Synthesis of sulfonate derivatives of carvacrol and thymol as anti-oomycetes agents

Article abstract of DOI:10.1080/10286020.2020.1758675

Two series of sulfonate derivatives of carvacrol and thymol were synthesized and screened in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of 32 derivatives, five compounds 3a, 4a, 4k, 3n, and 4n exhibited mo

Full text of DOI:10.1080/10286020.2020.1758675

Journal of Asian Natural Products Research
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Synthesis of sulfonate derivatives of carvacrol and
thymol as anti-oomycetes agents
Gen-Qiang Chen, Di Sun, Jin-Ming Yang, Song Zhang, Yue-E Tian, Zhi-Ping
Che, Sheng-Ming Liu, Jia Jiang & Xiao-Min Lin
To cite this article: Gen-Qiang Chen, Di Sun, Jin-Ming Yang, Song Zhang, Yue-E Tian, Zhi-
Ping Che, Sheng-Ming Liu, Jia Jiang & Xiao-Min Lin (2020): Synthesis of sulfonate derivatives of
carvacrol and thymol as anti-oomycetes agents, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2020.1758675
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1758675
Synthesis of sulfonate derivatives of carvacrol and thymol
as anti-oomycetes agents
Gen-Qiang Chen, Di Sun, Jin-Ming Yang, Song Zhang, Yue-E Tian, Zhi-Ping Che,
Sheng-Ming Liu, Jia Jiang and Xiao-Min Lin
Laboratory of Pesticidal Design and Synthesis, Department of Plant Protection, College of Forestry,
Henan University of Science and Technology, Luoyang 471023, China
ABSTRACT
ARTICLE HISTORY
Received 15 January 2020
Accepted 17 April 2020
Two series of sulfonate derivatives of carvacrol and thymol were
synthesized and screened in vitro for their anti-oomycete activity
against Phytophthora capsici, respectively. Among all of 32 deriva-
tives, five compounds 3a, 4a, 4k, 3n, and 4n exhibited more
potent anti-oomycete activity against P. capsici with EC50 values
of 66.66, 62.94, 68.65, 61.24, and 52.91 mg/L, respectively. This
suggested that introduction of different substitutions at the
hydroxyl position of 1/2 could have remarkable effect on anti-
oomycete activity. Overall, when R1 ¼ isopropyl and R2 ¼ methyl,
the anti-oomycete activities of the compounds were higher
than that of the corresponding compounds of R1 ¼ methyl and
R2 ¼ isopropyl.
KEYWORDS
Natural product; carvacrol;
thymol; sulfonylation; anti-
oomycete activity
1. Introduction
The oomycete pathogen Phytophthora capsici, is a virulent, hemibiotrophic pathogen of
vegetable crops, inflicting significant losses throughout the world for a long time [1].
Practice has proved: the pathogen P. capsici has shown remarkable adaptation to new
CONTACT Yue-E Tian
yueetian@haust.edu.cn; Zhi-Ping Che
zhipingche@163.com
Laboratory of Pesticidal
Design & Synthesis, Department of Plant Protection, College of Forestry, Henan University of Science and
Technology, 471023 Luoyang, China
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
G.-Q. CHEN ET AL.
Figure 1. Structures of carvacrol (1), thymol (2), aminoguanidine derivatives of N-arylsulfonyl-3-acy-
lindoles (I) and sulfonate derivatives of maltol (II).
hosts and fungicides. Its main hosts are pepper and cucurbits. Over the last 90 years, P.
capsici has spread geographically as agricultural cultivation of these hosts has intensified,
dynamically adapting to new hosts and fungicides [1, 2]. The resistance is an inevitable
result of evolution, and lead to the exploit of resistant germplasm resources more and
more difficult, thus chemical controlling is still the main way to reduce the incidence of
P. capsici on main hosts [3–5]. However, the pathogen P. capsici, which are hard to con-
trol, easily infects many crops. Therefore, design and synthesis of novel compounds that
effectively inhibit those agricultural diseases is still highly desirable.
Essential oils (Eos) do not have any obvious physiological significance for the growth
of the plant itself but function mainly as defense mechanisms against bacterial, viral,
and fungal infections [6]. Most of the antimicrobial activities of Eos from the Lamiaceae
herbaceous plant family thyme (Thymus spp.) and oregano (Origanum spp.) are attrib-
uted to their bioactive isomeric monoterpenoid constituents, carvacrol (1, 5-isopropyl-2-
methylphenol, Figure 1) and thymol (2, 2-isopropyl-5-methylphenol, Figure 1) [7].
Plant secondary metabolites, Eos play an important role in novel pesticide discov-
ery for their unique sources and potential target sites [8–10]. Phenolic compounds 1
and 2 are the excellent candidates for the study of antimicrobial activities [6–12],
insecticidal activities [13–15], acaricidal activities [16], and anti-biofilm activities [17].
