Synthesis and fungicidal activity of thiazoline derivatives containing halogenated indolyl moiety

Article abstract of DOI:10.1080/10426507.2010.532842

A series of novel 1,3-thiazoline derivatives containing a 5-or 6-position halogenated indole moiety were synthesized via a one-pot and three-step reaction. Their structures were confirmed by spectroscopic methods. The fungicidal activities of all the title compounds were evaluated. Most of them exhibited moderate to high activity against eight plant pathogens at the concentration of 50 ug/mL. Generally the fungicidal activity of fluorinated indolyl thiazolines was higher than that of chlorinated indolyl thiazoline derivatives. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor &Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.532842

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Synthesis and Fungicidal Activity of
Thiazoline Derivatives Containing
Halogenated Indolyl Moiety
Lei Liu a , Hui-zhu Yuan b , Zhao-hai Qin a , Xiao-jing Yan b , Yu-mei
Xiao a , Nan Li a & Bin Fu a
a Key Laboratory of Pesticide Chemistry and Application Technology,
Department of Applied Chemistry, China Agricultural University,
Beijing, PR China
b Institute of Plant Protection, Chinese Academy of Agricultural
Science, Beijing, PR China
To cite this article: Lei Liu , Hui-zhu Yuan , Zhao-hai Qin , Xiao-jing Yan , Yu-mei Xiao , Nan Li & Bin
Fu (2011): Synthesis and Fungicidal Activity of Thiazoline Derivatives Containing Halogenated Indolyl
Moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:8, 1790-1800
To link to this article: http://dx.doi.org/10.1080/10426507.2010.532842
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Phosphorus, Sulfur, and Silicon, 186:1790–1800, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.532842
SYNTHESIS AND FUNGICIDAL ACTIVITY
OF THIAZOLINE DERIVATIVES CONTAINING
HALOGENATED INDOLYL MOIETY
Lei Liu,1 Hui-zhu Yuan,2 Zhao-hai Qin,1 Xiao-jing Yan,2
Yu-mei Xiao,1 Nan Li,1 and Bin Fu1
1Key Laboratory of Pesticide Chemistry and Application Technology, Department
of Applied Chemistry, China Agricultural University, Beijing, PR China
2Institute of Plant Protection, Chinese Academy of Agricultural Science,
Beijing, PR China
GRAPHICAL ABSTRACT
S
3 steps
R1
COOH
R1
N
N
N
R2
H
H
R1 = 5-F, 5-Cl, 6-F, 6-Cl
50~85% yield
R2= Me, i-Pr, i-Bu, Bn, Ph
Abstract A series of novel 1,3-thiazoline derivatives containing a 5- or 6-position halogenated
indole moiety were synthesized via a one-pot and three-step reaction. Their structures were
confirmed by spectroscopic methods. The fungicidal activities of all the title compounds were
evaluated. Most of them exhibited moderate to high activity against eight plant pathogens at the
concentration of 50 ug/mL. Generally the fungicidal activity of fluorinated indolyl thiazolines
was higher than that of chlorinated indolyl thiazoline derivatives.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Fungicidal; halogenated; indolyl; synthesis; thiazoline
INTRODUCTION
The thiazoline ring is an important structural unit and exists in a large number of nat-
ural products,1,2 including althiomycin, thiangazole, and curacin A. Especially, thiazoline-
containing compounds have been found in many marine alkaloids such as lissoclinamides,
patellins, tawicyclamides, and bistratamides.3,4 Many thiazoline-containing compounds
Received 25 August 2010; accepted 14 October 2010.
The authors are grateful to the Chinese Universities Scientific Fund (2009JS31) and Key Laboratory of
Pesticide Chemistry and Application (MOAPCA201002, The Ministry of Agriculture) for Financial Support.
