaH, DBU, and KOtBu (Table S1, entry
2-4). Another substrate 1-hydroxy-4-methoxyanthraquinone
1ab instead of 1,4-dihydroxyanthraquinone also was
checked under the same reaction conditions (Table S1,
entry 5-10). But no desirable results were produced even at
different temperatures such as room temperature or differ-
ent solvents such as DMF.
the
desired
6-methoxy-naphtho[1,2,3-de]chromene-
2,7-dione-1-carboxylic acid ethyl ester (3a, 35% yield,
Table S1, entry 13), although it took several tries and
it was discovered that the suitable reaction tempera-
ture was essential for the reaction to efficiently
proceed.
To optimize the reaction temperature, several experi-
ments were performed at 70, 40, and 25ꢀC in DMSO
under a nitrogen atmosphere for 12 hours (Table 2, entry
1-3). As can be seen from Table 2, the reaction yield was
remarkably increased to 85% by raising the reaction tem-
perature (Table 2, entry 2). Using the above experimental
conditions, excessive reaction temperature would lead
to the decomposition of some substrates (Table 2, entry
1), and lower reaction temperature would require
prolonging the reaction time to 72 hours (Table 2, entry
4). Slightly lower yield was obtained by using 1-benzoyl-
4-methoxylanthraquinone 1ad with same preparation
process as compound 1ac under the same reaction condi-
tions (Table 2, entry 5-6). Different protective groups of
the hydroxyl group, such as 4-methoxylbenzoyl,
3,5-dimethylbenzoyl, and 4-(trifluoromethyl)benzoyl,
were of little impact to the efficiency of the reaction
between the different 1-acyl-4-methoxylanthraquinones
and diethyl malonate (Table 2, entry 7-9). It should be
noted that without the acyl group, the reaction does not
give the desired product.
Klimenko and coworkers discovered that reaction of
1-acetoxyanthraquinone with ethyl cyanoacetate led to a
π-expanded pyran derivative 1-cyanoanthra[1,9-b,c]
pyran-6-ones in the presence of NEt3 at room tempera-
ture.[10] In our experiment, the reaction of 1-acetyloxy-
4-methoxylanthraquinone 1ac, which was obtained by
reaction of 1ab with acetyl chloride in the presence of
potassium carbonate at room temperature in DMF, with
2a was conducted under the original reaction conditions
reported in literature (Table S1, entry 11).[10] Unfortu-
nately, no product was obtained even after extending the
reaction time to 24 hours. The decomposed product 1ab
was isolated in more than 90% yield if raising the reaction
temperature to 100ꢀC (Table S1, entry 12). It was rea-
soned that the reaction temperature is too high, resulting
in decomposition of 1ac. Thus, the reaction temperature
was lowered to 25ꢀC in the presence of potassium car-
bonate and, to our satisfaction, led to the formation of a
red compound as the only product, which after simple
work-up and NMR and MS analysis was confirmed to be

4
TAN ET AL.
TABLE 3 Substrate scope studies
FIGURE 1 Single-crystal X-ray structure of 3d
within 12 hours and further extension of the reaction time
can improve the reaction yield (Table 3, 3h, 55%). The
electronic effects from the electron-donating substituent
containing aryl group dramatically improved the reaction
efficiency within 24 hours under the typical reaction con-
ditions (Table 3, 3i, 80%). The two-positioned substituents
at the aryl moiety retarded the reaction (Table 3, 3j and
3k), and the yield of the reaction was less than 30% within
12 hours, revealing an apparent steric effect. Both the ste-
ric effect from the two-positioned substituents such as
methyl and methoxyl (it is one of main functional groups
with aspergiolide precursor) and electronic effects from
the four-positioned electron-donating substituents such as
methoxyl decreased the reaction efficiency. The best
results of up to 60% and 40% were achieved within 2 days
under 40ꢀC (Table 3, 3j-k), respectively, while higher
reaction temperature led to the decomposition of 1ac.
