Design, synthesis, and antifungal evaluation of novel coumarin-pyrrole hybrids

Article abstract of DOI:10.1002/jhet.4180

A series of coumarin derivatives bearing a pyrrole scaffold were designed, prepared, and assessed for their in vitro antifungal activities against six phytopathogenic fungi. The antifungal activity screening results suggest that some synthesized hybrids exhibited potential fungicidal activities against the tested fungi. In particular, compounds 6j, 6k, 6o, 6p, and 6r displayed significant antifungal effects against Rhizoctorzia solani, and possessed EC₅₀ values of 3.94, 7.75, 6.38, 6.25, and 7.67 μg/ mL, respectively. The above activities are more potent than the commercialized fungicide Boscalid (11.52 μg/mL) and Osthole (9.79 μg/mL). These results provide a significant reference for further rational design of coumarin-based fungicides.

Full text of DOI:10.1002/jhet.4180

Design, Synthesis, and Antifungal Evaluation of Novel Coumarin-
Pyrrole Hybrids
Shuguang Zhang, Xin Tan, Chaogen Liang and Weihua Zhang*
Abstract: A series of coumarin derivatives bearing a pyrrole scaffold
were designed, prepared and assessed for their in vitro antifungal
activities against six phytopathogenic fungi. The antifungal activity
screening results suggest that some synthesized hybrids exhibited
potential fungicidal activities against the tested fungi. In particular,
compounds 6j, 6k, 6o, 6p and 6r displayed significant antifungal
effects against Rhizoctorzia solani, and possessed EC50 values of
3.94, 7.75, 6.38, 6.25 and 7.67 μg/ mL, respectively. The above
activities are more potent than the commercialized fungicide
Boscalid (11.52 μg/mL) and Osthole (9.79 μg/mL). These results
structural fragment is widely found in drug molecules, natural
products and several biological molecular structures [15], such
as chlorophyll, hemoglobin, myoglobin, cytochrome and vitamin
B12. Pyrrole substructures exhibit different biological activities,
including anti-inflammatory, anti-bacterial, anti-fungal, anti-tumor,
anti-depression, anti-viral, insecticidal and protease inhibitor [16-
21]. For example, pyrrolactin A has obvious antibiotic activity
[22]; diphthalamide B and its derivatives showed significant
antibacterial activity [23-26]. Thus, hybridization of pyrrole and
coumarin into one single molecule may provide a key basis for
the development of promissing agrochemicals.
provide
a significant reference for further rational design of
coumarin-based fungicides.
Our previous research results showed that various structural
modifications to osthole could improve its inhibition activity
against certain phytopathogenic fungi in vitro [27-32]. Especially,
we found that some 7-pyrrole substituted coumarin derivatives
displayed stronger antifungal activity against Rhizoctorzia solani
than positive control Osthole [33]. Based on the aforementioned
results and as a part of continuous program to optimize 6-pyrrole
Introduction
China has a vast territory, a wide variety of crops, but crop
diseases are a serious threat to agricultural production. After a
series of metabolic changes in a plant, chemical metabolites
become non-toxic and harmless substances, some still remain
quite toxic, or metabolize new toxic substances, and even
become carcinogenic teratogenic substances. The long-term
overuse of traditional fungicides, has been brought about the
fungal resistances and environment pollution [1].
substituted
coumarin
hybrids
as
novel fungicides precursor compounds, a novel series of pyrrole-
coumarin hybrids was designed (Fig.1), prepared and assessed
for their in vitro fungicidal activity against six phytopathogenic
fungi.
Coumarin and its analogues are important secondary
metabolites, which are broadly distributed in the roots, flowers
and fruits. Many plants can synthesize coumarins, such as
Calendula officinalis, Angelica dahurica and Zanthoxylum
schinifolium. In addition, some fungi (such as Armillariella
tabescens, Fomitopsis officinalis) and bacteria (such as
Streptomyces niveus, Escherichia coil) can also synthesize
coumarins [2]. Due to the unique chemical structure of
coumarins, their skeletons can interact with many receptors in
the organism noncovalent, they usually display a variety of
biological activities, including anti-depression, anti-oxidation,
anti-inflammatory, antibacterial, anti-tumor, anti-asthmatic, anti-
viral and anti-coagulant effects, and are effective ingredients of
many traditional Chinese medicines. Many coumarin-like natural
products such as osthole, umbelliferone, pre-caprolactone,
coralin, alizarin and sulphate have significant inhibitory effects
on plant pathogenic fungi [3-14].
Figure 1. Illustration of the design strategy for pyrrole-coumarin hybrids.