Address correspondence to Bin Fu, Key Laboratory of Pesticide Chemistry and Application Technology,
Department of Applied Chemistry, China Agricultural University, Beijing 100193, PR China. E-mail: fubinchem@
cau.edu.cn
1790

THIAZOLINES WITH HALOGENATED INDOLYL MOIETY
1791
Br
O
F3C
N
S
F3C
N
Me
N
OCF3
COOMe
CHF2
S
N
H
S
N
S
N
O
Br
F3C
N
Me
O
CHF2
1
2
3
4
Figure 1 Typical thiazoline-containing compounds in food and agrochemicals
have been used in medicinal chemistry and asymmetric catalysis.5,6 In addition, some
thiazoline-containing compounds have found applications in food and agrochemical prod-
ucts.7,8 As shown in Figure 1, 2-acetylthiazoline 1 has been identified in many cooked foods
and exhibits aromatic flavors,9 trifluzamide 2 is a commercially available fungicide, while
thiazopyr 3 is a commercial herbicide,10 and iminothiazoline derivative 4 is a potential
commercial herbicide.11,12
Furthermore, indole derivatives are well known for their biological activity in medici-
nal chemistry and as plant growth regulators. However their antifungal activity in agrochem-
icals has rarely been reported; only a few examples have appeared.13,14 Considering that the
influence of halogens on the efficacy of a biologically active molecule can be remarkable
in a large number of pharmaceutical and agrochemical examples, then the introduction of
halogens into active ingredients has become an important concept in the quest for a mod-
ern agrochemical with optimal efficacy, environmental safety, and economic viability.15
As a continuation of our exploration into the application of thiazoline derivatives,16,17 in
this article we report the synthesis, characterization, and fungicidal activity of thiazolines
containing halogenated indolyl moiety.
RESULTS AND DISCUSSION
Chemistry
The synthetic route to the title thiazolines involves a one-pot, three-step sequence.16,17
The starting material, fluorine- or chlorine-substituted indole-2-carboxylic acid, was re-
fluxed in SOCl2 for 4 h, and the excess SOCl2 was removed in vacuo. The crude acyl
chlorides were dissolved in CH2Cl2 and added dropwise to the solution of amino alcohols
and Et3N in CH2Cl2 at 0◦C. After being stirred for 4 h, the solvent was removed in vacuo,
and the crude intermediate β-hydroxyamides were directly cyclized in the ring-closing
step without further purification. The mixture of P2S5 with β-hydroxyamides was refluxed
in toluene for 4–6 h under the presence of Et3N. The desired thiazolines 7, 8, 9, and 10
bearing fluorine or chlorine at the 5- or 6-position of indole were obtained in moderate to
good yield (50 ∼ 85%) after column chromatographic purification. The structures of all the
new compounds 7 ∼ 10 were characterized by spectroscopic methods. In addition, a single
crystal of thiazoline 7a was grown, and its structure was determined by X-ray diffraction
analysis as illustrated in Figure 2 and Table 1. The cif file is presented in the Supplemental
Materials (available online).
It can be seen from Figure 2 that the nitrogen atom of the thiazoline ring and the imino
group of the indole ring are oriented toward the same side; also, the thiazoline ring is not
planar, and it twists relative to the indole plane. The dihedral angle between the thiazoline

1792
L. LIU ET AL.
OH
i, ii
HN
O
R1
COOH
R1
R2
N
N
H
H
5
6
S
iii
R1
N
H
N
R2
7
8
9
a. R2= Me
b. R2 = i-Pr
c. R2 = i-Bu
d. R2 = Bn
e. R2 = Ph
R1 = 5-F
R1 = 5-Cl
R1 = 6-F
10 R1= 6-Cl
Reagent and condition:
i) SOCl2; 2) Amino alcohol, Et3N, DCM; 3) P2S5, Et3N, Toluene
Scheme 1
and indole rings is about 12.16◦. Selected bond lengths and torsion angles are listed in
Table 2. On the other hand, there exist two intermolecular hydrogen bonds between two
thiazoline molecular by head to tail fashion to each other as shown in Figure 3 and Table 3.
The nitrogen atom of the thiazoline ring is linked with the NH of indole moiety of another
thiazoline molecular through two N–H. . . N form.
Figure 2 The structure of compound 7a.

THIAZOLINES WITH HALOGENATED INDOLYL MOIETY
1793
Table 1 Crystal structure and data refinement parameters
Compound
7a
Empirical formula
Formula weight
C12H11FN2S
234.29
Crystal system/space group
Orthorhombic/ p(1)2(1)2
a / Å
12.935(3)
b / Å
15.581(4)
c / Å
11.885(3)
α / ◦
90◦
β / ◦
90◦
90◦
2395.3(9)
8
1.299
0.256
γ / ◦
V / Å3
Z
D calc (g/cm3)
µ (mm−1
)
Crystal size (mm)
Color / shape
Temp (K)
0.40 × 0.34 × 0.33
Colorless/block
296(2)K
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
1.71< θ <25.33deg
18284
4385
4385 / 20 / 299
1.258
R1 = 0.0696, wR2 = 0.1406
R1 = 0.0740, wR2 = 0.1427
0.186 and −0.162 e. Å −3
Largest difference peak/hole
Fungicidal Activity
The antifungal activities of the title compounds 7, 8, 9, and 10 were evaluated in
vitro against eight kinds of common plant pathogens (including R. solani, B. Cinerea, S.