However, the products could not be obtained in the case of
using the nitro-group at four-position of the aryl moiety as
an electron-withdrawing substituent due to the electronic
effect. The structure of compound 3d was confirmed by X-
ray analysis (Figure 1).[13]
With this one-pot procedure in hand, the scope and
generality of this methodology were explored using a
variety of dicarbonyl compounds under the optimized
conditions (Table 3, 3b-i). The yields of alkyl acetoacetate
instead of diethyl malonate as one of the substrate were
lower due to the low nucleophilicity of alkyl-substituted
β-ketoates (Table 3, 3b-e). Similarly, electron-donating
groups such as methoxy groups on acyloxy substituted
aromatic rings can increase the yield from the results of
the reactions (Table 3, 3f-g, 3l). And the reactions
exhibited higher yields for most of dicarbonyl substrates
containing aryl groups (Table 3, 3h-k). Ethyl ben-
zoylacetate converted to 3h resulted in a lower yield
Based on the above experimental results and the pre-
vious related literature,[4],[9] a possible reaction mecha-
nism of the formation of product 3a from 1ac is proposed
(Scheme 2). First, the reaction is initiated by extraction of
one hydrogen atom from diethyl malonate 2a with

TAN ET AL.
5
K2CO3 to generate anion species 2a0. The intermediate
4 is obtained by the nucleophilic reaction of carbanion
attack at 9-position of 1ac. Subsequently, the migration
of the acetyl group affording immediate 5 occurs and
elimination of the acetate anion gives the derivative 6 or
7, which is then ionized by K2CO3 to generate 8. Finally,
an intramolecular nucleophilic addition at the ester
group of diethyl malonate occurred and followed by a
leaving group of ethoxy to generate the 9-anthrone lac-
tone derivative 3a. Moreover, it is hard to react due to a
more nucleophilic phenoxy anion 9 or 10 formed under
the action of base, which the nucleophilic reaction
directly starts from 1ab as the substrate.
To gain information on the mechanistic aspect of the
transformation of 1ac to 3a, we then performed the den-
sity functional theory (DFT) calculations. The computed
energy profile of the most favorable pathway is shown
Figure 2. The energy of 1ac is set as 0.00 kcal/mol as ref-
erence for the potential energy profiles. Nucleophilic
addition of diethyl malonate anion 2a0 across to a C O
bond in 1ac could easily take place with little energy
change. Release of one molecule of KOAc from 4 by the
migration of the acetyl group then takes place via TS1
with an energy barrier of 33.7 kcal/mol to give intermedi-
ate 6. Finally, the departure of ethoxy group by the intra-
molecular cyclization between the alkoxy and ester group
in 8 via TS2 affords the thermodynamically stable prod-
uct 3a, which is equivalent to 3 observed experimentally.
The whole transformation of 1ac to 3a is exergonic by
6.4 kcal/mol. The overall energy barrier is 35.5 kcal/mol,
which is reasonable in view of the experimental
conditions (40ꢀC, 12-72 hours).
3 | CONCLUSIONS
In conclusion, 9-anthrone lactone derivatives have been
prepared from 1-acetyloxyanthraquinone series with
SCHEME 2 Proposed reaction mechanism [Color figure can
be viewed at wileyonlinelibrary.com]
FIGURE 2 Computed energy profile (in kcal/mol) for the transformation of 1ac to 3a [Color figure can be viewed at
wileyonlinelibrary.com]

6
TAN ET AL.
various dicarbonyl compounds in DMSO in the presence
of K2CO3 via the Knoevenagel condensation and intramo-
lecular cyclization. The reaction mechanism has been in-
vestigated theoretically using DFT. And the obtained
mechanistic insights should be valuable for not only
understanding the reaction procedures of the Knoevenagel
condensation, but also the design of efficient and highly
synthesis of 9-anthrone lactone. Furthermore, the reaction
could provide a practical method for the total synthesis of
aspergiolide and its derivatives.
purified by flash silica gel column chromatography with
petroleum ether (60-90ꢀC)/ethyl acetate, v/v 2:1) as the
eluent affording compound 1ac as an orange-yellow solid
(2.00 g, 86%).
3.1.3 | 1-Acetoxy-
4-methoxyanthraquinone (1ac)
1H NMR (CDCl3, 400 MHz) δ 8.21 (d, J = 7.2 Hz, 1H),
8.13 (d, J = 7.5 Hz, 1H), 7.77-7.69 (m, 2H), 7.37 (s, 2H),
4.05 (s, 3H, OCH3), 2.48 (s, COCH3). 13C NMR (CDCl3,
101 MHz) δ 182.50, 182.32, 170.04, 158.43, 143.26, 134.35,
133.36, 133.17, 131.00, 126.84, 126.46, 126.36, 122.49,
119.15, 56.88, 21.15. HRMS (ESI): m/z calcd for C17H13O5
[M + H] 297.0685, found 297.0683.