Research shows that the sulfonyl group introduced at the skeletons of different nat-
ural products is necessary for obtaining the potent compounds [3, 18]. Moreover,
aminoguanidine derivatives of N-arylsulfonyl-3-acylindoles (I, Figure 1) exhibited the
promising and pronounced antifungal activity [18]; and sulfonate derivatives of mal-
tol (II, Figure 1) showed significant anti-oomycete activity [3]. Inspired by the above-
mentioned interesting results, and according to the principle of superposition of bio-
activity, we have designed and synthesized two series of sulfonate derivatives of carva-
crol and thymol in this study, and first report the results of the anti-oomycete
activity of 32 derivatives against P. capsici in vitro. Additionally, their structure–activ-
ity relationship (SAR) studies were also described.
2. Results and discussion
2.1. Chemistry
As depicted in Scheme 1, carvacrol/thymol (1/2) reacted with 1.2 equiv. of ethanesul-
fonyl chloride/arylsulfonyl chloride (5a–p) in the presence of 1.5 equiv. of

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. The synthetic route of sulfonate derivatives of carvacrol (3a–p) and thymol (4a–p).
triethylamine to afford two series of sulfonate derivatives of carvacrol and thymol
(3a–p and 4a–p) in good yields [19–24]. The structures of all target compounds were
1
well characterized by H NMR, HRMS, and m.p.
2.2. Anti-oomycete activity
Two series (32) of sulfonated derivatives of carvacrol and thymol (3a–p and 4a–p)
were screened in vitro for their anti-oomycete activities against P. capsici. Zoxamide,
a commercially available agricultural fungicide, was used as a positive control. And
the inhibitory effects showed an obviously dose-dependent manner that with the con-
centration of compound increased, the colony diameter decreased.
As shown in Table 1, among all of thirty-two derivatives, five compounds 3a, 4a,
4k, 3n, and 4n exhibited more potent anti-oomycete activity against P. capsici with
EC50 values of 66.66, 62.94, 68.65, 61.24, and 52.91 mg/L, respectively. Meanwhile, a
brief SAR was determined. (1) Generally, the introduction of different substitutions at
the hydroxyl position of carvacrol/thymol (1/2) has remarkable effect on anti-oomy-
cete activity. (2) When isopropyl and methyl groups were introduced into different
positions of phenol, the anti-oomycete activities were different. Overall, when R1 ¼
isopropyl and R2 ¼ methyl, the anti-oomycete activities of the compounds were
higher than that of the corresponding compounds of R1 ¼ methyl and R2 ¼ isopro-
pyl (e.g. 3a,b,d–h,j-p versus 4a,b,d–h,j–p). (3) Moreover, through a comparative
study on the relationship between the chemical structures and anti-oomycete activity
of 3a–p and 4a–p, some interesting results were found as follows: (a) As compared
with 1-naphthalensulfonyl and 8-quinolinesulfonyl derivatives, 2-thiophenesulfonyl
derivative exhibited more potent anti-oomycete activity (3n/4n versus 3o/4o and 3p/
4p). For example, the EC50 values of 3n–p and 4n–p against P. capsici were 61.24,
126.99, 101.36 mg/L and 52.91, 98.93, 75.06 mg/L, respectively. (b) The introduction
of ethylsulfonyl at the hydroxyl position of carvacrol/thymol could lead to more
potent compound than introducing arylsulfonyl (except 2-thiophenesulfonyl) (e.g.,
3a/4a versus 3 b–m,o,p/4b–m,o,p). (c) Interestingly, we found that the introduction

4
G.-Q. CHEN ET AL.
Table 1. Anti-oomycete activites of compounds 3a–p, and 4a–p against P. capsici in vitro.
P. capsici
Compounds
EC50 (mg/L)
3a/4a
3b/4b
3c/4c
3d/4d
3e/4e
3f/4f
3g/4g
3h/4h
3i/4i
3j/4j
3k/4k
3l/4l
3m/4m
3n/4n
3o/4o
3p/4p
Zoxamide
66.66/62.94
79.80/77.47
108.20/134.51
104.67/87.46
269.33/192.67
129.27/78.04
111.95/76.45
93.15/76.15
100.37/111.95
98.23/70.74
95.93/68.65
134.51/115.94
202.77/179.28
61.24/52.91
126.99/98.93
101.36/75.06
26.87
of nitrophenylsulfonyl at the hydroxyl position of carvacrol/thymol, and the nitro
group at different position of the benzene ring, could lead to derivatives with differ-
ent anti-oomycete activity [meta-position for 3k/4k (EC50 ¼ 95.93/68.65 mg/L) and
ortho-position for 3j/4j (EC50 ¼ 98.23/70.74 mg/L) versus para-position for 3 l/4l
(EC50 ¼ 134.51/115.94 mg/L)]. (d) The introduction of phenylsulfonyl at the hydroxyl
position of carvacrol/thymol could lead to more potent compound than possessing
tosyl group, 4-methoxyphenylsulfonyl group and 4-tert-butylphenylsulfonyl group
(3b/4b versus 3c–e/4c–e). For example, the EC50 values of 3b–e and 4b–e against P.