Sclerotiorum, P. Asparagi, C. Sp, P. Capsici, P. Parasitica, P. oryzae Cav.). As shown in
Table S1 (see the Supplemental Materials), most of the title compounds indicated moderate
to high activity at the concentration of 50 µg/mL. For every type of thiazoline bearing
different substituents on the 4-position, the fungicidal activity was basically in the following
order: Me > i-Pr > i-Bu > Bn > Ph. In some cases, the inhibition rates of 7a and 9a against
several fungi were up to 100%, which is comparable with commercial carbendazim. The
results clearly suggest that methyl substituent on the 4-position of thiazoline ring in this
Table 2 Selected bond lengths (Å) and torsion angles (◦) of compound 7a
Selected
bond
Lengths
(Å)
Selected
bond
Lengths
(Å)
Selected
torsion angles
Torsion
angles (◦)
C1-C2
C1-C4
C1-N1
C3-N1
C3-S1
C2-S1
C3-C5
1.522 (9)
1.498 (7)
1.472 (5)
1.273 (5)
1.757 (4)
1.799 (8)
1.438 (5)
C5-N2
C5-C6
C6-C7
C7-C12
C12-N2
N2-H
1.367 (4)
1.375 (5)
1.414 (6)
1.412 (5)
1.378 (5)
0.86
N1-C1-C4
N1-C3-C5
C3-N1-C1
C3-S1-C2
N1-C3-S1
N2-C5-C3
F1-C9-C10
109.2 (4)
124.5 (3)
112.4 (3)
88.2 (4)
116.8 (3)
122.4 (3)
115.9 (5)
C9-F
1.372 (5)

1794
L. LIU ET AL.
Figure 3 Intermolecular hydrogen bond in 7a.
type of compound is an important structural factor influencing the antifungal spectrum and
activity.
TheEC50 values of four compounds 7a, 8a, 9a, and CAU-FB11 (thiazolinecompound
without substituent on indole ring) were determined as listed in Table S214. As expected,
both fluorinated and chlorinated indolyl thiazolines displayed better fungicidal activity than
CAU-FB 11 without halogen substituent.
CONCLUSION
In conclusion, a series of novel halogenated indolyl thiazoline derivatives have been
designed and synthesized using a one-pot reaction with three-step sequence. The prelimi-
nary bioassay results demonstrated that most of the title compounds showed moderate to
high fungicidal activity against eight kinds of plant pathogens. Compound 7a, 8a, 9a, and
10a with methyl substituent on the 4-position of thiazoline ring afforded higher fungicidal
activity than those bearing other groups. In general, halogenated indolyl thiazolines have a
higher fungicidal activity than those without halogen substitution on indole ring. Fluorine-
substituted indolyl thiazoline 7a and 9a exhibited higher activity than chlorine-substituted
indolyl thiazoline 8a and 10a. Our results may shed light on the design and discovery of
new fungicide. Further investigations on the in vivo screening and structural optimization
of 7a and 9a are in progress in our group.
Table 3 Hydrogen-bonding geometry (Å, ◦)
D–H. . .
A
D–H
H. . .
A
D. . .
A
<(D–H. . . A)
N(2)-H. . . N(3)
N(4)-H. . . N(1)
0.86
0.86
2.22
2.15
3.055 (4)
2.926 (5)
162.9
150.2

THIAZOLINES WITH HALOGENATED INDOLYL MOIETY
1795
EXPERIMENTAL
Instruments and Materials
1H NMR and 13C NMR were obtained at 300 MHz using a Bruker AV300 spectrometer
in CDCl3 solution, with tetramethylsilane as the internal standard. Chemical shift values (δ)
were given in parts per million (ppm). Infrared spectra were obtained on a Nicolet Avatar
330 FT-IR spectrometer. Elemental analyses were carried out on an Elementar Vario EL
instrument. The melting points were determined on an X-4 binocular microscope melting
point apparatus (Beijing Tech Instruments Co., Beijing, China) and were uncorrected. The
reagents were all analytically or chemically pure. All solvents and liquid reagents were
dried by standard methods in advance and distilled before use. 5- or 6-Fluoroindole-2-
carboxylic acid and 5- or 6-chloroindole-2-carboxylic acid were purchased from the Alfa
Aesar Company (Tianjin, China).