3.1 | Experimental section
3.1.1 | 1-Hydroxy-
4-methoxyanthraquinone (1ab)
To a stirred suspension of 1,4-dihydroanthraquinone
(3.00 g, 12.5 mmol) and K2CO3 (2.45 g, 25 mmol) in
100 mL DMF, a solution of methyl iodide (1.17 mL,
18.75 mmol) in 10 mL DMF was added dropwise at room
temperature over a period of 10 minutes. The resulting
mixture was stirred at room temperature for 12 hours
and then 10% aqueous HCl was added in portion to
quench the reaction at pH to 5. The aqueous phase was
exacted with CH2Cl2 (2 × 50 mL), and the extract was
washed with 30 mL of saturated aqueous NaCl solution,
dried over anhydrous MgSO4, filtered, and all the vola-
tiles were removed under reduced pressure. The residue
was purified by flash silica gel column chromatography
with petroleum ether (60-90ꢀC)/ethyl acetate, v/v 2:1) as
the eluent to give 1ab as a brick-red solid (2.00 g, 63%).
1H NMR (CDCl3, 400 MHz) δ 12.97 (s, 1H, OH), 8.30-8.27
(dd, J = 6.6, 4.7 Hz, 2H), 7.82-7.74 (dt, J = 18.2, 7.2 Hz,
2H) and 7.42-7.32 (dd, J = 32.8, 9.4 Hz, 2H), 4.05 (s, 3H).
13C NMR (CDCl3, 101 MHz) δ 188.89, 188.56, 157.36,
154.27, 135.03, 134.73, 133.26, 132.25, 127.33, 126.35,
126.32, 123.75, 119.21, 115.93, 57.02. HRMS (ESI): m/z
calcd for C15H11O4 [M + H] 255.0579, found 255.0577.
3.1.4 | 1-Benzoyloxy-4-methoxy-
4-methoxyanthraquinone (1ad)
1
Orange-yellow crystalline solid (2.48 g, 88%). H NMR
(CDCl3, 400 MHz) δ 8.28-8.30 (m, 2H), 8.21 (dd, J = 7.7,
1.0 Hz, 1H), 8.07 (dd, J = 7.7, 1.1 Hz, 1H), 7.72 (m, 1H),
7.66 (m, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.45 (dd, J = 32.7,
9.1 Hz, 2H), 4.07 (s, 3H, OCH3). 13C NMR (CDCl3,
101 MHz) δ 182.43, 182.37, 165.64, 158.53, 143.46, 134.36,
133.98, 133.64, 133.33, 133.18, 131.21, 130.47, 129.62,
128.65, 126.81, 126.67, 126.60, 122.56, 119.12, 56.93.
HRMS (ESI): m/z calcd for C22H15O5 [M + H] 359.0841,
found 359.0839.
3.1.5 | General procedure for the synthesis
of 9-anthrone lactone derivatives
Under a nitrogen atmosphere, the mixture of 1-acetoxy-
4-methoxyanthraquinone (1ac, 0.10 mmol), appropriate
active methylene compound (2, 0.20 mmol) and K2CO3
(1.0 mmol) in 5.0 mL DMSO was stirred at 40ꢀC for 12 to
48 hours. After diluting with 10 mL deionized water, the
resulting mixture was extracted with CH2Cl2 (2 × 50 mL).
The combined organic phase was dried over anhydrous
Na2SO4, filtered, and condensed under reduced pressure
and subject to purification by flash silica gel column
chromatography to afford the target product, which was
identified by comparison with the authentic sample
through NMR and HRMS analysis.