capsici were 79.80, 108.20, 104.67, 269.33 mg/L and 77.47, 134.51, 87.46, 192.67 mg/L,
respectively. Similarly, the introduction of 4-fluorophenylsulfonyl at the hydroxyl pos-
ition of carvacrol/thymol could lead to more potent compound than possessing 4-
bromophenylsulfonyl group (e.g. 93.15 mg/L for 3h and 76.15 mg/L for 4h versus
100.37 mg/L for 3i and 111.95 mg/L for 4i).
3. Experimental
3.1. General experimental procedures
Melting points were taken on a X-6 microscopic melting point apparatus (Beijing
Tech instrument Co., Ltd., Beijing, China) and are uncorrected. Nuclear magnetic res-
onance spectra (NMR) were recorded on a Bruker Avance DMX 400 MHz instrument
(Bruker Daltonik, Bremen, Germany) in CDCl3 (1H at 400 MHz) using TMS (tetra-
methylsilane) as the internal standard. Electrospray ion trap mass spectrometry
(ESI-TRAP-MS) was carried out with a Bruker ESI-TRAP Esquire 6000 plus mass
spectrometry instrument (Bruker, Germany). Carvacrol, thymol, triethylamine, etha-
nesulfonyl chloride and arylsulfonyl chloride were purchased from Aladdin Chemistry
Co., Ltd. (Shanghai, China). Ethyl acetate, dichloromethane and petroleum ether were
purchased from Beichen Fangzheng Reagent Factory (Tianjin, China). Analytical
thin-layer chromatography (TLC) was performed with silica gel plate using silica gel
60 GF254 (Qingdao Haiyang Chemical Co., Ltd., Shandong, China). Silica gel column

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
chromatography was performed with silica gel 200–300 mesh (Qingdao Haiyang
Chemical Co., Ltd., Shandong, China).
3.2. General procedure for the synthesis of sulfonate derivatives of carvacrol
and thymol (3a–p and 4a–p)
To a solution of carvacrol/thymol (1/2, 1.0 mmol) and ethanesulfonyl chloride/arylsul-
fonyl chloride (5, 1.2 mmol) in dry dichloromethane (CH2Cl2, 10 ml) at room tem-
perature, a solution of triethylamine (Et3N) (1.5 mmol) in dry CH2Cl2 (5 ml) was
added dropwise for 10 min. When the reaction was completed by TLC analysis, the
reaction mixture was diluted with water (15 ml), and extracted with CH2Cl2 (30 ml ꢀ
3). Subsequently, the combined organic phase was washed by saturated aq. brine
(30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica
gel column chromatography to afford title compounds in 40–97% yields. The data for
3a–p and 4a–p are shown as follows.
3.2.1. Data for 2-methyl-5-isopropylphenyl ethanesulfonate (3a)
Rf ¼ 0.31 (dichloromethane-petroleum ether, 1/1). Yield ¼ 82%, Yellow oily liquid.
1H NMR (400 MHz, CDCl3) d: 7.23 (d, J ¼ 8.0 Hz, 1H), 7.06-7.10 (m, 2H), 3.26-3.38
(m, 3H), 2.32 (s, 3H), 1.59 (t, J ¼ 7.6 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H). HRESIMS:
m/z 243.1045 [M þ H]þ (calcd for C12H19O3S, 243.1049).
3.2.2. Data for 2-methyl-5-isopropylphenyl benzenesulfonate (3b)
Rf ¼ 0.40 (dichloromethane-petroleum ether, 1/1). Yield ¼ 93%, Pale yellow oily
liquid. The spectroscopic characteristics of this compound were consistent with those
previously reported in the literature [25].
3.2.3. Data for 2-methyl-5-isopropylphenyl 4-methylbenzenesulfonate (3c)
Rf ¼ 0.45 (dichloromethane-petroleum ether, 1/1). Yield ¼ 89%, White solid, m.p.
69–70 ꢁC. The spectroscopic characteristics of this compound were consistent with
those previously reported in the literature [25].
3.2.4. Data for 2-methyl-5-isopropylphenyl 4-methoxybenzenesulfonate (3d)
Rf ¼ 0.32 (dichloromethane-petroleum ether, 1/1). Yield ¼ 94%, White solid, m.p.
