Novel fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety: Design, synthesis, crystal structure and biological evaluation

Article abstract of DOI:10.3390/molecules26020372

A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by¹H-NMR,¹³C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 μg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC₅₀ values of 5.75 μg/mL, which was obviously better than Osthole (33.20 μg/mL) and Azoxystrobin (64.95 μg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC₅₀ values of 28.96 μg/mL, which was better than Osthole (67.18 μg/mL) and equivalent to Azoxystrobin (21.34 μg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.

Full text of DOI:10.3390/molecules26020372

molecules
Article
Novel Fluorinated 7-Hydroxycoumarin Derivatives Containing
an Oxime Ether Moiety: Design, Synthesis, Crystal Structure
and Biological Evaluation
Qing-Qing Wang, Shu-Guang Zhang, Jian Jiao, Peng Dai and Wei-Hua Zhang *
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University,
Nanjing 210095, China; 2017211001@njau.edu.cn (Q.-Q.W.); shuguangz@njau.edu.cn (S.-G.Z.);
2018211005@njau.edu.cn (J.J.); 2018211004@njau.edu.cn (P.D.)
*
Correspondence: zhangweihua@njau.edu.cn; Tel.: +86-025-8439-5255
Abstract: A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety
have been designed, synthesized and evaluated for their antifungal activity. All the target compounds
were determined by H-NMR, 13C-NMR, FTIR and HR-MS spectra. The single-crystal structures
1
of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal
activities against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Gibberella zeae (G. zeae),
Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata)
were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds
displayed the promising antifungal activities against the above tested fungi. Strikingly, the target
compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 µg/mL,
with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive
control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
fungicide candidate against B. cinerea with the EC50 values of 5.75
than Osthole (33.20 g/mL) and Azoxystrobin (64.95 g/mL). Meanwhile, the compound 5f showed
remarkable antifungal activities against R. solani with the EC50 values of 28.96 g/mL, which was
better than Osthole (67.18 g/mL) and equivalent to Azoxystrobin (21.34 g/mL). The results provide
µg/mL, which was obviously better
µ
µ
Citation: Wang, Q.-Q.; Zhang, S.-G.;
Jiao, J.; Dai, P.; Zhang, W.-H. Novel
Fluorinated 7-Hydroxycoumarin
Derivatives Containing an Oxime
Ether Moiety: Design, Synthesis,
Crystal Structure and Biological
Evaluation. Molecules 2021, 26, 372.
https://doi.org/10.3390/molecules
µ
µ
µ
a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good
antifungal activity.
Keywords: fluorinated 7-hydroxycoumarin; oxime ether derivatives; synthesis; crystal structure;
antifungal activity
2
6020372
Received: 8 December 2020
Accepted: 28 December 2020
Published: 12 January 2021
1
. Introduction
The rapid growth of the world population will be a great challenge to obtain the
enough food produced by limited arable lands [ ]. In addition, the phytopathogenic fungi
have emerged as the destructive parasites that results inevitably in large reductions in the
yields and quality of agricultural products [ ], thus seriously hindering the sustainable
development of agriculture [ ]. Under these circumstances, the rational application of
agricultural fungicides has been identified as a most effective way to protect crops and to
elevate agriculture yields [ ]. However, fungicide-resistance problems have appeared in
1
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional clai-
ms in published maps and institutio-
nal affiliations.
2
3,4
5
recent years due to the unreasonable utilization of existing antifungal agents for a long
time, which leads to a series of side-effects including environmental pollution and food
safety threats [6,7]. Therefore, it is of great significance to develop novel high-efficiency
Copyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
and broad-spectrum fungicides.
Coumarin derivatives, the typical natural products containing benzopyrone struc-
tures, have widely served as secondary metabolites in plants [
ural coumarins exhibit the noticeable bioactivities including antitumor, anticoagulant,
anti-inflammatory, antioxidant, antifungal and antiviral effects [10 12]. In view of this,
8,9]. Interestingly, the nat-
–
4
.0/).
Molecules 2021, 26, 372. https://doi.org/10.3390/molecules26020372
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 372
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coumarin derivatives have been widely applied to agricultural and medicinal chemistries.
The corresponding synthesis methods and pharmacological activities were also well re-
ported, such as Osthole, Coumoxystrobin and Warfarin (Figure 1). Employing Osthole
as a lead structure, our group synthesized a series of coumarin derivatives against the
phytopathogenic fungi effectively (Figure 2), including coumarin [8,7-e][1,3]oxazine [13],
furo[3,2-c]coumarin [14], pyrano[3,2-c]chromene-2,5-dione [14], coumarin-3-carboxamide
derivatives [15], coumarin ring-opening derivatives [16] and pyrrole/pyrazole-substituted
coumarin derivatives [17]. Due to the pharmacological diversity of coumarin derivatives,
it has been described as one of “privileged scaffolds” [18,19]. Obviously, the diversified
derivatization of the coumarin parent ring is an important strategy for the development of
highly effective compounds, making coumarin a candidate for the development of more
efficient compounds.
Figure 1. Design strategy of target 7-hydroxycoumarin oxime ether structures.
Figure 2. Our group’s previous work on coumarin derivatives.

Molecules 2021, 26, 372
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As an active group, oxime ether has been extensively utilized in the modification
of agrochemical-related compounds [20–23], which displays a ground-breaking prospect,
such as Cymoxanil, Orysastrobin and Fenpyroximate (Figure 1). Specifically, Cymoxanil
marketed in the mid-1970s is a successful oxime ether fungicide [24]. It is reported that fluo-
rine atom can effectively enhance the stability and biological activity of compounds in many
ways owing to its small atomic radius and strong electronegativity, which thereby improves
the hydrophobicity and liposolubility of compounds [25–28]. In this regard, fluorinated
coumarin derivatives have been considered as a promising strategy in the application of
medicinal and agricultural chemistry [29]. To the best of our knowledge, there were few
researches regarding the investigation of the antifungal activity of fluorinated coumarin
oxime ether derivatives.
2. Results and Discussion
2.1. Construction for Target Compounds
Three kinds of fluorinated 7-hydroxycoumarins 1a, 1b and 1c were synthesized as the
parent compounds via Pechmann condensation reaction, as depicted in Scheme 1. Based on
the parent structure 7-hydroxycoumarins, formyl group (-CHO) was then introduced
at 8-position via Duff reaction using formylating agent hexamethylenetetramine [30,31].
The Duff reaction was the key step in the reaction route. In the literature procedure,
the molar ratio of 7-hydroxycoumarin and hexamethylenetetramine was 1:2, and the
reaction proceeded at reflux for 1.5 h. Then aqueous hydrochloric acid was added to the
mentioned-above reaction solution to perform acid hydrolysis. Subsequently, the mixture
◦
was cooled to 70 C and stirred for additional 45 min.
◦
Scheme 1. Synthetic route for the target compounds. Reagents and conditions. (i): Sulfuric acid, 0 C, 4 h; (ii): Trifluoroacetic
◦
acid, Hexamethylenetetramine, reflux, 1.5 h; 30% Hydrochloric acid, 70 C, 45 min; (iii): NH OH-HCl, 28% Sodium
2
◦
◦
◦
◦
hydroxide, 0 C, 30 min; 20 C, 1 h; (iv): R Br, 60 C, 6 h; (v): 36% Hydrochloric acid, Ethyl alcohol, 50 C, 5 h; (vi):
4
Ethyl alcohol, reflux, 1 h.
To synthesize a series of fluorinated 7-hydroxycoumarin oxime ether derivatives,
seven O-substituted hydroxylamines 3d–3j were synthesized according to the reported
methods with the use of cheap raw materials (Scheme 1) [32]. Compounds 3a (hydroxy-
lamine), 3b (N-methylhydroxyamine) and 3c (N-ethylhydroxylamine) in the form of the
hydrochloride salt were commercially available.
Finally, the thirty target compounds 4a
–
4j,
5a
–5j and 6a–6j were easily synthesized by
the reaction between compounds 2a 2c and 3a
–
–
3j under a mild condition for 1 h, as shown