Results and Discussion
Chemistry The general synthetic route for the target coumarin-
pyrrole hybrids 6a-6y was illustrated in scheme 1. Using
substituted and unsubstituted ethyl acetoacetate 1 and phenol
derivatives 2 as starting materials, a series of 2-aminocoumarin
derivatives 5 were synthesized via three steps, including
Pechmann condensation, nitration and reduction reaction.
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing
Agricultural University, Nanjing 210095, China
E-mail: njzhangwh@126.com
Subsequently, intermediate
5
was reacted with 2,5-
dimethoxytetrahydrofuran in H2O in the presence of FeCl3 at 60
oC to form the desired hybrids (6a-6m, 6w-6y). The hybrids 6n-
6v were achieved by treatment of intermediate
5 with
Supporting information for this article is given via a link at the end of
the document.
acetonylacetone in HOAc at 60 oC. The structures of the
synthesized compounds were elucidated by HRMS and NMR
spectroscopy. In addition, compounds 6e were further
determined through X-ray diffraction crystallography (Fig. 2).
Pyrrole is an important framework structure in pharmaceutical
chemistry, which can react with many biomolecules through
hydrogen bond and π-π stacking interaction. This basic
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Structure-activity relationships. The antifungal results in
Table 2 showed that most of the coumarin-pyrrole hybrids
exhibited unsatisfied activities, but we still can summarize the
structure-activity relationships. Firstly, most of the synthesized
compounds exhibited better inhibition effects against Botrytis
cinerea and Rhizoctorzia solani than that of other tested fungi.
Secondly, the fungicidal activities of target compounds against
the tested phytopathogenic fungi could generally decrease when
introducing the alkyl or halogen group at the R1 position and no
substituents at the R5 position. The presence of a methyl
substituent at the R5 position, the corresponding compounds 6s
and 6v exhibited the similar regulation. Thirdly, the title
compounds bearing a OH group at R3 position, methyl group at
R4 position and H at R5 position, such as 6j and 6k, displayed
better inhibition effects against Botrytis cinerea, Gibberella zeae
and Rhizoctorzia solani than those bearing a methyl group at R3
position, a H at R4 and R5 position(6b and 6e).
Figure 2. X-ray structures of compounds 6e.
In vitro antifungal activity assessment. The six
phytopathogenic fungi Botrytis cinerea, Rhizoctorzia solani,
Alternaria solani, Gibberella zeae, Alternaria leaf spot and
Cucumber anthrax, which are stored in the Laboratory of Plant
Disease Control at Nanjing Agricultural University. The above
phytopathogenic fungi are selected to evaluate the fungicidal
effects of target compounds. Fungicidal effects of the coumarin-
pyrrole hybrids 6a-6y and the positive control (Boscalid and
Osthole) were tested at 50 μg/mL based on the mycelium growth
rate method, and the preliminary results were presented in Table
2(For intermediates 4 and 5, see Table 1S in supplementary
information). As shown in Table 2, most of the synthesized
compounds displayed a certain degree of activity against all the
tested fungi. Among them, compounds 6j, 6k, 6o, 6p and 6r
showed significant activity against Rhizoctorzia solani at 50.0
μg/mL, with the corresponding inhibition rates of 78%, 68%, 75%,
77% and 68%, which are better than or similar that of Osthole
(68%). In addition, compound 6j effectively inhibited the
mycelium growth of Botrytis cinerea and Cucumber anthrax, with
the inhibition rates of 59% and 53%, respectively, which are
better than that of Osthole (47% and 17%, respectively).
Crystal. The Single-crystal of 6e was prepared by
the emulsion solvent evaporation method
from
hexane:
trichloromethane=3:1(v/v). The Single-crystal X-ray diffraction
analysis of 6e was performed with a Bruker D8 QUEST
diffractometer with graphite-monochromated Mo-Ka radiation
(λ=0.71073 Å) at 296(2)K. Data reduction and absorption
corrections were carried out on the SAINT and SADABS
software packages, respectively. The structures were
determined by direct methods and refined by the full matrix
least-squares based on F2 using SHELXL-2018 programme
package. The non-hydrogen atoms were refined anisotropically.
All hydrogen atoms were placed at the calculated positions and
refined as riding on the parent atoms. The data collection,
structure refinement and crystallography are summarized in the
Supporting Information. The ellipsoid contour % probability
levels in the caption for the image of the X-ray structure was
30% (Fig 2).
Aiming to learn more about the fungicidal activities of the
synthesized compounds, we tested the corresponding EC50
values of compounds 6j, 6k, 6o, 6p and 6r against Rhizoctorzia
solani. As shown in Table 3, the EC50 values of the above
compounds reached 3.94, 7.75, 6.38, 6.25 and 7.67 μg/mL,
respectively, which are more potent than that of Boscalid (11.52
μg/mL) and Osthole (9.79 μg/mL).