1
66–67 ꢁC. H NMR (400 MHz, CDCl3) d: 7.78–7.82 (m, 2H), 7.13 (d, J ¼ 8.0 Hz, 1H),
7.03 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.96–7.00 (m, 2H), 6.90 (q, J ¼ 0.8 Hz, 1H), 3.88 (s,
3H), 3.00–3.06 (m, 1H), 2.26 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H). HRESIMS: m/z
321.1156 [M þ H]þ (calcd for C17H21O4S, 321.1155).
3.2.5. Data for 2-methyl-5-isopropylphenyl 4-tert-butylbenzenesulfonate (3e)
Rf ¼ 0.47 (dichloromethane-petroleum ether, 3/2). Yield ¼ 52%, White solid, m.p.
1
78–79 ꢁC. H NMR (400 MHz, CDCl3) d: 7.75–7.79 (m, 2H), 7.51–7.54 (m, 2H), 7.11
(d, J ¼ 8.0 Hz, 1H), 7.01-7.04 (m, 1H), 6.93 (q, J ¼ 0.8 Hz, 1H), 2.90–2.96 (m, 1H),
2.26 (s, 3H), 1.34 (s, 9H), 0.96 (s, 3H), 0.94 (s, 3H). HRESIMS: m/z 347.1679
[M þ H]þ (calcd for C20H27O3S, 347.1675).

6
G.-Q. CHEN ET AL.
3.2.6. Data for 2-methyl-5-isopropylphenyl 2,4,6-trimethylbenzenesulfonate (3f)
Rf ¼ 0.53 (dichloromethane-petroleum ether, 3/2). Yield ¼ 60%, White solid, m.p.
1
65–66 ꢁC. H NMR (400 MHz, CDCl3) d: 7.18 (d, J ¼ 8.0 Hz, 1H), 6.99–7.03 (m, 3H),
6.55 (q, J ¼ 0.8 Hz, 1H), 3.20–3.27 (m, 1H), 2.59 (s, 6H), 2.34 (s, 3H), 2.18 (s, 3H),
1.13 (s, 3H), 1.12 (s, 3H). HRESIMS: m/z 333.1522 [M þ H]þ (calcd for
C19H25O3S, 333.1519).
3.2.7. Data for 2-methyl-5-isopropylphenyl 2,4,6-triisopropylbenzenesulfonate (3g)
Rf ¼ 0.43 (dichloromethane-petroleum ether, 1/2). Yield ¼ 85%, Pale yellow oily
1
liquid. H NMR (400 MHz, CDCl3) d: 7.22 (s, 2H), 7.19 (d, J ¼ 8.0 Hz, 1H), 6.98–7.01
(m, 1H), 6.52 (q, J ¼ 0.8 Hz, 1H), 4.07–4.13 (m, 2H), 3.23–3.30 (m, 1H), 2.91–2.98
(m, 1H), 2.16 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.21 (s, 6H), 1.19 (s, 6H), 1.14 (s,
3H), 1.12 (s, 3H). HRESIMS: m/z 417.2462 [M þ H]þ (calcd for
C25H37O3S, 417.2458).
3.2.8. Data for 2-methyl-5-isopropylphenyl 4-fluorobenzenesulfonate (3h)
Rf ¼ 0.58 (dichloromethane-petroleum ether, 1/1). Yield ¼ 97%, White solid, m.p.
1
58–59 ꢁC. H NMR (400 MHz, CDCl3) d: 7.87-7.92 (m, 2H), 7.19–7.24 (m, 2H), 7.15
(d, J ¼ 8.0 Hz, 1H), 7.03–7.06 (m, 1H), 6.88 (q, J ¼ 0.8 Hz, 1H), 2.95–3.02 (m, 1H),
2.27 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H). HRESIMS: m/z 309.0956 [M þ H]þ (calcd for
C16H18FO3S, 309.0955).
3.2.9. Data for 2-methyl-5-isopropylphenyl 4-bromobenzenesulfonate (3i)
Rf ¼ 0.59 (dichloromethane-petroleum ether, 1/1). Yield ¼ 95%, White solid, m.p.
103–104 ꢁC. The spectroscopic characteristics of this compound were consistent with
those previously reported in the literature [25].
3.2.10. Data for 2-methyl-5-isopropylphenyl 2-nitrobenzenesulfonate (3j)
Rf ¼ 0.43 (dichloromethane-petroleum ether, 1/1). Yield ¼ 96%, White solid, m.p.
71–72 ꢁC. The spectroscopic characteristics of this compound were consistent with
those previously reported in the literature [25].
3.2.11. Data for 2-methyl-5-isopropylphenyl 3-nitrobenzenesulfonate (3k)
Rf ¼ 0.43 (dichloromethane-petroleum ether, 1/1). Yield ¼ 97%, Yellow oily liquid.