Molecules 2021, 26, 372
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in Scheme 1. The reaction progress was monitored using TLC (Vethyl acetate/Vpetroleum ether
=
1:2). The desired target compounds were obtained by column chromatography from
a mixed solution of ethyl acetate/petroleum ether (Vpetroleum ether:Vethyl acetate = 1:20),
with yields of 17% to 83%. To the best of our knowledge, there have been no report on the
production of oxime ether derivatives of 7-hydroxycoumarin at 8-position [33
tures of all the synthetic coumarin derivatives were confirmed by H-NMR, C-NMR,
,
34]. The struc-
1
13
FTIR and HRMS spectral data. The data of target compound 5h was analyzed as a repre-
1
sentative example. The H-NMR spectrum of compound 5h showed two singlets at 11.53
and 8.88 ppm, which meant the molecular structure of compound 5h had a -OH group and
-
CH=N- group. The doublet at 4.82 ppm and the triplet at 2.59 ppm were attributed to the
presence of propynyl. In the 13C-NMR spectrum, a signal peak at 157.46 ppm indicated that
target compound 5h had a carbonyl group. The quadruple peaks at 141.04 and 113.18 ppm
were assigned to -CF group. Meanwhile, three singles at 77.65, 76.40 and 62.81 ppm
3
confirmed the existence of propynyl group in the structure of compound 5h. In the FTIR
−
1
spectrum of compound 5h, the absorption peak of alkynyl group appears at 2131.6 cm
−
1
and the strong peak at 1736.3 cm indicated the presence of carbonyl group. In the HRMS
spectrum of compounds 5h, the value of [M + H] ion absorption signal was 346.0088,
which was consistent with the calculated value (346.0086) for C H ClF NO [M + H] .
+
+
14
7
3
4
2
.2. Single Crystal Structures of Compounds 4e, 4h, 5h and 6c
To further understand the actual structure of synthesized compounds, the structures
of compound 4e 4h 5h and 6c were determined as representative examples by X-ray
,
,
diffraction analysis. The tested single crystals were crystallized from the methanol contain-
ing the title compounds under room temperature until the size of the crystals was enough
to test. The corresponding crystal structure diagram and crystal packing diagram were
presented in Figure 3.
Figure 3.
(A–D) The crystal structural diagram of 4e, 4h, 5h and 6c. (E–H) The corresponding crystal packing diagram of
4
e, 4h, 5h and 6c.

Molecules 2021, 26, 372
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As shown in Figure 3D, C9-O4···N1 was an important hydrogen bond that combined
with 7-hydroxy-2H-chromen-2-one and oxime ether fragment which construct the main
scaffold of 6c. From this figure we could also see that these four compounds had trans
structure, which might be owing to the low energy and stability of the trans structure.
As shown in Figure 3H, the intermolecular π-π conjugation force and hydrogen bonds
between neighboring molecules were primary force for establishing the three-dimensional
structure of compound 6c. The crystallographic data of compound 6c was deposited at
the Cambridge Crystallographic Data Centre with an assigned number of CCDC 2043279,
the crystallographic data were listed in Table 1. The CCDC numbers of 4e
, 4h and 5h were
2
043278, 2043275 and 2043276, respectively. The corresponding crystallographic data were
listed in Tables S1–S3 (Supplementary Materials).
Table 1. Crystal data of title compound 6c.
Crystal Data
CCDC Number
2043279
α = 90
◦
C H ClFNO
13
11
4
◦
FW = 299.68
Triclinic, P21
a = 18.195 (2) Å
b = 10.5938(7) Å
c = 6.8711(9) Å
F (000) = 616
β = 94.286 (10)
◦
γ = 90
3
V = 1320.7(2) Å
Z = 4
−
1
µ = 0.314 mm
3
Crystal size (mm ): 0.21 × 0.12 × 0.08
Data Collection
400 observed reflections with I > 2σ(I)
579 measured reflections
329 independent reflections
3
Radiation (Å): MoKα(λ = 0.71073)
Rint = 0.062
7
◦
◦
2
θm = 2.3 , θmax = 25.03
in
Refinement
1
84 parameters
S = 0.919
R[F > 2σ(F )] = 0.0486
2
2
2
327 reflections
2.3. In Vitro Antifungal Activity of Target Compounds
The in vitro antifungal activity was evaluated by a mycelium growth rate method and
the corresponding results were listed in Table 2. Osthole and Azoxystrobin were used as
the positive control fungicides throughout the experiment. Noteworthy, the antifungal
activities of target compounds against B. cinerea and R. solani were generally better than
that of A. solani, G. zeae, C. orbiculare and A. alternata. Especially, the target compounds
5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 µg/mL with
the corresponding inhibition rates of 90.1 and 85.0%, which were superior to the positive
control fungicides Osthole (83.6%) and Azoxystrobin (46.5%). Meanwhile, the intermediate
compounds 2a
activities against R. solani at 100
4.6, 71.7, 64.6, 72.6 and 70.1%, which were equivalent to the positive control fungicides
,
2b and target compounds 4f
, 5a, 5f and 6f showed remarkable antifungal
µg/mL with the corresponding inhibition rates of 86.2,
6
Osthole (82.7%) and Azoxystrobin (72.3%). Unfortunately, the partial target compounds
were not sensitive to A. solani and G. zeae.

Molecules 2021, 26, 372
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Table 2. Antifungal effects of target compounds at 100 µg/mL.
Inhibition (%)
Compound
B. cinerea
A. solani
G. zeae
R. solani
C. orbiculare
A. alternata
2
a
50.0 a
77.5
10.0
60.8
51.7
10.0
15.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
23.3
10.0
10.0
10.0
10.0
33.0
10.0
10.0
10.0
10.0
29.8
10.0
10.0
10.0
10.0
20.5
10.0
20.6
10.0
10.0
40.0
30.5
50.0
57.8
10.0
33.3
10.0
10.0
10.0
10.0
10.0
11.4
10.0
10.0
10.0
37.5
10.0
10.0
10.0
10.0
58.7
10.0
10.0
10.0
10.0
26.0
17.6
10.2
10.0
10.0
13.3
17.1
32.9
10.0
36.2
56.7
71.7
86.2
64.6
35.1
38.5
10.0
12.3
10.0
10.0
71.7
10.0
10.0
47.2
10.0
64.6
16.9
16.9
24.6
10.0
72.6
23.8
10.0
28.3
11.2
49.1
36.4
10.0
10.0
27.3
70.1
10.0
53.8
41.7
28.3
82.7
72.3
45.3
56.3
10.0
53.1
10.0
14.1
12.5
10.0
29.7
23.0
10.0
14.1
10.0
55.6
17.2
14.1
10.0
14.1
46.9
12.3
10.0
10.0
10.0
51.1
19.6
16.0
10.7
19.6
32.8
13.7
58.5
20.3
10.0
16.7
94.5
39.7
64.1
18.3
27.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
46.5
10.0
10.0
10.0
10.0
10.8
10.0
10.0
10.0
10.0
51.5
17.6
10.0
10.0
14.7
10.0
10.0
10.9
10.0
10.0
22.4
61.1
2
b
b
2
4
c
a
37.5
12.5
18.8
13.5
18.8
10.0
10.0
15.4
10.0
10.0
62.5
21.3
12.5
18.8
10.0
90.1
10.8
10.0
10.0
27.7
58.9
29.8
29.8
38.6
29.8
10.0
13.8
85.0
20.6
39.2
83.6
76.5
4
b
4
c
4
4
d
e
4
f
4
g
4
h
4
4
i
j
5
a
5
b
5
c
5
5
d
e
5
f
5
g
5
h
5
5
i
j
6
a
6
b
6
c
6
6
d
e
6
f
6
g
6
h
6
6
i
j
Osthole
Azoxystrobin
a
Average value of three replications; b 10.0 indicated the data below 10% inhibitory ratio.
To better investigate the inhibitory performance of target compounds against phy-
topathogenic fungi, the compounds that exhibited the inhibition rates exceeding 60% at
00 µg/mL were further tested for their EC50 values. Osthole and Azoxystrobin were
served as the positive control. As exhibited in Table 3, the EC50 values of target compounds
and 6h were notably as low as 5.75 g/mL and 13.75 g/mL, proving that they were
much more effective than Osthole (33.20 g/mL) and Azoxystrobin (64.95 g/mL) against
B. cinerea. Meanwhile, as listed in Table 4, the EC50 values of all the detected compounds
were lower than Osthole (67.18 g/mL) against R. solani. Specifically, the EC50 values of
the target compounds 2b 4f 5a 5f and 6f were 17.72, 7.48, 33.10, 28.96 and 28.70 g/mL,
1
5f
µ
µ
µ
µ
µ
,
,
,
µ
respectively. The corresponding in vitro antifungal performances of compound 5f, Osthole
and Azoxystrobin against B. cinerea were presented in Figure 4, which visually exhibited
the corresponding in vitro inhibition of B. cinerea.