Scheme 1. Synthesis of the coumarin-pyrrole hybrids. Reagents and
conditions: (a) 70% H2SO4, 0 oC(3a-3i); 98% H2SO4, 0 oC (3j-3m); (b) H2SO4,
KNO3, -10 oC; (c) Fe, HOAc, EtOH, H2O, rt (5a-5i); SnCl2, HCl, EtOH, reflux
(5j-5m); (d) 2,5-dimethoxytetrahydrofuran, FeCl3, H2O, 60oC (6a-6m, 6w-6y);
acetonylacetone, HOAc, 60oC (6n-6v)
Table 1. Structures and yields of 6-pyrrolecoumarins.
Yield
(%)
Compound
6a
R1
H
R2
H
R3
H
R4
H
R5
H
76
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6b
6c
6d
6e
6f
H
CH3
CF3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
71
59
53
87
59
85
Compound
Dose(μg/mL)
50
50
50
50
50
50
H
H
6a
6b
32
25
23
10
18
18
9
20
8
27
20
22
5
68
42
45
44
27
35
28
10
2
0
4
30
38
11
9
CH2Cl
CH3CH2CH2
CH3
H
6c
8
13
7
CH3
CH3CH2
6d
17
0
6g
CH3
6e
11
8
40
15
9
11
2
6f
7
6h
54
6g
0
8
4
6h
7
0
8
13
12
1
15
11
53
0
6i
6j
Cl
CH3
CH3
CH3
OH
OH
OH
H
H
H
H
H
41
43
44
28
6i
9
0
13
52
24
20
17
27
13
42
8
H
H
CH3
CH3
CH3
6j
59
42
27
25
38
34
50
30
32
9
16
17
0
78
68
50
56
42
75
77
38
68
20
72
37
42
40
69
59
92
68
6k
6l
CH3CH2CH2
CH3
6k
2
CH3CH2
6l
3
9
6m
6n
0
7
2
6m
56
0
22
9
51
15
19
19
15
6
6n
6o
6p
6q
6r
H
H
CH3
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
67
59
78
47
35
43
36
6o
0
H
CH3
CH3
CH3
CH3
CH3
CH3
6p
16
0
39
6
H
H
CF3
6q
CH2Cl
CH3CH2CH2
CH3
6r
3
5
6
H
6s
0
5
0
6s
6t
CH3
CH3CH2
6t
43
5
3
27
6
30
0
23
6
CH3
6u
0
6v
25
63
48
34
100
47
0
5
0
17
18
16
3
6u
22
6w
6x
2
30
36
13
18
45
20
11
11
93
15
0
6v
6w
6x
Cl
H
CH3
CH3CH2CH2
CH3
CH3
OH
OH
H
CH3
CH3
CH3
35
62
28
6y
0
CH3
CH3
Boscalidc
Ostholec
38
3
23
17
CH3CH2
[a] Average of three replicates. [b] BOT Botrytis cinerea, ALT Alternaria solani,
GIB Gibberella zeae, RHI Rhizoctorzia solani, ALS Alternaria leaf spot, CUC
Cucumber anthrax. [c] A commercial agricultural fungicides boscalid and
osthole were used for comparison of antifungal activities.
6y
74
Table 3. EC50 values of some target compounds against Rhizoctorzia solania.
Table 2. Antifungal activity of target compounds(inhibitory rate, %)a
Speciesb
BOT ALT GIB RHI ALS
95%
confidence
interval
Regression
equation
EC50 (μ
g/mL)
Compound
R
CUC
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22.4976-
26.2001
6a
Y=2.1302+2.0718x
0.9997
0.9863
0.9949
0.9557
0.9766
0.9897
0.9993
0.9906
0.9928
24.2783
3.9437
7.7521
6.3825
6.2457
7.6655
16.1358
11.5212
9.7850
The general procedure for the preparation of intermediates
5a-5i.
3.2149-
4.8376
The precursors 3 and 4 were prepared via literature methods
[34-35]. A mixture of precursor 4 (10.0 mmol) and iron power
(30.0 mmol, 3.0 equiv) in EtOH (20.0 mL), HOAc (20.0 mL), H2O
(10.0 mL) was reacted at room temperature, and the reaction
was monitored by TLC. After the reaction finished, the
precipitated solid was filtered, washed with ethyl acetate (50.0
mL), and the filtrate was extracted with ethyl acetate (3 × 50.0
mL). Using the saturated aqueous Na2CO3 to wash the
combined extracts until it reached pH 8.0, dried over with
Na2SO4 and filtrated, and the filtrate was concentrated in vacuo
to form the target compounds in 46%-97% yields.