General Synthetic Procedures for the Preparation of Thiazoline 7–10
The halogenated indole 2-carboxylic acid (3.00 mmol) was refluxed with SOCl2
(3.0 mL) for 4 h, then the excess SOCl2 was removed in vacuo. Benzene (5 mL) was
added and removed again to dryness to remove the trace amount of SOCl2 and afforded
the acyl chloride. The acyl chloride in CH2Cl2 (15 mL) was added dropwise to a solution
of amino alcohol (3.10 mmol) and Et3N (2 mL, 14.5 mmol) in CH2Cl2 (15 mL) at 0◦C
and stirred at r.t. for 4 h. The reaction mixture was evaporated to remove the solvent in
vacuo, and toluene (20 mL) and Et3N (4 mL, 28.9 mmol) were added to the crude hydroxyl
amide. P2S5 (1.0 g, 4.5 mmol) was added under refluxing in 3 portions within 1 h, and
the suspension was continued to reflux for another 4–6 h. After being cooled to room
temperature, the solution was washed with H2O (2 × 5 mL), dried over anhydrous Na2SO4,
and concentrated to give the crude product. Column chromatographic purification on silica
gel (V/V, ethyl acetate:petroleum ether, 1:5) afforded the thiazoline compounds 7a–e, 8a–e,
9a–e, and 10a–e.
2-[5-Fluoroindole-2-yl]-4-methylthiazoline (7a). Colorless crystals; yield
1
80%; mp: 103–104◦C. H NMR (300 MHz, CDCl3): δ 9.92 (s, 1H, NH), 7.21–7.28 (m,
2H, ArH), 6.97–7.02 (m, 1H, ArH), 6.87 (d. J = 1.17 Hz, 1H, ArH), 4.70–4.77 (m, 1H,
CHN ), 3.57 (dd, J = 7.80, 10.80 Hz, 1H, one of CH2S), 3.08 (dd, J = 7.38, 10.50 Hz,
1H, one of CH2S), 1.40 (d, J = 6.66 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ 159.9,
159.4, 156.2, 133.7, 132.4, 128.0, 127.8, 113.3, 113.0, 112.3, 107.4, 107.4, 106.1, 105.8,
71.6, 39.7, 19.9. IR (cm−1): 3072, 2965, 1600, 1340, 1304, 1141, 938, 751, 737, 699. Anal.
Calcd. for C12H11FN2S (234.06): C 61.52, H 4.73, N 11.96. Found: C 61.62, H 4.78, N
11.80.
1
2-[5-Fluoroindole-2-yl]-4-isopropylthiazoline (7b). Pale oil; yield 64%. H
NMR (300 MHz, CDCl3): δ 9.94 (s, 1H, NH), 7.20–7.27 (m, 2H, Ar), 6.96–7.02 (m, 1H,
ArH), 6.85 (d, J = 1.11 Hz, 1H, ArH), 4.42–4.50 (m, 1H, CHN ), 3.46 (dd, J = 8.64,
11.40 Hz, 1H, one of CH2S), 3.02 (dd, J = 9.06, 10.80 Hz, 1H, one of CH2S), 2.01–2.09
(m, 1H, CHMe2), 1.07 (d, J = 6.75 Hz, 3H, CH3), 1.00 (d, J = 6.75 Hz, 3H, CH3). 13C
NMR (75 MHz, CDCl3): δ 159.5, 159.4, 156.4, 133.5, 132.5, 128.2, 128.0, 113.4, 113.1,
112.2, 112.1, 107.3, 107.2, 106.3, 106.0, 83.2, 35.5, 33.2, 19.6, 19.0. IR (cm−1): 3162,
2960, 1600, 1340, 1302, 1138, 1039, 800, 735. Anal. Calcd. for C14H15FN2S (262.09): C
64.09, H 5.76, N 10.68. Found: C 64.28, H 5.48, N 10.40.