Molecules 2021, 26, 372
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Table 3. EC50 values determination of some target compounds against B. cinerea.
Compound
Toxic Regression
R
EC50 (µg/mL)
EC50 (µM)
2
5
5
b
a
f
y = 2.02x + 1.59
y = 1.30x + 3.27
y = 0.35x + 4.74
y = 0.93x + 3.93
y = 1.31x + 3.00
y = 1.06x + 3.10
0.99
0.99
0.98
0.98
0.99
0.99
47.73
13.25
5.75
13.75
33.20
64.95
163.12
43.07
16.54
44.40
148.02
161.01
6
h
Osthole
Azoxystrobin
The EC50 value was the average value of three replications.
Table 4. EC50 values determination of some target compounds against R. solani.
Compound
Toxic Regression
R
EC50 (µg/mL)
EC50 (µM)
2
4
5
5
6
b
f
a
f
f
y = 1.50x + 3.12
y = 0.53x+4.53
y = 1.26x + 3.07
y = 0.45x + 4.34
y = 1.19x + 3.26
y = 0.95x + 3.25
y = 0.86x + 3.80
0.99
0.91
0.99
0.96
0.99
0.99
0.99
17.72
7.48
33.10
28.96
28.70
67.18
21.34
60.56
23.88
107.60
83.30
92.08
299.52
52.90
Osthole
Azoxystrobin
The EC50 value was the average value of three replications.
Figure 4. In vitro inhibition of mycelial growth of B. cinerea by compound 5f, Osthole and Azoxystrobin.
2.4. Structure-Activity Relationships
The bioassay results in Tables 2–4 indicated that the antifungal activities of most syn-
thesized 7-hydroxycoumarin oxime derivatives were certain poor, which made it difficult
to extract a clear structure-activity relationship analysis. Nevertheless, some broad conclu-
sions could still be drawn. First, the most target compounds were noticeably more efficient
against B. cinerea and R. solani than A. solani, G. zeae, C. orbiculare and A. alternata. Second,
compounds 4a, 5a, 5f, 6a and 6h displayed the preferable activity than the positive control
Osthole against C. orbiculare. Meanwhile, compound 6a also possessed more effective
activity against A. alternata than Osthole. Third, the antifungal activities generally could be
improved if R was Cl and R was H atom, allyl or propargyl, highlighted by 4f, 5a, 5f, 6a,
3
4

Molecules 2021, 26, 372
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6f
and 6h, all of which displayed a broad spectrum of antifungal activity against B. cinerea
and R. solani. Forth, we still could find that the intermediate compounds 2a and 2b showed
a broad antifungal spectrum, which could be served as the active candidates for structure
optimization.
3. Experimental Section
3.1. Chemicals and Instruments
Resorcin, 4-chlororesorcinol, ethyl 4,4,4-trifluoroacetoacetate and ethyl
-fluoroacetoacetate were obtained from Sinopharm Chemical Reagent Co. Ltd., Shanghai,
2
China. Hydroxylamine hydrochloride, hexamethylenetetramine and trifluoroacetic acid
were purchased from Aladdin Reagent Co. Ltd., Shanghai, China. All other chemicals were
commercially available and used without further purification. The progress of reactions
and the purity of products were monitored by TLC using silica gel GF/UV 254. The melting
points of coumarin compounds were measured on an X-4 apparatus (uncorrected). Fourier
transform infrared (FTIR) spectra were recorded on a Bruker Tensor 27 spectrometer (Bil-
1
13
lerica, MA, USA), and all samples were prepared as KBr plates. H-NMR and C-NMR
spectra were detected on a Bruker Avance 400 MHz spectrometer with TMS as an internal
standard. HR-MS (ESI) spectra were operated using a Thermo Exactive spectrometer
(Waltham, MA, USA). X-rays were measured at 296 K on a Bruker SMART APEX2 CCD
area detector diffractometer.
3.2. Chemistry
3.2.1. General Procedure for the Synthesis of the Intermediates 2
Fluorinated 7-hydroxycoumarins were synthesized through reported procedures [25].
Trifluoroacetic acid (38 mL) containing 7-hydroxycoumarin (8.7 mmol) and
hexamethylenetetramine (43.5 mmol) was stirred at reflux for 1.5 h. Then, aqueous hy-
drochloric acid (30%, 75 mL) was added into the mentioned-above reaction solution.
◦
After stirring 45 min under 70 C, the resulting mixture was quenched with ice wa-
ter and extracted with ethyl acetate. The obtained organic layer was neutralized by
sodium bicarbonate solution, washed with water, dried by anhydrous sodium sulfate
and filtered. After concentrating under vacuum, the residue containing an intermedi-
ate
2
was purified by the column chromatography using ethyl acetate/petroleum ether
(
Vethyl acetate/Vpetroleum ether = 1:2) as eluent.
◦
-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one (1a): pink solid; mp 186.8–187.8 C; yield 54%;
7
1
H-NMR (400 MHz, DMSO-d6)
δ 10.97 (s, 1H), 7.53 (s, 1H), 6.95–6.86 (m, 1H), 6.81 (d,
−
1
J = 2.3 Hz, 1H), 6.78–6.68 (m, 1H); IR (KBr)
ν
(cm ) 3419, 3096, 1703, 1600, 1409, 1280, 1127,
866, 842.
◦
6
-chloro-7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one (1b): pink solid; mp 184.9–185.0 C;
1
yield 34%; H-NMR (400 MHz, DMSO-d )
δ 11.85 (s, 1H), 7.57 (s, 1H), 7.02 (s, 1H), 6.88
6
−
1
(
s, 1H); IR (KBr) ν (cm ) 3595, 3414, 3096, 1694, 1598, 1400, 1280, 1247, 1145, 866, 836.
◦
-chloro-3-fluoro-7-hydroxy-4-methyl-2H-chromen-2-one (1c): pink solid; mp 235.6–236.1 C;
6
1
yield 41%; H-NMR (400 MHz, Acetone-d ) δ 9.73 (s, 1H), 7.69 (s, 1H), 6.92 (s, 1H), 2.41 (s,
6
−
1
3
H); IR (KBr) ν (cm ) 3071, 1695, 1603, 1384, 1302, 1137, 858, 750.
7
1
-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde (2a): white solid; mp 129.0–
◦
29.7 C; yield 44%; H-NMR (400 MHz, DMSO-d ) δ 12.05 (s, 1H), 10.39 (s, 1H), 7.76 (d,
6
1
13
J = 8.9 Hz, 1H), 7.01 (d, J = 9.1 Hz, 1H), 6.89 (s, 1H); C-NMR (101 MHz, DMSO-d6)
δ
1
1
90.31, 164.78, 158.01, 156.43, 139.83 (q, J = 32.5 Hz), 132.15, 121.93 (d, J = 275.6 Hz), 115.29,
−
1
13.66 (q, J = 4.0Hz), 110.31, 105.64; IR (KBr)
ν (cm ) 3097, 2920, 1745, 1405, 1280; HR-MS
+
(
ESI): m/z calcd. for C H F O ([M + H] ) 259.0140, found 259.0774.
11
5
3
4
6
-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde (2b): yellow solid;
◦
1
mp 164.9–165.7 C; yield 75%; H-NMR (400 MHz, DMSO-d )
δ
11.79 (s, 1H), 10.41 (s,
6
1
H), 7.83 (s, 1H), 7.07 (s, 1H); 13C-NMR (101 MHz, DMSO-d6)
δ
192.26, 159.99, 157.41,