The spectroscopic characteristics of this compound were consistent with those previ-
ously reported in the literature [25].
3.2.12. Data for 2-methyl-5-isopropylphenyl 4-nitrobenzenesulfonate (3l)
Rf ¼ 0.37 (dichloromethane-petroleum ether, 1/1). Yield ¼ 56%, White solid, m.p.
82–83 ꢁC. The spectroscopic characteristics of this compound were consistent with
those previously reported in the literature [25].
3.2.13. Data for 2-methyl-5-isopropylphenyl 3-nitro-4-chlorobenzenesulfonate (3m)
Rf ¼ 0.39 (dichloromethane-petroleum ether, 1/1). Yield ¼ 52%, Yellow oily liquid.
1H NMR (400 MHz, CDCl3) d: 8.36 (d, J ¼ 2.0 Hz, 1H), 8.00–8.03 (m, 1H), 7.78 (d,

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
J ¼ 8.4 Hz, 1H), 7.19 (d, J ¼ 8.0 Hz, 1H), 7.08-7.10 (m, 1H), 6.87-6.88 (m, 1H),
2.95–3.02 (m, 1H), 2.30 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H). HRESIMS: m/z 370.0515
[M þ H]þ (calcd for C16H17ClNO5S, 370.0510).
3.2.14. Data for 2-methyl-5-isopropylphenyl thiophene-2-sulfonate (3n)
Rf ¼ 0.44 (dichloromethane-petroleum ether, 1/1). Yield ¼ 57%, Pale yellow oily
liquid. The spectroscopic characteristics of this compound were consistent with those
previously reported in the literature [25].
3.2.15. Data for 2-methyl-5-isopropylphenyl naphthalene-1-sulfonate (3o)
Rf ¼ 0.51 (dichloromethane-petroleum ether, 3/2). Yield ¼ 65%, White solid, m.p.
104–105 ꢁC. 1H NMR (400 MHz, CDCl3) d: 8.82–8.85 (m, 1H), 8.20 (dd, J ¼ 7.2,
1.2 Hz, 1H), 8.14–8.17 (m, 1H), 7.97–8.00 (m, 1H), 7.72–7.76 (m, 1H), 7.64–7.68 (m,
1H), 7.54 (dd, J ¼ 8.4, 7.6 Hz, 1H), 7.12 (d, J ¼ 8.0 Hz, 1H), 6.96–6.99 (m, 1H), 6.56
(q, J ¼ 0.8 Hz, 1H), 3.07–3.17 (m, 1H), 2.13 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).
HRESIMS: m/z 341.1205 [M þ H]þ (calcd for C20H21O3S, 341.1206).
3.2.16. Data for 2-methyl-5-isopropylphenyl quinoline-8-sulfonate (3p)
Rf ¼ 0.52 (dichloromethane-petroleum ether, 15/1). Yield ¼ 65%, White solid, m.p.
1
151–152 ꢁC. H NMR (400 MHz, CDCl3) d: 9.24 (dd, J ¼ 4.4, 2.0 Hz, 1H), 8.46 (dd,
J ¼ 7.2, 1.6 Hz, 1H), 8.32 (dd, J ¼ 8.4, 2.0 Hz, 1H), 8.17 (dd, J ¼ 8.0, 1.6 Hz, 1H),
7.59–7.65 (m, 2H), 7.14 (d, J ¼ 8.0 Hz, 1H), 6.98–7.00 (m, 1H), 6.80 (q, J ¼ 0.8 Hz,
1H), 3.28–3.35 (m, 1H), 2.17 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H). HRESIMS: m/z
342.1155 [M þ H]þ (calcd for C19H20NO3S, 342.1158).
3.2.17. Data for 2-isopropyl-5-methylphenyl ethanesulfonate (4a)
Rf ¼ 0.30 (dichloromethane-petroleum ether, 1/1). Yield ¼ 48%, Pale yellow oily
1
liquid. H NMR (400 MHz, CDCl3) d: 7.23 (d, J ¼ 8.0 Hz, 1H), 7.05–7.10 (m, 2H),
3.26–3.38 (m, 3H), 2.32 (s, 3H), 1.59 (t, J ¼ 7.2 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H).
HRESIMS: m/z 243.1051 [M þ H]þ (calcd for C12H19O3S, 243.1049).
3.2.18. Data for 2-isopropyl-5-methylphenyl benzenesulfonate (4 b)
Rf ¼ 0.41 (dichloromethane-petroleum ether, 1/1). Yield ¼ 40%, Pale yellow oily
liquid. 1H NMR (400 MHz, CDCl3) d: 7.87–7.89 (m, 2H), 7.63–7.69 (m, 1H),
7.52–7.56 (m, 2H), 7.14 (d, J ¼ 8.0 Hz, 1H), 7.04 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.88 (d,
J ¼ 2.0 Hz, 1H), 2.94–3.02 (m, 1H), 2.26 (s, 3H), 0.97–1.01 (m, 6H). HRESIMS: m/z
291.1049 [M þ H]þ (calcd for C16H19O3S, 291.1049).