6j
Y=4.1113+1.4914x
Y=4.2795+0.8101x
Y=3.5803+1.7636x
Y=4.2405+0.9547x
Y=3.6410+1.5364x
Y=3.7873+1.0041x
Y=4.3785+0.5855x
Y=4.2160+0.7915x
6.7126-
8.9406
6k
6o
3.9795-
10.2366
4.6584-
8.3739
6p
6.0046-
9.7859
6r
14.6206-
17.8080
The general procedure for the preparation of intermediates
5j-5m.
6t
A solution of precursor 4 (10.0 mmol) in EtOH (10.0 mL), HCl
(10.0 mL) was added SnCl2 (10.0 mmol), then refluxed for 0.5 h.
The mixture was cooled to -20 °C for 24 h after the reaction
finished, and the precipitated solid was filtered, washed with
saturated aqueous Na2CO3 (150.0 mL), and the solid was
dissolved into isopropanol (100.0 mL). The precipitated solid
was filtered, and the filtrate was concentrated in vacuo to
generate the title compounds in 71%-83% yields.
9.4778-
14.0052
Boscalidb
Ostholeb
8.2946-
11.5433
[a] Average of three replicates. [b] A commercial agricultural fungicides
boscalid and osthole were used for comparison of antifungal activities.
The general procedure for preparing target compounds 6a-
6m, 6w-6y.
Conclusions
A
mixture of precursor
5
(1.0 mmol) and 2,5-
In summary, aiming to develop novel structure coumarin
derivatives against plant fungi, we designed and synthesized a
novel series of coumarin derivatives bearing a pyrrole moiety.
The fungicidal activities of the target compounds against six
phytopathogenic fungi in vitro were evaluated. All hybrids
exhibited considerable activities against the tested fungi, among
them, compounds 6j, 6k, 6o, 6p and 6r showed remarkable
fungicidal activities against Rhizoctorzia solani, and possessed
the EC50 values of 3.94, 7.75, 6.38, 6.25, and 7.67 μg/ mL,
respectively, which are more potent than Boscalid (11.52 μg/mL)
and Osthole (9.79 μg/mL). The structure-activity relationship
may provide useful reference for the further development of
more efficient coumarin-based agricultural fungicides.
dimethoxytetrahydrofuran (1.2 mmol, 1.2 equiv), and fused
FeCl3･7H2O (5.0 mol%) in H2O (5.0 mL) was stirred at 60 °C for
24 h. After the reaction completed, the mixture was cooled to
room temperature, filtered and extracted with dichloromethane
(3 × 20.0 mL). The combined extracts were dried over with
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography
(petroleum ether:ethyl acetate=10:1 to 4:1, v/v) to obtain the title
compounds in 28%-87% yields (Table 1).
6-(1H-pyrrol-1-yl)-2H-chromen-2-one (6a) [36]: white solid; mp:
144.3-145.6 ℃; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 9.6 Hz,
1H), 7.54 (dd, J = 8.8, 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.36
(d, J = 8.9 Hz, 1H), 7.06 (t, J = 2.1 Hz, 2H), 6.47 (d, J = 9.6 Hz,
1H), 6.39 – 6.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.4,
151.6, 142.9, 137.3, 124.2, 119.5, 118.8, 118.1, 117.8, 111.1;
HRMS: (m/z) Anal. Calcd for C13H10NO2 [M + H]+, 212.0706;
Found, 212.0706.
Experimental Section
Chemistry. Melting points of the target compounds were carried
out on an uncorrected WRS-1B digital melting point apparatus
(Jingmi Science, China). Using CDCl3, Acetone-d6 and DMSO-d6
as a solvent and tetramethylsilane as an internal standard, a
Bruker 400 spectrometer (Bruker, Germany) was used for
characterizing the 1H-NMR and 13C-NMR spectra of title
compounds. Mass spectra were characterized on a TRACE
2000 spectrometer (Finnigan, America). X-Rays were carried out
at 296 K on a Bruker SMART APEX2 CCD area detector
diffractometer. All reagents and solvents were analytically pure
and were not pretreatment.
4,7-dimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one (6b): white
solid; mp: 145.5-146.9 ℃; 1H NMR (400 MHz, CDCl3) δ 7.46 (s,
1H), 7.20 (s, 1H), 6.78 (t, J = 2.1 Hz, 2H), 6.32 (t, J = 2.1 Hz,
2H), 6.24 (d, J = 1.0 Hz, 1H), 2.38 (d, J = 1.1 Hz, 3H), 2.25 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 152.2, 151.9, 139.1,
137.0, 122.5, 122.2, 118.7, 118.2, 114.9, 109.3, 18.5, 18.0;
HRMS: (m/z) Anal. Calcd for C15H14NO2 [M + H]+, 240.1019;
Found, 240.1019.