Molecules 2021, 26, 372
9 of 16
1
1
55.59, 138.86 (q, J = 32.5 Hz), 130.75, 121.71 (d, J = 275.3 Hz), 118.83, 115.20 (q, J = 4.7 Hz),
−
1
10.64, 106.21; IR (KBr)
ν
(cm ) 3094, 2920, 1740, 1427, 1394, 1296; HR-MS (ESI): m/z calcd.
+
for C H ClF O ([M + H] ) 292.9750, found 293.0403.
11
4
3
4
6
-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (2c): yellow solid;
◦
1
mp 145.5–146.4 C; yield 48%; H-NMR (400 MHz, DMSO-d )
δ
12.32 (s, 1H), 10.42 (s,
192.57 (s), 158.46 (s), 153.56 (d,
J = 30.8 Hz), 150.88 (d, J = 2.3 Hz), 142.59 (d, J = 245.2 Hz), 132.79 (d, J = 5.7 Hz), 132.00
6
1
H), 8.20 (s, 1H), 2.39 (s, 3H); 13C-NMR (101 MHz, DMSO)
δ
−
1
(d, J = 13.9 Hz), 118.69 (s), 112.39 (s), 109.95 (s), 10.62 (d, J = 3.2 Hz). IR (KBr)
ν
(cm
)
+
3
2
095, 3031, 2952, 1723, 1613, 1302; HR-MS (ESI): m/z calcd. for C H ClFO ([M + Na] )
11 6 4
78.9939, found 279.0235.
.2.2. General Procedure for Synthesis of O-substituted hydroxylamines 3d–3j
3
The water (5 mL) mixing hydroxylamine hydrochloride (0.10 mol), ethyl acetate
◦
(
0.18 mol) and 28% sodium hydroxide aqueous solution (25 mL) were stirred at 0 C.
The resultant mixture was then stirred at room temperature for 1 h. After that, halogenated
◦
hydrocarbon (0.11 mol) was dropwise added and the reaction was stirred at 60 C for
further 6 h. Subsequently, the reaction mixture was extracted with petroleum ether and
ethyl acetate. The organic layer was combined and dried by anhydrous sodium sulfate,
then the solvent was removed under reduced pressure and oily product was obtained.
The obtained oily product was dissolved in ethyl alcohol, and 36% aqueous hydrochloric
◦
acid was added to the solution. The mixture was stirred at 50 C for 4 h. Finally, the reaction
was neutralized to pH 7.0 by saturated sodium bicarbonate aqueous solution, and then
extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate,
and concentrated under vacuum to obtain the title compounds 3d–3j.
3
.2.3. General Procedure for Synthesis of Compounds 4a–6j
A mixture of intermediate compound (3.8 mmol) and O-substituted hydroxylamines
intermediate compound (4.56 mmol) in ethyl alcohol (10 mL) was stirred at reflux for
. After the reaction was completed, the solvent was removed under reduced pressure,
2
3
1
h
and purified by the column chromatography (Vpetroleum ether:Vethyl acetate = 1:20) to produce
title compounds 4a–6j.
(
E)-7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde oxime (4a): white solid;
◦
1
mp 236.2–237.2 C; yield 60%; H-NMR (400 MHz, DMSO-d )
δ
12.05 (s, 1H), 11.46 (s, 1H),
6
8
.55 (t, J = 25.2 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 5.7 Hz,
13
1
H); C-NMR (101 MHz, DMSO-d6)
δ 161.03, 158.39, 153.25, 143.68, 140.10 (q, J = 32.0 Hz),
−
1
126.70, 122.10 (d, J = 275.6 Hz), 114.43, 113.18 (q, J = 6.3 Hz), 106.51, 105.92; IR (KBr)
ν
(cm
)
3
2
494, 3105, 3009, 2915, 1730, 1280; HR-MS (ESI): m/z calcd. for C H NF O ([M + H]+
)
11
6
3
4
74.0249, found 274.0490.
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehydeO-methyloxime (4b): white
◦
1
solid; mp 201.4–202.3 C, yield 34%; H-NMR (400 MHz, DMSO-d )
1
δ 11.14 (s, 1H), 8.50 (s,
6
13
H), 8.00–7.35 (m, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.90 (s, 1H), 3.99 (s, 3H); C-NMR (101 MHz,
CDCl3)
δ 157.58, 157.23, 151.75, 144.79, 141.04 (q, J = 33.7 Hz), 126.87, 122.59, 119.68 (d,
−
1
J = 32.2 Hz), 113.09 (q, J = 7.1 Hz), 106.22 (d, J = 9.4 Hz), 63.33, 29.72; IR (KBr)
ν
(cm
)
3
494, 3105, 3009, 2956, 1738, 1284; HR-MS (ESI): m/z calcd. for C H NF O ([M + H]+
)
12
8
3
4
288.0405, found 288.0654.
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-ethyl oxime (4c): yellow
◦
1
solid; mp 199.8–199.9 C, yield 30%; H-NMR (400 MHz, CDCl )
1
2
(
(
δ
11.15 (s, 1H), 8.65 (s,
H), 7.62 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 9.1 Hz, 1H), 6.64 (s, 1H), 1.82 (dd, J = 14.2, 7.0 Hz,
H), 1.02 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
159.38, 157.79, 153.55, 144.87
q, J = 22.2 Hz), 142.07, 123.89, 118.40, 112.67 (q, J =5.9 Hz), 105.91 (d, J = 49.6 Hz), 71.09
3
δ
−
1
d, J = 12.3 Hz), 70.23, 14.57, 14.23; IR (KBr)
ν
(cm ) 3494, 3100, 2891, 1744, 1407, 1288;
+
HR-MS (ESI): m/z calcd. for C H NF O ([M + H] ) 302.0562, found 302.0535.
13
10
3
4