1796
L. LIU ET AL.
2-[5-Fluoroindole-2-yl]-4-isobutylthiazoline (7c). Colorless crystals; yield
1
51%; mp: 148–149◦C. H NMR (300 MHz, CDCl3): δ 9.63 (s, 1H, NH), 7.22–7.28 (m,
2H, ArH), 6.97–7.04 (m, 1H, ArH), 6.85 (d, J = 1.23 Hz, 1H, ArH), 4.64–4.74 (m, 1H,
CHN ), 3.54 (dd, J = 8.10, 10.50 Hz, 1H, one of CH2S), 3.08 (dd, J = 7.80, 10.70 Hz,
1H, one of CH2S), 1.71–1.92 (m, 2H, CH2), 1.41–1.51(m, 1H, CHMe2), 0.95 (d, J = 6.51
Hz, 6H, 2×CH3). 13C NMR (75 MHz, CDCl3): δ 160.6, 159.7, 157.3, 134.2, 133.4, 129.0,
128.9, 114.1, 113.8, 112.9, 112.8, 107.9, 107.0, 106.7, 75.6, 44.5, 39.0, 26.0, 22.9, 22.8.
IR (cm−1): 2944, 2932, 1605, 1580, 1490, 1450, 1381, 1274, 892, 760, 699. Anal. Calcd.
for C15H17FN2S (276.11): C 65.19, H 6.20, N 10.14. Found: C 65.32, H 6.45, N 10.32.
2-[5-Fluoroindole-2-yl]-4-benzylthiazoline (7d). Colorless crystals; yield
1
76%; mp: 98–100◦C. H NMR (300 MHz, CDCl3): δ 9.48 (s, 1H, NH), 7.21–7.34 (m,
6H, ArH), 6.98–7.09 (m, 1H, ArH), 6.87 (d, J = 1.29Hz, 1H, ArH), 4.85–4.95 (m, 1H,
CHN ), 3.37–3.44 (dd, J = 8.10, 11.40 Hz, 1H, one of CH2S), 3.16–3.22 (m, 2H, one
of CH2S and one of CH2Ph), 2.85 (dd, J = 8.61, 13.80 Hz, 1H, one of CH2Ph). 13C
NMR (75 MHz, CDCl3): δ 160.7, 160.6, 158.5, 139.3, 134.3, 133.2, 130.0, 129.4, 129.0,
128.9, 127.4, 114.3, 114.0, 113.0, 112.9, 108.1, 108.1, 107.1, 106.8, 78.4, 40.4, 37.9. IR
(cm−1): 3060, 1600, 1585, 1450, 1415, 1344, 1038, 906, 802, 734, 699. Anal. Calcd. for
C19H15FN2S (310.09): C 69.65, H 4.87, N 9.03. Found: C 69.40, H 5.01, N 9.17.
2-[5-Fluoroindole-2-yl]-4-phenylthiazoline (7e). Colorless crystals; yield
66%; mp: 114–115◦C. 1H NMR (300 MHz, CDCl3): δ 9.37 (s, 1H, NH), 7.21–7.37 (m, 7H,
ArH), 6.98–7.05 (m, 1H, ArH), 6.93 (d, J = 1.65Hz, 1H, ArH), 5.66 (t, J = 9.0 Hz, 1H,
CHN ), 3.82 (dd, J = 8.60, 11.70 Hz, 1H, one of CH2S), 3.36 (dd, J = 9.30, 12.30 Hz,
1H, one of CH2S). 13C NMR (75 MHz, CDCl3): δ 161.6, 160.6, 157.5, 142.4, 134.2,
133.1, 129.6, 129.0, 128.8, 128.7, 127.4, 114.5, 114.1, 113.0, 112.9, 108.3, 108.2, 107.1,
106.8, 80.5, 41.4. IR (cm−1): 3060, 1600, 1585, 1450, 1415, 1344, 1038, 906, 802, 734,
699. Anal. Calcd. for C17H13FN2S (296.08): C 68.90, H 4.42, N 9.45. Found: C 68.71, H
4.53, N 9.42.
2-[5-Chloroindole-2-yl]-4-methylthiazoline (8a). Pale oil; yield 77%. 1H
NMR (300 MHz, CDCl3): δ 10.20 (s, 1H, NH), 7.15–7.24 (m, 2H, ArH), 6.84 (s, 1H,
ArH), 4.69–4.81 (m, 1H, CHN ), 3.57 (dd, J = 8.10, 10.80 Hz, 1H, one of CH2S), 3.08
(dd, J = 7.23, 10.80 Hz, 1H, one of CH2S), 1.38 (d, J = 6.63 Hz, 3H, CH3). 13C NMR (75
MHz, CDCl3): δ 159.3, 132.1, 128.8, 125.9, 124.9, 121.0, 112.5, 106.8, 71.9, 40.0, 20.2.