3.2.19. Data for 2-isopropyl-5-methylphenyl 4-methylbenzenesulfonate (4c)
Rf ¼ 0.45 (dichloromethane-petroleum ether, 1/1). Yield ¼ 77%, White solid. m.p.
68–69 ꢁC. 1H NMR (400 MHz, CDCl3) d: 7.76 (dd, J ¼ 6.4, 2.0 Hz, 2H), 7.33
(d, J ¼ 8.0 Hz, 2H), 7.13 (d, J ¼ 8.0 Hz, 1H), 7.04 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.89
(t, J ¼ 1.2 Hz, 1H), 2.97–3.04 (m, 1H), 2.45 (s, 3H), 2.26 (s, 3H), 1.01 (s, 3H), 0.99
(s, 3H). HRESIMS: m/z 305.1209 [M þ H]þ (calcd for C17H21O3S, 305.1206).

8
G.-Q. CHEN ET AL.
3.2.20. Data for 2-isopropyl-5-methylphenyl 4-methoxybenzenesulfonate (4d)
Rf ¼ 0.31 (dichloromethane-petroleum ether, 1/1). Yield ¼ 62%, Pale yellow solid,
1
m.p. 68–69 ꢁC. H NMR (400 MHz, CDCl3) d: 7.78–7.82 (m, 2H), 7.13 (d, J ¼ 8.0 Hz,
1H), 7.03 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.96–7.00 (m, 2H), 6.90 (t, J ¼ 0.8 Hz, 1H), 3.88 (s,
3H), 3.00–3.07 (m, 1H), 2.26 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H). HRESIMS: m/z
321.1158 [M þ H]þ (calcd for C17H21O4S, 321.1155).
3.2.21. Data for 2-isopropyl-5-methylphenyl 4-tert-butylbenzenesulfonate (4e)
Rf ¼ 0.45 (dichloromethane-petroleum ether, 3/2). Yield ¼ 72%, White solid, m.p.
1
78–79 ꢁC. H NMR (400 MHz, CDCl3) d: 7.75–7.79 (m, 2H), 7.51–7.54 (m, 2H), 7.11
(d, J ¼ 8.0 Hz, 1H), 7.03 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.92 (q, J ¼ 0.8 Hz, 1H), 2.90–2.97
(m, 1H), 2.26 (s, 3H), 1.34 (s, 9H), 0.96 (s, 3H), 0.94 (s, 3H). HRESIMS: m/z
347.1675 [M þ H]þ (calcd for C20H27O3S, 347.1675).
3.2.22. Data for 2-isopropyl-5-methylphenyl 2,4,6-trimethylbenzenesulfonate (4f)
1
Rf ¼ 0.52 (dichloromethane-petroleum ether, 3/2). Yield ¼ 58%, White liquid. H
NMR (400 MHz, CDCl3) d: 7.18 (d, J ¼ 8.0 Hz, 1H), 7.00–7.02 (m, 3H), 6.56
(q, J ¼ 0.8 Hz, 1H), 3.20–3.27 (m, 1H), 2.59 (s, 6H), 2.34 (s, 3H), 2.18 (s, 3H), 1.13
(s, 3H), 1.12 (s, 3H). HRESIMS: m/z 333.1520 [M þ H]þ (calcd for
C19H25O3S, 333.1519).
3.2.23. Data for 2-isopropyl-5-methylphenyl 2,4,6-triisopropylbenzenesulfo-
nate (4g)
1
Rf ¼ 0.43 (dichloromethane-petroleum ether, 1/2). Yield ¼ 73%, White liquid. H
NMR (400 MHz, CDCl3) d: 7.22 (s, 2H), 7.19 (d, J ¼ 8.0 Hz, 1H), 7.01 (dd, J ¼ 8.0,
1.6 Hz, 1H), 6.53 (q, J ¼ 0.8 Hz, 1H), 4.07–4.14 (m, 2H), 3.23–3.30 (m, 1H), 2.91–2.98
(m, 1H), 2.16 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.21 (s, 6H), 1.19 (s, 6H) 1.14 (s,
3H), 1.12 (s, 3H). HRESIMS: m/z 417.2455 [M þ H]þ (calcd for
C25H37O3S, 417.2458).
3.2.24. Data for 2-isopropyl-5-methylphenyl 4-fluorobenzenesulfonate (4h)
Rf ¼ 0.56 (dichloromethane-petroleum ether, 1/1). Yield ¼ 73%, White solid, m.p.