Molecules 2021, 26, 372
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(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-propyl oxime (4d): white
◦
1
solid; mp 169.9–170.0 C, yield 34%; H-NMR (400 MHz, CDCl )
δ
11.15 (s, 1H), 8.85 (s, 1H),
3
7
.62 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 6.64 (s, 1H), 4.20 (t, J = 6.6 Hz, 2H), 1.79 (dd,
13
J = 14.2, 7.0 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); C-NMR (101 MHz, CDCl3)
δ
161.81, 158.32,
1
1
53.48, 144.91, 141.85 (q, J = 33.0 Hz), 127.23, 122.85, 120.11, 114.75, 111.79 (q, J = 5.5 Hz),
−
1
05.94, 105.48, 22.11, 10.25. IR (KBr)
ν
(cm ) 3092, 2983, 2941, 2884, 1741, 1286; HR-MS
+
(
ESI): m/z calcd. for C H NF O ([M + H] ) 316.0718, found 316.0689.
14
12
3
4
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-butyl oxime (4e): white
◦
1
solid; mp 149.0–149.1 C; yield 51%; H-NMR (400 MHz, DMSO-d )
1
1
δ
δ
11.10 (s, 1H), 8.49 (s,
H), 7.61 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.87 (s, 1H), 4.21 (t, J = 6.6 Hz, 2H),
.79–1.59 (m, 2H), 1.54–1.29 (m, 2H), 0.93 (t, J = 7.4 Hz,3H); 13C-NMR (101 MHz, DMSO-d6)
159.98, 159.12, 153.26, 140.16 (q, J = 31.8 Hz), 133.41, 123.60, 123.50, 120.86, 118.08, 114.11,
6
−
1
1
1
13.46 (q, J = 5.2 Hz), 109.84, 107.02, 69.45, 8.49; IR (KBr)
ν
(cm ) 3103, 2941, 2873, 1743,
+
397, 1277; HR-MS (ESI): m/z calcd. for C H NF O ([M + H] ) 330.0875, found 330.1160.
15
14
3
4
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-allyl oxime (4f): white
◦
1
solid; mp 159.9–160.5 C; yield 76%; H-NMR (500 MHz, CDCl )
δ
11.03 (s), 11.03 (s),
3
8
6
.86 (s), 7.70–7.68 (m), 7.60 (dd, J = 9.1, 1.5 Hz), 7.60 (dd, J = 9.1, 1.5 Hz), 6.96 (d, J = 9.1 Hz),
1
3
.62 (s), 6.06–5.97 (m), 5.42–5.36 (m), 5.34–5.30 (m), 4.69 (dd, J = 6.0, 0.8 Hz). C-NMR
161.82 (s), 158.24 (s), 153.59 (s), 145.40 (s), 141.84 (q, J = 32.6 Hz), 132.83
s), 129.85 (d, J = 208.9 Hz), 127.42 (d, J = 2.4 Hz), 119.50 (s), 114.80 (s), 111.84 (q, J = 5.8 Hz),
(101 MHz, CDCl3) δ
(
−
1
1
05.95 (s), 105.36 (s), 76.09 (s). FTIR (KBr)
ν
(cm ) 3450.6, 3092.1, 1736.2, 12292.2; HR-MS
+
(
ESI): m/z calcd. for C H F NO ([M + H] ) 314.0635, found 314.0633.
14
10
3
4
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-(3-methylbut-2-en-1-yl)
◦
1
oxime (4g): white solid; mp 165.9–166.4 C; yield 61%; H-NMR (600 MHz, CDCl )
δ
11.16
3
(
5
s, 1H), 8.82 (s, 1H), 7.60 (dd, J = 9.1, 1.8 Hz, 1H), 6.97 (d, J = 9.1 Hz, 1H), 6.62 (s, 1H),
1
3
.50–5.44 (m, 1H), 4.71 (d, J = 7.3 Hz, 2H), 1.82 (s, 3H), 1.79 (d, J = 0.7 Hz, 3H). C-NMR
161.87 (s), 158.28 (s), 153.54 (s), 145.02 (s), 141.84 (q, J = 32.8 Hz),
40.23 (s), 127.23 (d, J = 2.3 Hz), 121.52 (d, J = 275.7 Hz), 118.81 (s), 114.75 (s), 111.81 (q,
(151 MHz, CDCl3) δ
1
−
1
J = 5.8 Hz), 105.93 (s), 105.58 (s), 71.65 (s), 25.86 (s), 18.16 (s). FTIR (KBr)
3
ν
(cm ) 3476.1,
+
104.2, 1753.1, 1294, 1278.7; HR-MS (ESI): m/z calcd. for C H F NO ([M + H] ) 342.0948,
16
14
3
4
found 342.0945.
(
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-prop-2-yn-1-yl oxime
◦
4h): white solid; mp 189.9–190.2 C; yield 56%; H-NMR (600 MHz, CDCl ) δ 10.86 (s,
3
1
1
H), 8.90 (s, 1H), 7.65 (dd, J = 9.1, 1.8 Hz, 1H), 7.01 (d, J = 9.1 Hz, 1H), 6.64 (s, 1H), 4.81 (d,
J = 2.4 Hz, 2H), 2.57 (t, J = 2.4 Hz, 1H). 13C-NMR (151 MHz, CDCl3)
δ 161.85 (s), 158.15 (s),
1
1
ν
53.80 (s), 146.57 (s), 141.84 (q, J = 32.8 Hz), 127.85 (d, J = 2.4 Hz), 121.47 (q, J = 275.6 Hz),
14.91 (s), 111.95 (q, J = 5.8 Hz), 106.03 (s), 105.09 (s), 78.00 (s), 76.01 (s), 62.57 (s). FTIR (KBr)
−
1
(cm ) 3476.6, 3110.8, 2962.9, 1737.4, 1401.5; HR-MS (ESI): m/z calcd. for C H F NO
14
8
3
4
+
(
[M + H] ) 312.0478, found 312.0473.
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-benzyl oxime (4i): white
◦
1
solid; mp 169.5–170.4 C; yield 75%; H-NMR (600 MHz, CDCl )
δ
10.93 (s, 1H), 8.89 (s,
3
1
6
H), 7.60 (dd, J = 9.1, 1.7 Hz, 1H), 7.41 (s, 1H), 7.40 (d, J = 2.2 Hz, 2H), 7.38–7.34 (m, 1H),
.95 (d, J = 9.1 Hz, 1H), 6.62 (s, 1H), 5.23 (s, 2H). 13C-NMR (151 MHz, CDCl3)
δ 161.79 (s),
158.20 (s), 153.60 (s), 145.76 (s), 141.82 (q, J = 32.9 Hz), 136.14 (s), 128.73 (s), 128.59 (s), 128.57
(
1
s), 127.45 (d, J = 2.3 Hz), 121.48 (q, J = 275.5 Hz), 114.77 (s), 111.85 (q, J = 5.7 Hz), 105.95 (s),
−
1
05.35 (s), 77.30 (s). FTIR (KBr)
ν
(cm ) 3494, 3105, 3009, 2915, 1730, 1280; HR-MS (ESI):
+
m/z calcd. for C H F NO ([M + H] ) 364.0791, found 364.0795.
18
12
3
4
(
E)-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-(4-fluorobenzyl) oxime
◦
1
(
4j): white solid; mp 175.7–176.2 C; yield 74%; H-NMR (600 MHz, CDCl )
δ
10.88 (s,
H), 8.88 (s, 1H), 7.61 (dd, J = 9.1, 1.8 Hz, 1H), 7.40–7.38 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H),
.96 (d, J = 9.0 Hz, 1H), 6.62 (s, 1H), 5.19 (s, 2H). 13C-NMR (151 MHz, CDCl3)
162.88 (d,
J = 247.3 Hz), 161.77 (s), 158.18 (s), 153.63 (s), 145.98 (s), 141.83 (q, J = 32.8 Hz), 131.98 (d,
3
1
6
δ