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7-methyl-6-(1H-pyrrol-1-yl)-4-(trifluoromethyl)-2H-chromen-2-one
(6c): yellow solid; mp: 168.7-170.3 ℃ ; 1H NMR (400 MHz,
CDCl3) δ 7.62 (s, 1H), 7.35 (s, 1H), 6.79 (t, J = 2.0 Hz, 3H), 6.36
(t, J = 2.1 Hz, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.6, 153.1, 141.2, 141.1 (q, J = 33.2 Hz), 138.0, 123.0 (q, J =
2.2 Hz), 122.3, 121.4 (q, J = 276.4 Hz), 119.5, 116.0 (q, J =
5.7Hz), 111.8, 109.8, 18.4; HRMS: (m/z) Anal. Calcd for
C15H11F3NO2 [M + H]+, 294.0736; Found, 294.0746.
118.2, 109.6, 18.2, 16.3; HRMS: (m/z) Anal. Calcd for
C15H13ClNO2 [M + H]+, 274.0629; Found, 274.0635.
7-hydroxy-4,8-dimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one
(6j): white solid; mp: 196.9-197.7 ℃; 1H NMR (400 MHz, CDCl3)
δ 7.37 (s, 1H), 6.85 (t, J = 2.1 Hz, 2H), 6.44 (t, J = 2.1 Hz, 2H),
5.98 (s, 1H), 2.52 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.3, 152.1, 150.2, 147.8, 125.6, 122.2, 120.1, 118.8,
114.0, 113.1, 111.4, 16.4, 8.9; HRMS: (m/z) Anal. Calcd for
C15H14NO3 [M + H]+, 256.0968; Found, 256.0949.
4-(chloromethyl)-7-methyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one
(6d): white solid; mp: 153.7-154.3 ℃; 1H NMR (400 MHz, CDCl3)
δ 7.54 (s, 1H), 7.30 (s, 1H), 6.78 (t, J = 2.0 Hz, 2H), 6.57 (s, 1H),
6.36 (t, J = 2.0 Hz, 2H), 4.61 (s, 2H), 2.28 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.2, 152.8, 149.2, 140.0, 137.5, 122.4, 122.2,
119.4, 116.0, 115.7, 109.7, 41.2, 18.3; HRMS: (m/z) Anal. Calcd
for C15H13ClNO2 [M + H]+, 274.0629; Found, 274.0628.
7-hydroxy-8-methyl-4-propyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-
1
one (6k): white solid; mp: 213.2-213.8 ℃; H NMR (400 MHz,
CDCl3) δ 7.37 (s, 1H), 6.85 (t, J = 2.0 Hz, 2H), 6.43 (t, J = 2.0 Hz,
2H), 6.17 (s, 1H), 5.98 (s, 1H), 2.66 (t, J = 7.5 Hz, 2H), 2.38 (s,
3H), 1.76 – 1.65 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 161.5, 156.2, 152.5, 152.0, 125.0, 122.2, 119.4,
114.0, 112.6, 111.7, 111.1, 33.9, 21.5, 14.0, 8.8; HRMS: (m/z)
Anal. Calcd for C17H18NO3 [M + H]+, 284.1281; Found, 284.1279.
7-methyl-4-propyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one
(6e):
1
white solid; mp: 130.3-130.8 ℃; H NMR (400 MHz, CDCl3) δ
7.50 (s, 1H), 6.78 (t, J = 2.1 Hz, 2H), 6.36 (t, J = 2.1 Hz, 2H),
6.29 (s, 1H), 2.74 – 2.66 (m, 2H), 2.25 (s, 3H), 1.78 – 1.67 (m,
3-ethyl-7-hydroxy-4,8-dimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-
2H), 1.04 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, one (6l): white solid; mp: 189.2-190.2 ℃; H NMR (400 MHz,
1
155.5, 152.5, 139.0, 137.0, 122.3, 119.0, 117.6, 113.7, 109.3,
33.5, 21.2, 18.0, 13.9; HRMS: (m/z) Anal. Calcd for C17H18NO2
[M + H]+, 268.1332; Found, 268.1333.