1
69–70 ꢁC. H NMR (400 MHz, CDCl3) d: 7.88–7.93 (m, 2H), 7.19–7.25 (m, 2H), 7.15
(d, J ¼ 8.0 Hz, 1H), 7.05 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.88 (q, J ¼ 0.8 Hz, 1H), 2.96–3.03
(m, 1H), 2.27 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H). HRESIMS: m/z 309.0959 [M þ H]þ
(calcd for C16H18FO3S, 309.0955).
3.2.25. Data for 2-isopropyl-5-methylphenyl 4-bromobenzenesulfonate (4i)
Rf ¼ 0.56 (dichloromethane-petroleum ether, 1/1). Yield ¼ 71%, White solid, m.p.
1
105–106 ꢁC. H NMR (400 MHz, CDCl3) d: 7.72–7.76 (m, 2H), 7.67–7.70 (m, 2H),
7.15 (d, J ¼ 8.0 Hz, 1H), 7.06 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.88 (q, J ¼ 0.8 Hz, 1H),
2.95–3.01 (m, 1H), 2.27 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H). HRESIMS: m/z 369.0153
[M þ H]þ (calcd for C16H18BrO3S, 369.0155).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
9
3.2.26. Data for 2-isopropyl-5-methylphenyl 2-nitrobenzenesulfonate (4j)
Rf ¼ 0.43 (dichloromethane-petroleum ether, 1/1). Yield ¼ 73%, Pale yellow oily
liquid. 1H NMR (400 MHz, CDCl3) d: 8.00–8.03 (m, 1H), 7.81–7.87 (m, 2H),
7.70–7.74 (m, 1H), 7.21 (d, J ¼ 8.0 Hz, 1H), 7.09 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.89 (q,
J ¼ 0.8 Hz, 1H), 3.18-3.27 (m, 1H), 2.26 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H). HRESIMS:
m/z 336.0901 [M þ H]þ (calcd for C16H18NO5S, 336.0900).
3.2.27. Data for 2-isopropyl-5-methylphenyl 3-nitrobenzenesulfonate (4k)
Rf ¼ 0.42 (dichloromethane-petroleum ether, 1/1). Yield ¼ 73%, Pale yellow solid,
1
m.p. 67–68 ꢁC. H NMR (400 MHz, CDCl3) d: 8.75–8.76 (m, 1H), 8.52–8.55 (m, 1H),
8.21–8.23 (m, 1H), 7.82 (t, J ¼ 8.0 Hz, 1H), 7.17 (d, J ¼ 8.0 Hz, 1H), 7.09 (dd, J ¼ 8.0,
1.6 Hz, 1H), 6.89 (q, J ¼ 0.8 Hz, 1H), 2.95-3.02 (m, 1H), 2.28 (s, 3H,), 1.04 (s, 3H),
1.03(s, 3H). HRESIMS: m/z 336.0895 [M þ H]þ (calcd for C16H18NO5S, 336.0900).
3.2.28. Data for 2-isopropyl-5-methylphenyl 4-nitrobenzenesulfonate (4l)
Rf ¼ 0.38 (dichloromethane-petroleum ether, 1/1). Yield ¼ 79%, White solid. m.p.
1
84–85 ꢁC. H NMR (400 MHz, CDCl3) d: 8.38–8.42 (m, 2H), 8.09–8.12 (m, 2H), 7.18
(d, J ¼ 8.0 Hz, 1H), 7.09 (dd, J ¼ 8.0, 1.6 Hz, 1H), 6.87 (q, J ¼ 0.8 Hz, 1H), 2.94–3.00
(m, 1H), 2.28 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H). HRESIMS: m/z 336.0900 [M þ H]þ
(calcd for C16H18NO5S, 336.0900).
3.2.29. Data for 2-isopropyl-5-methylphenyl 3-nitro-4-chlorobenzenesulfonate (4m)
Rf ¼ 0.38 (dichloromethane-petroleum ether, 1/1). Yield ¼ 44%, Pale yellow oily
liquid. 1H NMR (400 MHz, CDCl3) d: 8.36 (d, J ¼ 2.0 Hz, 1H), 8.03 (dd, J ¼ 8.4,
2.0 Hz, 1H), 7.78 (d, J ¼ 8.4 Hz, 1H), 7.19 (d, J ¼ 8.0 Hz, 1H), 7.10 (dd, J ¼ 8.0, 1.6 Hz,
1H), 6.88 (t, J ¼ 1.6 Hz, 1H), 2.95–3.01 (m, 1H), 2.30 (s, 3H), 1.07 (s, 3H), 1.05 (s,
3H). HRESIMS: m/z 370.0513 [M þ H]þ (calcd for C16H17ClNO5S, 370.0510).