Molecules 2021, 26, 372
11 of 16
J = 3.3 Hz), 130.46 (d, J = 8.3 Hz), 127.57 (d, J = 2.3 Hz), 121.47 (q, J = 275.6 Hz), 115.71 (d,
J = 21.6 Hz), 114.78 (s), 111.89 (q, J = 5.7 Hz), 106.00 (s), 105.27 (s), 76.49 (s). FTIR (KBr)
ν
−
cm ) 3476.9, 3105.7, 1752.2, 1293.5, 1277.7; HR-MS (ESI): m/z calcd. for C H F NO
18 11 4 4
1
(
+
(
[M + H] ) 382.0697, found 382.0694.
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde oxime (5a): yellow
◦
1
solid; mp 121.5–122.0 C; yield 70%; H-NMR (400 MHz, DMSO-d )
(
1
(
(
δ
12.47 (s, 1H), 12.21
s, 1H), 8.60 (s, 1H), 7.65 (s, 1H), 7.04 (s, 1H); 13C-NMR (101 MHz, DMSO-d6)
157.67,
56.31, 151.54, 143.97, 139.03 (q, J = 32.9 Hz), 125.35, 121.80 (d, J = 275.8 Hz), 117.96, 114.92
6
δ
−
+
1
q, J = 5.7 Hz), 107.18, 106.40; IR (KBr) ν (cm ) 3435, 3086, 3006, 2879, 1725, 1279; HR-MS
ESI): m/z calcd. for C H ClF O ([M + H] ) 307.9859, found 307.9824.
11
4
3
4
(
(
1
1
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-methyl oxime
◦
1
5b): white solid; mp 203.8–204.5 C; yield 55%; H-NMR (400 MHz, DMSO-d )
δ
11.47 (s,
157.58,
57.23, 151.75, 144.79, 141.04 (q, J = 33.7 Hz), 126.87, 122.59, 119.68 (d, J = 32.2 Hz), 113.09 (q,
6
H), 8.62 (s, 1H), 7.70 (s, 1H), 7.05 (s, 1H), 4.06 (s, 3H); 13C-NMR (101 MHz, CDCl3)
δ
−
1
J = 6.0 Hz), 106.22 (d, J = 9.4 Hz), 63.33, 29.72; IR (KBr)
1
ν
(cm ) 3434, 3085, 2918, 1725, 1399,
+
279; HR-MS (ESI): m/z calcd. for C H ClF NO ([M + Na] ) 322.0016, found 321.9968.
12
7
3
4
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-ethyl oxime (5c):
◦
1
white solid; mp 194.7–194.8 C; yield 46%; H-NMR (400 MHz, DMSO-d )
δ
11.53 (s, 1H),
6
8
.62 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 4.34 (dd, J = 14.0, 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H);
13
C-NMR (101 MHz, CDCl3)
δ 157.57, 157.22, 151.71, 144.57, 141.19, 140.86 (q, J = 32.0 Hz),
−
1
126.71, 119.46, 113.07 (q, J = 5.7 Hz), 106.39, 106.23, 71.40, 14.20; IR (KBr)
ν
(cm ) 3209, 3086,
+
2
901, 1731, 1400, 1278; HR-MS (ESI): m/z calcd. for C H ClF NO ([M + H] ) 336.0172,
13
9
3
4
found 336.0123.
(
(
1
2
1
2
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-propyl oxime
◦
1
5d): white solid; mp 179.9–180.9 C; yield 40%; H-NMR (400 MHz, DMSO-d )
δ
11.54 (s,
H), 8.63 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 4.25 (t, J = 6.6 Hz, 2H), 1.71 (dt, J = 14.1, 7.0 Hz,
H), 0.96 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
157.59, 157.21, 151.69, 144.48,
41.63 (q, J = 32.0 Hz), 126.66, 122.60, 119.86, 119.46, 113.05 (q, J = 5.6 Hz), 106.41, 106.23,
6
δ
−
1
2.08, 10.20; IR (KBr)
ν
(cm ) 3208, 3083, 2963, 1730, 1399, 1290; HR-MS (ESI): m/z calcd.
+
for C H ClF NO ([M + H] ) 350.0329, found 350.0637.
14
11
3
4
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-butyl oxime (5e):
◦
1
white solid; mp 164.9–165.6 C; yield 42%; H-NMR (400 MHz, DMSO-d ) δ 11.54 (s, 1H),
6
8
.62 (s, 1H), 7.67 (s, 1H), 7.05 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 1.75-1.64 (m, 2H), 1.41 (dq,
J = 14.7, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C-NMR (151 MHz, CDCl3)
δ
157.60 (s), 157.26
(s), 151.73 (s), 144.48 (s), 141.08 (q, J = 33.2 Hz), 126.69 (d, J = 2.4 Hz), 121.25 (q, J = 275.8 Hz),
1
19.49 (s), 113.06 (q, J = 5.7 Hz), 106.45 (s), 106.25 (s), 75.67 (s), 30.78 (s), 18.99 (s), 13.80 (s).
−
(cm ) 3082, 2966, 2936, 1744, 1290; HR-MS (ESI): m/z calcd. for C H ClF NO
15 13 3 4
1
IR (KBr)
ν
+
(
[M + H] ) 364.0485, found 364.0815.
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-allyl oxime (5f):
◦
1
white solid; mp 169.5–169.9 C; yield 83%; H-NMR (400 MHz, CDCl )
δ
11.73 (s, 1H),
3
8
.85 (s, 1H), 7.72 (d, J = 1.5 Hz, 1H), 6.69 (s, 1H), 6.04 (m, J = 16.5, 10.4, 6.1 Hz, 1H), 5.44
1
3
(
(
1
dd, J = 17.2, 1.4 Hz, 1H), 5.38 (dd, J = 10.4, 1.1 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H). C-NMR
101 MHz, CDCl3) 157.55 (s), 157.21 (s), 151.77 (s), 144.95 (s), 142.39–139.57 (m), 132.50 (s),
26.83 (d, J = 2.6 Hz), 122.58 (s), 120.00 (s), 119.50 (s), 113.08 (q, J = 5.6 Hz), 106.28 (s), 106.23
δ
−
1
(s), 76.38 (s). FTIR (KBr)
ν (cm ) 3570.1, 1744.7, 1640.7, 1402.0; HR-MS (ESI): m/z calcd.
+
for C H ClF NO ([M + H] ) 348.0245, found 348.0247.
14
9
3
4
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-(3-methylbut-2-
◦
1
en-1-yl) oxime (5g): white solid; mp 163.4–164.2 C; yield 72%; H-NMR (600 MHz, CDCl )
δ
3
1
2
1
1.84 (s, 1H), 8.80 (s, 1H), 7.70 (s, 1H), 6.67 (s, 1H), 5.47 (t, J = 7.8 Hz, 1H), 4.73 (d, J = 7.3 Hz
H), 1.82 (s, 3H), 1.79 (s, 3H). 13C-NMR (151 MHz, CDCl3)
157.61 (s), 157.31 (s), 151.74 (s),
44.62 (s), 141.06 (q, J = 33.1 Hz), 140.63 (s), 126.67 (d, J = 2.3 Hz), 121.26 (d, J = 275.6 Hz),
,
δ

Molecules 2021, 26, 372
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1
19.48 (s), 118.53 (s), 113.04 (q, J = 5.7 Hz), 106.51 (s), 106.21 (s), 71.97 (s), 25.87 (s), 18.21
−
1
(s). FTIR (KBr)
ν
(cm ) 3476.6, 3476.6, 3414.2, 1744.5, 1288.6; HR-MS (ESI): m/z calcd.
4
+
for C H ClF NO ([M + H] ) 376.0558, found 376.0556.
16
13
3
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-prop-2-yn-1-yl
◦
1
oxime (5h): white solid; mp 179.9–180.4 C; yield 54%; H-NMR (600 MHz, CDCl )
δ 11.53
3
(
s, 1H), 8.88 (s, 1H), 7.75 (d, J = 1.4 Hz, 1H), 6.69 (s, 1H), 4.82 (d, J = 2.4 Hz, 2H), 2.59 (t,
J = 2.4 Hz, 1H). 13C-NMR (151 MHz, CDCl3)
δ
157.46 (s), 157.28 (s), 151.99 (s), 146.13 (s),
1
41.04 (q, J = 33.2 Hz), 127.29 (d, J = 2.4 Hz), 121.21 (d, J = 275.6 Hz), 119.68 (s), 113.18
−
1
(q, J = 5.7 Hz), 106.33 (s), 106.04 (s), 77.65 (s), 76.40 (s), 62.81 (s). FTIR (KBr)
ν
(cm
552.7, 3464.2, 3091.2, 2131.6, 1736.3, 1286.8; HR-MS (ESI): m/z calcd. for C H ClF NO
4
)
3
14
7
3
+
(
[M + H] ) 346.0088, found 346.0086.
(
(
1
1
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-benzyl oxime
◦
1
5i): white solid; mp 185.4–185.9 C; yield 56%; H-NMR (600 MHz, CDCl )
δ
11.60 (s,
H), 8.87 (s, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.41 (s, 2H), 7.41 (s, 2H), 7.38 (dd, J = 8.2, 4.3 Hz,
H), 6.67 (s, 1H), 5.24 (s, 2H). 13C-NMR (151 MHz, CDCl3)
157.52 (s), 157.23 (s), 151.80
3
δ
(s), 145.39 (s), 141.02 (q, J = 33.3 Hz), 135.80 (s), 128.81 (s), 128.73 (s), 128.59 (s), 126.90 (d,
J = 2.4 Hz), 121.21 (q, J = 275.8 Hz), 119.50 (s), 113.08 (q, J = 5.7 Hz), 106.29 (s), 106.24 (s),
−
1
7
7.61 (s). FTIR (KBr)
ν
(cm ) 3452.2, 3085.8, 1753.1, 1401.7, 1287.7; HR-MS (ESI): m/z calcd.
+
for C H ClF NO ([M + H] ) 398.0401, found 398.0397.
18
11
3
4
(
E)-6-chloro-7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehyde O-(4-fluorobenzyl)
◦
1
oxime (5j): white solid; mp 200.7-201.2 C; yield 71%; H-NMR (600 MHz, CDCl )
(
1
(
1
(
1
δ
11.54
s, 1H), 8.86 (s, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.10 (t, J = 8.7 Hz, 2H), 6.67 (s,
H), 5.20 (s, 2H). 13C-NMR (151 MHz, CDCl3)
162.88 (d, J = 247.3 Hz), 161.77 (s), 158.18
s), 153.63 (s), 145.98 (s), 141.83 (q, J = 32.8 Hz), 131.98 (d, J = 3.3 Hz), 130.46 (d, J = 8.3 Hz),
27.57 (d, J = 2.3 Hz), 121.47 (q, J = 275.6 Hz), 115.71 (d, J = 21.6 Hz), 114.78 (s), 111.89
3
δ
−
1
q, J = 5.7 Hz), 106.00 (s), 105.27 (s), 76.49 (s). FTIR (KBr)
ν
(cm ) 3476.7, 3414.7, 3085.4,
+
752.9, 1401.5, 1212.2; HR-MS (ESI): m/z calcd. for C H ClF NO ([M + H] ) 416.0307,
18
10
4
4
found 416.0304.
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime (6a): white
◦
1
solid; mp 240.1–241.6 C; yield 24%; H-NMR (400 MHz, DMSO-d )
(
δ
12.35 (s, 1H), 11.82
6
s, 1H), 8.58 (s, 1H), 7.91 (s, 1H), 2.37 (d, J = 2.4 Hz, 3H); 1 C-NMR (101 MHz, CDCl3)
3
δ
155.15 (d, J = 2.4 Hz), 153.76 (d, J = 30.5 Hz), 147.23, 144.96, 143.87, 141.38, 130.73 (d,
J = 13.6 Hz), 126.29 (d, J = 6.0 Hz), 119.15, 112.16, 105.73, 63.24, 10.34 (d, J = 3.5 Hz); IR (KBr)
−
1
ν
(cm ) 3381.78, 3077.75, 2921.54, 2850.53, 1703.49, 1320.36; HR-MS (ESI): m/z calcd.
+
for C H ClFNO ([M + Na] ) 294.0048, found 294.0133.
1
1
7
4
(
(
(
(
(
1
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-methyl oxime
◦
1
6b): white solid; mp 184.9–186.2 C; yield 33%; H-NMR (400 MHz, CDCl )
s, 1H), 8.82 (s, 1H), 7.64–7.54 (m, 1H), 4.08 (s, 3H), 2.40 (d, J = 2.7 Hz, 3H); C-NMR
δ 11.47
3
1
3
101 MHz, CDCl3)
δ 155.15 (d, J = 2.4 Hz), 153.76 (d, J = 30.5 Hz), 147.23, 144.96, 142.62
d, J = 250.0 Hz), 130.73 (d, J = 13.6 Hz), 126.29 (d, J = 6.0 Hz), 119.15, 112.16, 105.73, 63.24,
−
1
0.34 (d, J = 3.5 Hz); IR (KBr)
ν
(cm ) 3489.32, 2955.37, 2923.50, 1738.95, 1306.48; HR-MS
+
(
ESI): m/z calcd. for C H ClFNO ([M + Na] ) 308.0204, found 308.0311.
12
9
4
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-ethyl oxime (6c):
◦
1
white solid; mp 163.9–164.1 C; yield 36%; H-NMR (400 MHz, CDCl )
δ
11.60 (s, 1H),
3
8
3
.84 (s, 1H), 7.58 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.40 (d, J = 2.8 Hz, 3H), 1.40 (t, J = 7.1 Hz
,
13
H); C-NMR (101 MHz, CDCl3)
δ 155.13(d, J = 2.4 Hz), 154.62 (d, J = 30.1 Hz), 147.21,
1
1
2
44.76, 141.75 (d, J = 250.0 Hz), 130.64 (d, J = 13.5 Hz), 126.14 (d, J = 6.0 Hz), 119.10,
−
1
12.14, 105.97, 71.25, 14.19, 10.32 (d, J = 3.5 Hz); IR (KBr)
ν
(cm ) 3489.52, 2981.09, 2956.24,
+
923.25, 1748.64, 1288.04; HR-MS (ESI): m/z calcd. for C H ClFNO ([M + Na] ) 322.0361,
13
11
4
found 322.0466.