CDCl3) δ 7.33 (s, 1H), 6.84 (t, J = 2.1 Hz, 2H), 6.40 (t, J = 2.1 Hz,
2H), 6.12 (s, 1H), 2.66 (q, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.34 (s,
3H), 1.13 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9,
151.2, 150.7, 145.6, 125.8, 124.9, 122.3, 119.7, 114.0, 113.4,
110.8, 20.9, 14.7, 13.2, 8.7; HRMS: (m/z) Anal. Calcd for
C17H18NO3 [M + H]+, 284.1281; Found, 284.1281.
3,4,7-trimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one (6f): white
solid; mp: 182.2-183.3 ℃; 1H NMR (400 MHz, Acetone-d6) δ
7.60 (s, 1H), 7.29 (s, 1H), 6.89 (t, J = 2.1 Hz, 2H), 6.26 (t, J = 2.1
Hz, 2H), 2.46 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.9, 150.9, 145.5, 137.7, 137.0, 122.5, 122.4,
122.4, 119.0, 118.5, 109.3, 18.0, 15.2, 13.6; HRMS: (m/z) Anal.
Calcd for C16H16NO2 [M + H]+, 254.1176; Found, 254.1177.
7-hydroxy-6-methyl-8-(1H-pyrrol-1-yl)-2,3-
dihydrocyclopenta[c]chromen-4(1H)-one (6m): white solid; mp:
1
213.7-214.5 ℃; H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.84
(t, J = 1.9 Hz, 2H), 6.44 (t, J = 1.9 Hz, 2H), 5.72 (s, 1H), 3.01 (t,
J = 7.6 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.41 (s, 3H), 2.20 (dd, J
= 15.1, 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 160.4, 156.3,
152.9, 151.4, 125.7, 124.8, 122.2, 119.7, 113.8, 112.1, 111.2,
32.2, 30.6, 22.7, 9.0; HRMS: (m/z) Anal. Calcd for C17H16NO3 [M
+ H]+, 282.1125; Found, 282.1120.
3-ethyl-4,7-dimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one (6g):
1
white solid; mp: 170.1-170.3 ℃; H NMR (400 MHz, CDCl3) δ
7.47 (s, 1H), 7.19 (s, 1H), 6.77 (t, J = 2.0 Hz, 2H), 6.34 (t, J = 2.0
Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.15
(t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 151.0,
145.0, 137.7, 137.0, 128.2, 122.6, 122.3, 119.1, 118.4, 109.2,
21.1, 17.9, 14.6, 13.1; HRMS: (m/z) Anal. Calcd for C17H18NO2
[M + H]+, 268.1332; Found, 268.1335.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-7-hydroxy-8-methyl-4-propyl-2H-
1
chromen-2-one (6w): white solid; mp: 191.1-192.0 ℃; H NMR
(400 MHz, CDCl3) δ 7.28 (s, 1H), 6.19 (s, 1H), 6.00 (s, 2H), 5.71
(s, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.97 (s, 6H), 1.74 –
1.62 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.4, 156.3, 153.9, 153.2, 129.4, 121.8, 121.7, 113.9, 112.9,
7-methyl-8-(1H-pyrrol-1-yl)-2,3-dihydrocyclopenta[c]chromen-
1
4(1H)-one (6h): white solid; mp: 208.7-209.2 ℃; H NMR (400
MHz, CDCl3) δ 7.32 (s, 1H), 7.27 (s, 1H), 6.77 (t, J = 2.1 Hz, 2H), 111.7, 107.5, 34.1, 21.8, 14.1, 12.6, 8.9; HRMS: (m/z) Anal.
6.34 (t, J = 2.1 Hz, 2H), 1.78 – 1.67 (m, 2H), 2.93 (t, J = 7.5 Hz,
2H), 2.26 (s, 3H), 2.24 – 2.19 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.0, 155.6, 153.1, 138.1, 137.0, 128.2, 122.7, 122.4,
118.6, 117.2, 109.4, 32.1, 30.8, 22.6, 18.3; HRMS: (m/z) Anal.
Calcd for C17H16NO2 [M + H]+, 266.1176; Found, 266.1174.
Calcd for C19H22NO3 [M + H]+, 312.1594; Found, 312.1585.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-ethyl-7-hydroxy-4,8-dimethyl-
2H-chromen-2-one (6x): white solid; mp: 216.5-217.1 ℃; 1H
NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 5.98 (s, 2H), 5.61 (s, 1H),
2.68 (dd, J = 14.6, 7.2 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 1.97 (s,
6H), 1.15 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8,
152.9, 151.4, 145.6, 129.4, 125.8, 121.8, 121.6, 114.3, 113.1,
107.3, 21.0, 14.8, 13.2, 12.5, 8.8; HRMS: (m/z) Anal. Calcd for
C19H22NO3 [M + H]+, 312.1594; Found, 312.1588.