3.2.30. Data for 2-isopropyl-5-methylphenyl thiophene-2-sulfonate (4n)
Rf ¼ 0.45 (dichloromethane-petroleum ether, 1/1). Yield ¼ 65%, Pale yellow oily
1
liquid. H NMR (400 MHz, CDCl3) d: 7.72 (dd, J ¼ 5.2, 1.6 Hz, 1H), 7.65 (dd, J ¼ 4.0,
1.6 Hz, 1H), 7.16 (d, J ¼ 8.0 Hz, 1H), 7.13 (dd, J ¼ 5.2, 4.0 Hz, 1H), 7.03-7.06 (m, 1H),
6.94 (q, J ¼ 0.8 Hz, 1H), 3.01–3.10 (m, 1H), 2.28 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
HRESIMS: m/z 297.0619 [M þ H]þ (calcd for C14H17O3S2, 297.0614).
3.2.31. Data for 2-isopropyl-5-methylphenyl naphthalene-1-sulfonate (4o)
Rf ¼ 0.49 (dichloromethane-petroleum ether, 3/2). Yield ¼ 45%, White solid, m.p.
1
104–105 ꢁC. H NMR (400 MHz, CDCl3) d: 8.85 (d, J ¼ 8.0 Hz, 1H), 8.20 (dd, J ¼ 7.6,
1.6 Hz, 1H), 8.16 (d, J ¼ 8.4 Hz, 1H), 7.99 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.72–7.76 (m, 1H),
7.64–7.68 (m, 1H), 7.54 (t, J ¼ 8.0 Hz, 1H), 7.12 (d, J ¼ 8.0 Hz, 1H), 6.99 (dd, J ¼ 8.0,
1.6 Hz, 1H), 6.56 (t, J ¼ 0.8 Hz, 1H), 3.08–3.17 (m, 1H), 2.13 (s, 3H), 0.99 (s, 3H),
0.97 (s, 3H). HRESIMS: m/z 341.1201 [M þ H]þ (calcd for C20H21O3S, 341.1206).

10
G.-Q. CHEN ET AL.
3.2.32. Data for 2-isopropyl-5-methylphenyl quinoline-8-sulfonate (4p)
Rf ¼ 0.51 (dichloromethane-petroleum ether, 15/1). Yield ¼ 58%, White solid, m.p.
1
151–152 ꢁC. H NMR (400 MHz, CDCl3) d: 9.24 (dd, J ¼ 4.4, 2.0 Hz, 1H), 8.46 (dd,
J ¼ 7.2, 1.6 Hz, 1H), 8.31 (dd, J ¼ 8.4, 1.6 Hz, 1H), 8.17 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.65
(dd, J ¼ 8.4, 7.6 Hz, 1H), 7.62 (dd, J ¼ 8.4, 4.0 Hz, 1H), 7.14 (d, J ¼ 8.0 Hz, 1H), 7.00
(dd, J ¼ 8.0, 1.6 Hz, 1H), 6.81 (q, J ¼ 0.8 Hz, 1H), 3.29–3.36 (m, 1H), 2.18 (s, 3H),
1.00 (s, 3H), 0.99 (s, 3H). HRESIMS: m/z 342.1157 [M þ H]þ (calcd for
C19H20NO3S, 342.1158).
3.3. Bioassay method
Thirty-two sulfonate derivatives of carvacrol and thymol (3a–p and 4a–p) were
screened in vitro for their anti-oomycete activity against P. capsici. Potato dextrose
agar (PDA) medium was prepared in the flasks and sterilized. Compounds 3a–p,
4a–p and zoxamide (used as a positive control) were dissolved in acetone before mix-
ing with PDA. The ranges of 3a–p, 4a–p and zoxamide concentrations for the assays
were defined in preliminary experiments, and the final concentrations in medium
were 5, 25, 50, 75, and 100 mg/L. Pure acetone mixed with PDA was served as the
control, while zoxamide, a commercially available agricultural fungicide, was used as
a positive control. The medium was then poured into sterilized Petri dishes. Mycelial
plugs (5-mm diameter) were cut from the growing edge of a 7-day-old colony and
then placed on the PDA plates, and incubated at 28 ꢁC in the dark, respectively.
Colony growth rate (mm/7 days) was determined on PDA medium. Three plates were
evaluated for each compounds and an average colony diameter was calculated. The
radial growths of the colonies were measured and the data were statistically analyzed.
Mean colony diameter (minus the diameter of the plug) was measured for each treat-
ment and expressed as a percentage of growth inhibition. The median effective con-
centration (EC50) of 3a–p, 4a–p and zoxamide for P. capsici isolate was calculated by
linear regression of relative percentage of growth inhibition against log transformed
samples concentration.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by Henan Science and Technology Planning Project
(Grant No. 202102110068), Natural Science Foundation of Henan Province (Grant No.
182300410043, 182300410016), National Natural Science Foundation of China (Grant
No. 31901863).
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