Molecules 2021, 26, 372
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(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-propyl oxime (6d):
◦
1
yellow solid; mp 136.8–139.2 C; yield 27%; H-NMR (400 MHz, CDCl )
δ
11.59 (s, 1H),
3
8
.84 (s, 1H), 7.57 (s, 1H), 4.22 (t, J = 6.6 Hz, 2H), 2.40 (d, J = 2.7 Hz, 3H), 1.79 (dt, J = 14.1, 7.0
13
Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); C-NMR (101 MHz, CDCl3)
δ 155.19 (d, J = 2.3 Hz), 153.96
(
1
2
d, J = 4.4 Hz), 153.68, 147.24 (d, J = 2.5 Hz), 144.74, 143.87, 130.79, 126.13 (d, J = 6.0 Hz),
−
1
19.13, 112.17, 106.04, 22.09, 10.35 (d, J = 3.4 Hz), 10.21; IR (KBr) ν (cm ) 3460.10, 3069.21,
+
969.96, 1731.93, 1285.02; HR-MS (ESI): m/z calcd. for C H ClFNO ([M + Na] ) 336.0517,
14 13 4
found 336.0629.
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-butyl oxime (6e):
◦
1
yellow solid; mp 117.2–118.7 C; yield 21%; H-NMR (400 MHz, CDCl )
8
2
δ
11.61 (s, 1H),
.84 (s, 1H), 7.58 (s, 1H), 4.26 (t, J = 6.6 Hz, 2H), 2.40 (d, J = 2.6 Hz, 3H), 1.80–1.71 (m,
H), 1.46 (dd, J = 15.0, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
3
δ
155.14 (d, J = 2.2 Hz), 153.79 (d, J = 30.4 Hz), 147.20 (d, J = 2.4 Hz), 144.65, 141.37, 130.72 (d,
J = 13.8 Hz), 126.10 (d, J = 6.0 Hz), 119.09, 112.15, 105.99, 75.52, 30.76, 18.98, 13.81, 10.34 (d,
−
1
J = 3.6 Hz); IR (KBr)
ν
(cm ) 3496.26, 2955.49, 2937.11, 1748.95, 1288.56; HR-MS (ESI): m/z
4
+
calcd. for C H ClFNO ([M + Na] ) 350.0674, found 350.0816.
15
15
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-allyl oxime (6f):
◦
1
white solid; mp 120.2–120.7 C; yield 76%; H-NMR (400 MHz, CDCl )
δ
11.40 (s, 1H), 8.81
3
(
s, 1H), 7.55 (s, 1H), 6.03 (m, J = 16.5, 10.4, 6.0 Hz, 1H), 5.43 (dd, J = 17.2, 1.4 Hz, 1H), 5.37 (dd,
13
J = 10.4, 1.1 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 2.39 (d, J = 2.9 Hz, 3H). C-NMR (126 MHz, )
155.22 (d, J = 2.8 Hz), 153.86 (d, J = 30.6 Hz), 147.33 (d, J = 2.6 Hz), 145.21 (s), 142.68 (d,
J = 249.9 Hz), 132.71 (s), 130.83 (d, J = 13.8 Hz), 126.37 (d, J = 6.2 Hz), 119.93 (s), 119.22 (s),
12.22 (d, J = 2.8 Hz), 105.93 (d, J = 1.5 Hz), 76.36 (s), 10.43 (d, J = 3.7 Hz). FTIR (KBr)
δ
1
(
(
ν
−
cm ) 3470.7, 3415.1, 1753.4, 1377.7, 1267.7; HR-MS (ESI): m/z calcd. for C H ClFNO
14 11 4
1
+
[M + H] ) 312.0433, found 312.0433.
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-(3-methylbut-2-
◦
1
en-1-yl) oxime (6g): white solid; mp 135.7–136.6 C; yield 55%; H-NMR (600 MHz, CDCl )
3
δ
11.52 (s, 1H), 8.79 (s, 1H), 7.54 (s, 1H), 5.48–5.45 (m, 1H), 4.71 (d, J = 7.3 Hz, 2H), 2.37
d, J = 2.9 Hz, 3H), 1.81 (s, 3H), 1.78 (s, 3H). 13C-NMR (151 MHz, CDCl3)
155.24 (d,
J = 2.3 Hz), 153.80 (d, J = 30.5 Hz), 147.27 (d, J = 2.3 Hz), 144.84 (s), 142.00 (d, J = 56.4 Hz),
(
δ
1
40.38 (s), 130.68 (d, J = 13.7 Hz), 126.12 (d, J = 6.0 Hz), 119.12 (s), 118.66 (s), 112.11 (d,
−
1
J = 2.6 Hz), 106.11 (s), 71.86 (s), 25.86 (s), 18.20 (s), 10.33 (d, J = 3.4 Hz). FTIR (KBr)
ν
(cm
)
3
494, 3092.8, 2982.8, 1764.6, 1265.2, 1123.6; HR-MS (ESI): m/z calcd. for C H ClFNO
16 15 4
+
(
[M + H] ) 340.0746, found 340.0749.
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-prop-2-yn-1-yl
◦
1
oxime (6h): white solid; mp 157.2–158.0 C; yield 67%; H-NMR (600 MHz, CDCl )
δ 11.15
3
(
s, 1H), 8.79 (s, 1H), 7.51 (s, 1H), 4.74 (d, J = 2.4 Hz, 2H), 2.51 (t, J = 2.4 Hz, 1H), 2.31 (d,
J = 2.9 Hz, 3H). 13C-NMR (151 MHz, CDCl3)
δ 154.21 (d, J = 2.3 Hz), 152.70 (d, J = 30.7 Hz),
146.48 (d, J = 2.3 Hz), 145.35 (s), 141.65 (d, J = 250.3 Hz), 129.67 (d, J = 13.7 Hz), 125.73 (d,
J = 6.0 Hz), 118.30 (s), 111.22 (d, J = 2.5 Hz), 104.61 (s), 76.76 (s), 75.22 (s), 61.69 (s), 9.34 (d,
−
1
J = 3.4 Hz). FTIR (KBr)
ν
(cm ) 3476.0, 2923.2, 1734.8, 1261.9; HR-MS (ESI): m/z calcd.
+
for C H ClFNO ([M + H] ) 310.0277, found 310.0279.
14
9
4
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-benzyl oxime (6i):
◦
1
white solid; mp 176.8–177.5 C; yield 70%; H-NMR (600 MHz, CDCl )
δ 11.29 (s, 1H),
3
8
.86 (s, 1H), 7.53 (s, 1H), 7.41 (s, 2H), 7.40 (s, 2H), 7.37–7.35 (m, 1H), 5.23 (s, 2H), 2.36 (d,
J = 2.9 Hz, 3H). 13C-NMR (151 MHz, CDCl3)
δ 155.21 (d, J = 2.3 Hz), 153.78 (d, J = 30.6 Hz),
1
1
47.35 (d, J = 2.2 Hz), 145.67 (s), 142.64 (d, J = 250.2 Hz), 135.97 (s), 130.68 (d, J = 13.7 Hz),
28.77 (s), 128.65 (s), 128.55 (s), 126.36 (d, J = 5.9 Hz), 119.17 (s), 112.16 (d, J = 2.5 Hz), 105.92
−
1
(
(
s), 77.48 (s), 10.33 (d, J = 3.4 Hz). FTIR (KBr) ν (cm ) 3446.2, 1751.0, 1123.0, 1120.3; HR-MS
ESI): m/z calcd. for C H ClFNO ([M + H] ) 362.0590, found 362.0590.
+
18
13
4
(
E)-6-chloro-3-fluoro-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde O-(4-fluorobenzyl)
◦
1
oxime (6j): white solid; mp 197.1–197.7 C; yield 75%; H-NMR (400 MHz, CDCl )
δ
3