3-chloro-4,7-dimethyl-6-(1H-pyrrol-1-yl)-2H-chromen-2-one (6i):
1
white solid; mp: 221.7-222.4 ℃; H NMR (400 MHz, CDCl3) δ
7.50 (s, 1H), 7.26 (s, 1H), 6.78 (t, J = 2.0 Hz, 1H), 6.35 (t, J = 2.0
Hz, 2H), 2.54 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
156.9, 150.2, 147.3, 139.4, 137.8, 122.9, 122.3, 121.0, 118.9,
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8-(2,5-dimethyl-1H-pyrrol-1-yl)-7-hydroxy-6-methyl-2,3-
Acetone-d6) δ 7.66 (s, 1H), 7.36 (s, 1H), 6.29 (s, 1H), 5.84 (s,
2H), 2.89 – 2.84 (m, 2H), 1.98 (s, 3H), 1.89 (s, 6H), 1.80 – 1.70
(m, 2H), 1.04 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, Acetone-d6)
δ 160.5, 156.8, 154.2, 142.6, 135.3, 128.5, 125.9, 119.3, 118.8,
114.4, 106.7, 34.0, 22.5, 17.3, 14.1, 12.7; HRMS: (m/z) Anal.
Calcd for C19H22NO2 [M + H]+, 296.1645; Found, 296.1643.
dihydrocyclopenta[c]chromen-4(1H)-one (6y): white solid; mp:
1
172.2-173.1 ℃; H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 5.94
(s, 2H), 5.75 (s, 1H), 3.00 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.5 Hz,
3H), 2.40 (s, 3H), 2.25 – 2.15 (m, 2H), 1.96 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.4, 156.3, 153.4, 153.3, 129.3, 125.4,
121.9, 121.7, 113.5, 112.3, 107.3, 32.2, 30.5, 22.6, 12.5, 9.0;
HRMS: (m/z) Anal. Calcd for C19H20NO3 [M + H]+, 310.1438;
Found, 310.1436.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4,7-trimethyl-2H-chromen-2-
1
one (6s): white solid; mp: 184.0-184.5 ℃; H NMR (400 MHz,
Acetone-d6) δ 7.59 (s, 1H), 7.33 (s, 1H), 5.84 (s, 2H), 2.46 (s,
3H), 2.18 (s, 3H), 1.97 (s, 3H), 1.88 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 162.0, 151.6, 145.6, 140.5, 134.5, 128.5, 124.6, 122.4,
119.4, 118.5, 105.9, 17.5, 15.3, 13.6, 12.8; HRMS: (m/z) Anal.
Calcd for C18H20NO2 [M + H]+, 282.1489; Found, 282.1482.
The general procedure for preparing target compounds 6n-
6v.
To a solution of compound 5 (1.0 mmol) (1.1 mmol, 1.1 equiv) in
acetic acid (5.0 mL) was added substituted ethyl acetoacetates
(1.1 mmol, 1.1 equiv). After stirring at 60 °C for 12 h, the mixture
was poured into 40.0 mL ice water. The mixture was extracted
with dichloromethane (3 × 20.0 mL). The extracts were dried
over with Na2SO4 and the solvent was concentrated in vacuo.
The crude product was purified by silica gel column
chromatography (petroleum ether:ethyl acetate=10:1 to 4:1, v/v)
to give the title compounds in 22%-78% yields (Table 1).
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-ethyl-4,7-dimethyl-2H-chromen-
1
2-one (6t): white solid; mp: 146.8 -147.6 ℃; H NMR (400 MHz,
Acetone-d6) δ 7.59 (s, 1H), 7.31 (s, 1H), 5.83 (s, 2H), 2.68 (q, J
= 7.5 Hz, 2H), 2.49 (s, 3H), 1.97 (s, 3H), 1.88 (s, 6H), 1.12 (t, J =
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 151.7, 145.1,
140.5, 134.5, 128.4, 128.2, 124.7, 119.5, 118.4, 105.9, 21.2,
17.4, 14.7, 13.1, 12.7; HRMS: (m/z) Anal. Calcd for C19H22NO2
[M + H]+, 296.1645; Found, 296.1644.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-2H-chromen-2-one (6n): white
1
solid; mp: 171.0-171.6 ℃; H NMR (400 MHz, DMSO-d6) δ 8.08
(d, J = 9.6 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 2H), 6.59 (d, J = 9.6 Hz, 8-(2,5-dimethyl-1H-pyrrol-1-yl)-7-methyl-2,3-
1H), 5.82 (s, 2H), 1.98 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
160.4, 153.2, 142.9, 135.5, 131.8, 129.0, 127.2, 119.3, 117.9,
117.8, 106.4, 13.1; HRMS: (m/z) Anal. Calcd for C15H14NO2 [M +
H]+, 240.1019; Found, 240.1017.