IR (cm−1): 2954, 2930, 1604, 1580, 1450, 1382, 1270, 1010, 890, 760, 699. Anal. Calcd.
for C12H11ClN2S (250.03): C 57.48, H 14.14, N 11.17. Found: C 57.54, H 14.42, N 11.20.
1
2-[5-Chloroindole-2-yl]-4-iso-propylthiazoline (8b). Pale oil; yield 85%. H
NMR (300 MHz, CDCl3): δ 9.55 (s, 1H, NH), 7.59 (d, J = 1.86Hz, 1H, ArH), 7.18–7.28
(m, 2H, ArH), 6.82 (d, J = 0.90 Hz, 1H, ArH), 4.38–4.46 (m, 1H, CHN ), 3.46 (dd,
J = 8.58, 10.50 Hz, 1H, one of CH2S), 3.20 (dd, J = 9.39, 10.50 Hz, 1H, one of CH2S),
2.00–2.10(m, 1H, CHMe2), 1.09 (d, J = 6.75 Hz, 3H, CH3), 1.01 (d, J = 6.75 Hz, 3H,
CH3). 13C NMR (75 MHz, CDCl3): δ 158.9, 135.1, 132.2, 128.4, 126.0, 124.9, 121.0,
112.5, 106.6, 83.3, 35.6, 33.2, 19.7, 19.1. IR (cm−1): 2950, 2928, 1606, 1580, 1490, 1381,
1270, 1010, 890, 758, 699. Anal. Calcd. for C14H15ClN2S (278.06): C 60.31, H 5.42, N
10.05. Found: C 60.47, H 5.20, N 10.01.
1
2-[5-Chloroindole-2-yl]-4-iso-butylthiazoline (8c). Pale oil; yield 74%. H
NMR (300 MHz, CDCl3): δ 10.13 (s, 1H, NH), 7.58 (d, J = 1.53Hz, 1H, ArH), 7.15–7.24
(m, 2H, ArH), 6.83 (d, J = 1.35 Hz, 1H, ArH), 4.65–4.72 (m, 1H, CHN ), 3.55 (dd,
J = 8.10, 10.80 Hz, 1H, one of CH2S), 3.09 (dd, J = 7.50, 10.50 Hz, 1H, one of CH2S),
1.69–1.88 (m, 2H, CH2), 1.39–1.48 (m, 1H, CHMe2), 0.89–0.93 (m, 6H, 2 × CH3). 13C

THIAZOLINES WITH HALOGENATED INDOLYL MOIETY
1797
NMR (75MHz, CDCl3): δ 159.2, 135.3, 132.2, 128.8, 125.9, 124.8, 121.0, 112.4, 106.8,
74.9, 44.1, 38.7, 25.7, 22.7, 22.5. IR (cm−1): 2944, 2932, 1605, 1580, 1490, 1450, 1381,
1274, 1010, 892, 760, 699. Anal. Calcd. for C15H17ClN2S (292.08): C 61.52, H 5.85, N
9.57. Found: C 61.71, H 5.60, N 9.34.
2-[5-Chloroindole-2-yl]-4-benzylthiazoline (8d). Pale oil; yield 62%. 1H NMR
(300 MHz, CDCl3): δ 9.94 (s, 1H, NH), 7.58 (s, 1H, ArH), 7.20–7.28 (m, 7H, ArH), 6.83 (d,
J = 1.11 Hz, 1H, ArH), 4.89–4.93 (m, 1H, CHN ), 3.40 (dd, J = 8.10, 11.10 Hz, 1H, one
of CH2S), 3.13–3.22 (m, 2H, one of CH2S and one of CH2Ph), 2.83 (dd, J = 8.46, 13.50 Hz,
1H, one of CH2Ph). 13C NMR (75 MHz, CDCl3): δ 160.4, 138.1, 135.3, 131.9,129.1, 128.7,
128.5, 126.6, 125.9, 124.9, 121.0, 112.5, 107.2, 77.7, 40.3, 37.5. IR (cm−1): 2932, 1600,
1584, 1490, 1453, 1260, 1017, 764, 750, 699. Anal. Calcd. for C18H15ClN2S (326.06): C
66.15, H 4.63, N 8.57. Found: C 66.36, H 4.79, N 8.77.