3.1.2 | 1-Acyloxy-4-methoxyanthraquinone
synthesis of 1ac
To a solution of 1-hydroxy-4-methoxyanthraquinone
(2.00 g, 7.87 mmol) and Et3N (6.04 mL, 43.29 mmol) in
100 mL CH2Cl2 was added dropwise acetyl chloride (2.23
mL, 31.5 mmol) at 0ꢀC over a period of 10 minutes. After
warmed to ambient temperature, the mixture was stirred
for 60 minutes. All the volatiles were removed under
reduced pressure and the resultant residue was extracted
with CH2Cl2 (2 × 50 mL). The extract was washed with
20 mL of saturated aqueous NaCl solution, dried over
anhydrous Na2SO4, and filtered, and all the volatiles were
removed under reduced pressure. The residue was
3.1.6 | 6-Methoxy-2,7-dioxo-
2,7-dihydronaphtho[1,2,3-de]chromene-
1-carboxylate (3a)
Orange-yellow crystalline solid, M.p.: 214ꢀC. H NMR
(CDCl3, 400 MHz) δ 8.43 (d, J = 7.7 Hz, 1H), 8.00 (d, J =
8.0 Hz, 1H), 7.75 (dd, J = 10.7, 4.2 Hz, 1H), 7.71-7.61 (m,
1

TAN ET AL.
7
2H), 7.40 (d, J = 9.3 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H),
4.09 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
101 MHz) δ 180.65, 165.88, 158.42, 145.24, 138.00,
133.97, 132.81, 132.64, 129.38, 128.71, 126.79, 123.35,
120.34, 118.00, 117.28, 116.18, 63.05, 56.89, 13.80. HRMS
(ESI): m/z calcd for C20H15O6 [M + H] 351.0790, found
351.0788.
3.1.10 | 1-(2,4-Dimethoxy-
6-methylbenzoyl)-6-methoxynaphtho
[1,2,3-de]chromene-2,7-dione (3k)
Orange-yellow crystalline solid, M.p.: 224ꢀC. 1H NMR
(400 MHz, CDCl3) δ 8.40 (dd, J = 7.9, 1.3 Hz, 1H), 7.93
(d, J = 8.0 Hz, 1H), 7.67-7.56 (m, 2H), 7.52-7.43 (m, 1H),
7.35 (d, J = 9.3 Hz, 1H), 6.50 (d, J = 2.1 Hz, 1H), 6.28 (d,
J = 2.3 Hz, 1H), 4.08 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H),
2.73 (s, 3H). 13C NMR (CDCl3, 101 MHz) δ 192.22,
181.47, 164.03, 162.62, 159.30, 158.20, 146.44, 144.92,
134.30, 134.02, 132.23, 131.83, 131.45, 130.61, 128.88,
128.25, 122.82, 119.57, 119.28, 116.58, 115.85, 110.29,
96.42, 56.87, 56.03, 55.49, 23.41. HRMS: Calcd for
C27H21O7: 457.1209, found 457.1207.
3.1.7 | 1-Acetyl-6-methoxynaphtho
[1,2,3-de]chromene-2,7-dione (3b)
Orange-yellow crystalline solid, M.p.: 205ꢀC. 1H NMR
(400 MHz, CDCl3) δ 8.47 (dd, J = 7.8, 1.5 Hz, 1H),
7.86 (d, J = 7.7 Hz, 1H), 7.78-7.71 (m, 1H), 7.68 (dd,
J = 7.8, 1.5 Hz, 1H), 7.66-7.61 (m, 1H), 7.40 (d, J =
9.3 Hz, 1H), 4.09 (s, 3H), 2.72 (s, 3H). 13C NMR
(CDCl3, 101 MHz) δ 202.01, 180.60, 158.67, 158.44,
145.15, 136.98, 134.04, 132.92, 132.53, 129.34, 128.92,
127.67, 127.49, 123.32, 118.30, 117.08, 116.20, 56.90,
31.44. HRMS: Calcd for C19H13O5 [M + H]: 321.0685,
found 321.0686.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Founda-
tion of China (21102079, 21506109, 51503116, 21808118)
and the Open Fund of the Key Laboratory of Marine
Drugs, Ministry of Education (KLMD (OUC)201301) for
support of this research. We also thank Professor Qian-
qun Gu and De-hai Li (OUC, China) for helpful sugges-
tions and support in experiments.