dihydrocyclopenta[c]chromen-4(1H)-one (6u): white solid; mp:
200.6-201.3 ℃; H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.29
1
(s, 1H), 5.90 (s, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.4 Hz,
2H), 2.28 – 2.17 (m, 2H), 2.01 (s, 3H), 1.91 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 159.8, 155.5, 153.4, 140.8, 134.3, 128.1,
127.9, 124.6, 118.3, 117.3, 105.7, 31.9, 30.6, 22.4, 17.5, 12.5;
HRMS: (m/z) Anal. Calcd for C19H20NO2 [M + H]+, 294.1489;
Found, 294.1489.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-4,7-dimethyl-2H-chromen-2-one
(6o): white solid; mp: 144.8-145.7 ℃ ; 1H NMR (400 MHz,
Acetone-d6) δ 7.61 (s, 1H), 7.36 (s, 1H), 6.33 (s, 1H), 5.84 (s,
2H), 2.51 (d, J = 1.2 Hz, 3H), 1.99 (s, 3H), 1.89 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.7, 153.1, 152.0, 142.2, 134.7, 128.4,
124.8, 118.9, 118.8, 115.1, 106.1, 18.8, 17.6, 12.8; HRMS: (m/z)
Anal. Calcd for C17H18NO2 [M + H]+, 268.1332; Found, 268.1336.
3-chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4,7-dimethyl-2H-
1
chromen-2-one (6v): white solid; mp: 174.5-175.7 ℃; H NMR
(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.32 (s, 1H), 5.95 (s, 2H), 2.55
(s, 3H), 2.03 (s, 3H), 1.92 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
156.9, 150.9, 147.4, 142.2, 135.3, 128.3, 125.1, 121.0, 118.8,
118.6, 106.2, 17.6, 16.3, 12.7; HRMS: (m/z) Anal. Calcd for
C17H17ClNO2 [M + H]+, 302.0942; Found, 302.0948.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-7-methyl-4-(trifluoromethyl)-2H-
1
chromen-2-one (6p): yellow solid; mp: 120.5-121.9 ℃; H NMR
(400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.37 (s, 1H), 7.11 (s, 1H),
5.86 (s, 2H), 2.50 (s, 3H), 1.97 (s, 3H), 1.85 (s, 6H); 13C NMR
(100 MHz, DMSO-d6) δ 158.1, 153.2, 143.2, 138.5 (q, J = 32.6
Hz), 134.5, 127.3, 124.2, 121.5 (q, J = 276.6 Hz), 119.3, 117.34
(q, J = 4.3 Hz), 111.7, 106.1, 16.9, 12.2; HRMS: (m/z) Anal.
Calcd for C17H15F3NO2 [M + H]+, 322.1049; Found, 322.1049.
Biological assay. The in vitro fungicidal activity of the target
compounds was evaluated based on the mycelium growth rate
method against six phytopathogenic fungi Botrytis cinerea,
Alternaria solani, Rhizoctorzia solani, Alternaria leaf spot,
Gibberella zeae and Cucumber anthrax. After retrieval from the
storage tube, the strains were incubated in Potato Dextrose
Agar at 25℃ for one week to get new mycelia for the antifungal
assay. All the target compounds were dissolved in N, N-
dimethylformamide (5.0 mL) to generate a 100 ppm stock
solution. The tested solutions were prepared by diluting the
above solution.
4-(chloromethyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-7-methyl-2H-
1
chromen-2-one (6q): white solid; mp: 132.7-133.3 ℃; H NMR
(400 MHz, CDCl3) δ 7.53 (s, 1H), 7.34 (s, 1H), 6.56 (s, 1H), 5.94
(s, 2H), 4.62 (s, 2H), 2.04 (s, 3H), 1.93 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 160.1, 153.3, 149.3, 142.8, 134.8, 128.3, 124.5,
119.1, 115.9, 115.7, 106.1, 41.1, 17.6, 12.7; HRMS: (m/z) Anal.
Calcd for C17H17ClNO2 [M + H]+, 302.0942; Found, 302.0945.
6-(2,5-dimethyl-1H-pyrrol-1-yl)-7-methyl-4-propyl-2H-chromen-2-
one (6r): white solid; mp: 146.5-147.4 ℃; H NMR (400 MHz,
Acknowledgements
1
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Shuguang Zhang, Xin Tan, Chaogen
Liang and Weihua Zhang**
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Design, Synthesis, and Antifungal
Evaluation of Novel Coumarin-Pyrrole
Hybrids
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