Molecules 2021, 26, 372
14 of 16
1
(
1.26 (s, 1H), 8.87 (s, 1H), 7.57 (s, 1H), 7.43–7.39 (m, 2H), 7.11 (t, J = 8.7 Hz, 2H), 5.21
s, 2H), 2.39 (d, J = 2.9 Hz, 3H). 13C-NMR (151 MHz, CDCl3)
δ
161.58 (d, J = 31.9 Hz),
1
55.18 (d, J = 2.3 Hz), 153.77 (d, J = 30.6 Hz), 147.37 (d, J = 2.2 Hz), 145.87 (s), 142.65 (d,
J = 250.1 Hz), 133.35 (d, J = 39.3 Hz), 131.82 (d, J = 3.2 Hz), 130.48 (d, J = 8.3 Hz), 130.32 (d,
J = 8.1 Hz), 126.48 (d, J = 6.0 Hz), 119.19 (s), 112.21 (d, J = 2.5 Hz), 105.84 (s), 75.61 (s), 10.34
−
1
(
d, J = 3.4 Hz). FTIR (KBr)
ν
(cm ) 3548.1, 3414.9, 1736.7, 1614.7, 1266.7; HR-MS (ESI): m/z
+
calcd. for C H ClF NO ([M + H] ) 380.0496, found 380.0495.
18
12
2
4
3.3. Single Crystal X-Ray Diffraction Analysis
Fluorinated 7-hydroxycoumarin oxime ether derivatives (0.1 mmol) were dissolved
in methanol (10 mL), then the solution was kept undisturbed at room temperature in
the test tubes. Single-crystals suitable for X-ray diffraction were formed within three
weeks [35,36]. X-ray measurement on the selected crystal was performed on a quartz
fiber with protection oil. Cell dimensions and intensities were measured at 296 K on a
Bruker SMART APEX2 CCD area detector diffractometer with graphite monochromated
Mo K
α
radiation (λ = 0.71073 Å). The molecular structures were solved via full-matrix
2
least-squares procedure on all the F data, and the SHELXS-97 and SHELXL-97 programs
were employed for structure deal and refinement, respectively. The crystallographic data
for the compounds 4e, 4h, 5h and 6c can be obtained free of charge via http://www.
ccdc.cam.ac.uk (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; E-mail:
deposit@ccdc.cam.ac.uk).
3.4. Antifungal Bioassay
The test strains Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Gibberella zeae
(G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria
alternata (A. alternata) were provided by the State & Local Joint Engineering Research Center
of Green Pesticide Invention and Application at Nanjing Agricultural University. The anti-
fungal activities of target compounds were implemented at an equivalent concentration of
100
µg/mL using mycelia growth inhibitory rate methods according to our published liter-
ature [16,37]. Every title compound (30.0 mg) was dissolved in 0.6mL dimethyl sulfoxide
and evenly mixed with 299.4 mL of PSA (potato sucrose agar) medium. An equal volume
of methanol in 299.4 mL medium was used as the blank control. Meanwhile, the Osthole
and Azoxystrobin were tested as the positive control fungicides at the same concentration.
It carried out on a 100 mm
×
15 mm Petri plate under a sterile condition with 3 replicates.
◦
The fungi were inoculated to the center of the medium and cultured at 25 C for 2–8 days
in a dark environment. When the mycelia colony of the control grew to 6.5 cm (2.5 d for B.
cinerea, 7.0 d for A. solani, 3.5 d for G. zeae, 1.5 d for R. solani, 5.0 d for C. orbiculare and 8.0 d
for A. alternate), the diameters of the mycelium colonies were measured, and the inhibitory
percentages were then calculated. The antifungal results of all the compounds were listed
in Table 2. The title compounds with inhibition rates exceeding 60% at 100
further tested for their antifungal effects at five double-declining concentrations (50.00,
5.00, 12.50, 6.25 and 3.125 g/mL) for calculating the EC50 values. Similarly, Osthole
µg/mL were
2
µ
and Azoxystrobin were employed as positive control fungicides, which were exhibited in
Tables 3 and 4.
4. Conclusions
We designed and synthesized three series of fluorinated 7-hydroxycoumarin oxime
1
ether derivatives for the first time. All the target compounds were identified by H-
NMR, 13C-NMR, FTIR and HR-MS. Specifically, the compounds 4e
4h 5h and 6c were
,
,
obtained by single-crystal X-ray analysis. The antifungal bioassays in vitro showed that
some fluorinated 7-hydroxycoumarin derivatives exhibited a potential biological activ-
ity. In particular, the compounds 4a
active ones. The EC50 values of compounds 2a
,
4f
,
5a
,
5f
,
,
6a and 6h were evaluated as the most
2b 4f 5a and 5f together with Osthole
,
,
and Azoxystrobin were further tested. The compound 5f was identified as the promising

Molecules 2021, 26, 372
15 of 16
fungicide candidate against B. cinerea with the EC50 values of 5.75
ously better than Osthole (33.20 g/mL) and Azoxystrobin (64.95
the compound 5f possessed outstanding antifungal activities against R. solani with the EC50
values of 28.96 µg/mL, which was superior to Osthole (67.18 g/mL) and equivalent to
µg/mL, which was obvi-
µ
µg/mL). Additionally,
µ
Azoxystrobin (21.34 µg/mL). The present work provides a practical foundation for further
structural optimization of fluorinated coumarin oxime ether derivatives with the aim to
improve the antifungal activity.
Supplementary Materials: The Supplementary Materials containing H-NMR, 13C-NMR, FTIR and
1
HR-MS spectra of the title compounds and the crystal structure data of compounds 4e, 4h, 5h and 6c
can be accessed online.
Author Contributions: W.-H.Z. conceived and designed the experiments; Q.-Q.W. and J.J. carried out
the synthesis, characterization and antifungal activity assay of all the compounds; P.D. performed the
X-ray analysis; Q.-Q.W. and S.-G.Z. prepared the manuscript for publication; All authors discussed
the contents of the manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was funded by National Key R&D Program of China, grant number
2017YFD0200506 and the Fundamental Research Funds for the Central Universities, grant num-
ber KYTZ201604.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Conflicts of Interest: The author declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.
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