3.1.8 | 1-Benzoyl-6-methoxynaphtho
[1,2,3-de]chromene-2,7-dione (3h)
Orange-yellow crystalline solid, M.p.: 210 ꢀC. 1H NMR
(400 MHz, CDCl3) δ 8.44 (d, J = 7.9 Hz, 1H), 8.04 (d,
J = 7.4 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 (d, J =
9.3 Hz, 1H), 7.64 (dd, J = 16.4, 7.7 Hz, 2H), 7.51 (t, J =
7.7 Hz, 2H), 7.47-7.40 (m, 2H), 4.12 (s, 3H). 13C NMR
(CDCl3, 101 MHz) δ 194.33, 180.91, 169.43, 159.14,
158.50, 145.52, 139.04, 135.39, 134.87, 134.04, 133.36,
132.86, 132.40, 131.99, 129.48, 129.37, 129.34, 128.79,
128.61, 128.56, 127.36, 125.80, 123.46, 118.41, 117.18,
116.28, 56.95. HRMS: Calcd for C24H15O5 [M + H]:
383.0841, found 383.0841.
ORCID
Weiqiang Tan https://orcid.org/0000-0003-2737-2018
REFERENCES
[1] R. D. H. Murray, J. Mendez, S. A. Brown, The natural Couma-
rins Occurrence Chemistry and Biochemistry, New York, Wiley
and Sons 1982.
[2] a) R. O. O'Kennedy, R. D. Zhorenes, Coumarins: Biology Appli-
cations and Mode of Action, Chichester, John Wiley and Sons
1997. b) I. Kempen, D. Papapostolou, N. Thierry, L. Pochet,
S. Counerotte, B. Masereel, J.-M. Foidart, M. Reboud-Ravaux,
A. Noël, B. Pirotte, Br. J. Cancer 2003, 88, 1111. c)
C. Kontogiorgis, D. Hadjipavlou-Litina, J. Enzyme Inhib. Med.
Chem. 2008, 18, 63. d) C. Spino, M. Dodier, S. Sotheeswaran,
Bioorg. Med. Chem. Lett. 1998, 8, 3475. e) E. Quezada,
G. Delogu, C. Picciau, L. Santana, G. Podda, F. Borges,
V. García-Morales, D. Viña, F. Orallo, Molecules 2010, 15, 270.
f) S. Vilar, E. Quezada, L. Santana, E. Uriarte, M. Yánez,
N. Fraiz, C. Alcaide, E. Cano, F. Orallo, Bioorg. Med. Chem.
Lett. 2006, 16, 257.
[3] a) X. M. Peng, G. L. Damu, C. H. Zhou, Curr. Pharm. Des.
2013, 19, 3884. b) K. H. Drexhage, In Dye Lasers, F. P. Schafer,
Ed. Springer: New York, 1977, pp 144; c) W. H. Li,
G. H. Zheng, Photochem. Photobiol. Sci. 2012, 11, 460. d)
C. Bazzicalupi, C. Caltagirone, Z. F. Cao, Q. B. Chen, C. Di
Natale, A. Garau, V. Lippolis, L. Lvova, H. L. Liu,
I. Lundström, M. C. M. M. Nieddu, R. Paolesse,
3.1.9 | 6-Methoxy-1-(4-methoxybenzoyl)
naphtho[1,2,3-de]chromene-2,7-dione (3i)
1
Orange-yellow crystalline solid, M.p.: 201 ꢀC. H NMR
(400 MHz, CDCl3) δ 8.43 (dd, J = 7.8, 1.3 Hz, 1H),
8.00 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.69
(d, J = 9.2 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.46-7.40
(m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.11 (s, 3H), 3.87 (s,
3H). 13C NMR (CDCl3, 101 MHz) δ 192.65, 180.96,
164.95, 159.18, 158.43, 145.48, 138.54, 134.01, 132.84,
132.26, 131.84, 129.62, 128.67, 128.64, 128.57, 126.12,
123.38, 118.47, 117.02, 116.29, 114.66, 56.94, 55.65.
HRMS: Calcd for C25H17O6 [M + H]: 413.0947, found
413.0946.

8
TAN ET AL.
L. P. M. Sgarzi, N. Zaccheroni, Chem. Eur. J. 2013, 19, 14639.
e) N. C. Lim, J. V. Schuster, M. C. Porto, M. A. Tanudra,
L. L. Yao, H. C. Freake, C. Brückner, Inorg. Chem. 2005, 44,
2018. f) P. Kotchapadist, N. Prachumrak, T. Sunonnam,
S. Namuangruk, T. Sudyoadsuk, T. Keawin, S. Jungsuttiwong,
V. Promarak, Eur. J. Org. Chem. 2015, 3, 496. g) T. Z. Yu,
P. Zhang, Y. L. Zhao, H. Zhang, J. Meng, D. W. Fan, Org. Elec-
tron. 2009, 10, 653. h) M.-T. Lee, C.-K. Yen, W.-P. Yang, H.-
H. Chen, C.-H. Liao, C.-H. Tsai, C. H. Chen, Org. Lett. 2004, 6,
1241.
[8] J. D. Hepworth, C. D. Gabbut, B. M. Heron, Comprehensive
Heterocyclic Chemistry, 2nd ed., Oxford, Pergamon Press
1996.
[9] Q. S. Meng, Study on synthesis of aspergiolide A and Its ana-
logues, Ocean University of China 2012.
[10] L. Ya, L. Mainagashev, S. Kiimenko, Russ. Chem. Bull. 1996,
45, 2569.
ꢀ
[11] a M. K. Węcławski, M. Tasior, T. Hammann, P. J. Cywinski,
D. T. Gryko, Chem. Commun. 2014, 50, 9105. bM. Tasior,
D. Kim, S. Singha, M. Krzeszewski, K. H. Ahn, D. T. Gryko,
J. Mater. Chem. C 2015, 3, 1421.
[4] a W. H. Perkin, J. Chem. Soc. 1875, 28, 10. b C. Mhiri,
F. Ladhar, R. E. Gharbi, Y. L. Bigot, Synth. Commun. 1999, 29,
1451. c M. E. Langmuir, J. R. Yang, A. M. Moussa, R. Laura,
[12] L. Du, T. J. Zhu, Y. C. Fang, H. B. Liu, Q. Q. Gu, W. M. Zhu,
Tetrahedron 2008, 64, 1085.
K. A. Lecompte, Tetrahedron Lett. 1995, 36, 3989.
d
[13] CCDC-1921343 (3d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
L. M. Kabeya, A. A. D. Marchi, A. Kanashiro, N. P. Lopes,
C. H. T. P. D. Silva, M. T. Pupo, Y. M. Lucisano-Valima, Bio-
org. Med. Chem. 2007, 15, 1516. e M. J. Matos, D. Viña,
E. Quezada, C. Picciau, G. Delogu, F. Orallo, L. Santana,
E. Uriarte, Bioorg. Med. Chem. Lett. 2009, 19, 3268.
f
SUPPORTING INFORMATION
M. A. Salem, M. H. Helal, M. A. Gouda, Y. A. Ammar,
M. S. A. El-Gaby, S. Y. Abbas, Synth. Commun. 2018, 48, 1534.
[5] a K. J. Tao, L. Du, X. Q. Sun, M. H. Cai, T. J. Zhu, X. S. Zhou,
Q. Q. Gu, Y. X. Zhang, Tetrahedron Lett. 2009, 50, 1082. b
Y. Y. Wang, X. Qi, D. H. Li, T. J. Zhu, X. M. Mo, J. Li, Drug
Des. Dev. Ther 2014, 8, 1965.
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[6] For biosynthesis of aspergiolide A see:aY. Wu, Y. N. Ren,
X. S. Zhou, M. H. Cai, Y. X. Zhang, J. Basic Microb. 2017, 57,
873. b X. Q. Sun, X. S. Zhou, M. H. Cai, J. S. Zhou,
Y. X. Zhang, Bioresour. Technol. 2010, 101, 3609. c X. Q. Sun,
X. S. Zhou, M. H. Cai, K. J. Tao, Y. X. Zhang, Bioresour.
Technol. 2009, 100, 4244.
How to cite this article: Tan W, Zheng J,
Guan J, et al. An efficient synthesis of 9-anthrone
lactone derivatives via the Knoevenagel
condensation and intramolecular cyclization.
J Heterocyclic Chem. 2020;1–8. https://doi.org/10.
1002/jhet.3785
[7] L. Qiao, Z. W. Duan, Y. H. Chen, Y. P. Luan, Q. Q. Gu,
Y. K. Liu, D. H. Li, J. Org. Chem. 2019, 84, 4451.