2-[5-Chloroindole-2-yl]-4-phenylthiazoline (8e). Paleoil; yield64%. 1HNMR
(300 MHz, CDCl3): δ 9.78 (s, 1H, NH), 7.57 (s, 1H, ArH), 7.24–7.30 (m, 4H, ArH), 7.16
(d, J = 1.62 Hz, 2H, ArH), 6.87 (d, J = 1.86 Hz, 1H, ArH), 5.63 (t, J = 8.82 Hz, 1H,
CHN ), 3.78 (dd, J = 8.64, 13.40 Hz, 1H, one of CH2S), 3.32 (dd, J = 9.12, 10.80 Hz,
1H, one of CH2S). 13C NMR (75 MHz, CDCl3): δ 161.0, 141.2, 135.2, 131.8, 128.7, 127.8,
126.5, 125.9, 125.0, 121.0, 112.5, 107.2, 79.7, 40.9. IR (cm−1): 3030, 2932, 1607, 1593,
1490, 1450, 1272, 1016, 895, 769, 750, 699. Anal. Calcd. for C17H13ClN2S (312.05): C
65.27, H 4.19, N 8.96. Found: C 65.60, H 4.32, N 8.68.
2-[6-Fluoroindole-2-yl]-4-methylthiazoline (9a). Paleoil; yield61%. 1HNMR
(300 MHz, CDCl3): δ 10.75 (s, 1H, NH), 7.52 (dd, J = 5.40, 8.70 Hz, 1H, ArH), 6.82–6.96
(m, 3H, ArH), 4.69–4.81 (m, 1H, CHN ), 3.55 (dd, J = 7.80, 10.80 Hz, 1H, one of CH2S),
3.06 (dd, J = 6.90, 10.80 Hz, 1H, one of CH2S), 1.36 (d, J = 10.20 Hz, 3H, CH3). 13C-NMR
(75MHz, CDCl3): δ 162.7, 159.8, 159.5, 137.3, 137.1, 131.4, 131.4, 124,4, 122.8, 122.6,
109.6, 109.2, 107.7, 97.6, 97.2, 71.6, 39.7, 20.0. IR (cm−1): 2970, 1601, 1520, 1302, 1262,
1107, 834, 764. Anal. Calcd. for C12H11FN2 S (234.06): C 61.52, H 4.73, N 11.96. Found:
C 61.33, H 4.86, N 11.87.
1
2-[6-Fluoroindole-2-yl]-4-iso-propylthiazoline (9b). Pale oil; yield 55%. H
NMR (300 MHz, CDCl3): δ 10.23 (s, 1H, NH), 7.53 (d, J = 5.40 Hz, 1H), 6.82–6.95 (m,
3H, ArH), 4.45–4.52 (m, 1H, CHN ), 3.49 (dd, J = 8.70, 10.50 Hz, 1H, one of CH2S),
3.21 (dd, J = 8.70, 10.50 Hz, 1H, one of CH2S), 2.00-2.07 (m, 1H, CHMe2), 1.06 (d, J =
6.75 Hz, 3H, CH3), 0.99 (d, J = 6.66Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ 162.8,
159.6, 159.4, 137.1, 137.0, 131.6, 131.5, 124,5, 122.7, 122.7, 109.7, 109.3, 107.5, 97.6,
97.24, 83.09, 35.5, 33.2, 19.6, 19.0. IR (cm−1): 2959, 1601, 1520, 1251, 1160, 1141, 982,
738. Anal. Calcd. for C14H15FN2S (262.09): C 64.09, H 5.76, N 10.68. Found: C 64.30, H
5.62, N 10.61.
1
2-[6-Fluoroindole-2-yl]-4-iso-butylthiazoline (9c). Pale oil; yield 52%. H
NMR (300 MHz, CDCl3): δ 11.02 (s, 1H, NH), 7.51 (dd, J = 5.40, 8.70 Hz, 1H, ArH),
6.80–6.94 (m, 3H, ArH), 4.72–4.78 (m, 1H, CHN ), 3.55 (dd, J = 8.10, 10.50 Hz, 1H,
one of CH2S), 3.08 (dd, J = 6.60, 11.10 Hz, 1H, one of CH2S), 1.64–1.82 (m, 2H, CH2),
1.33–1.41 (m, 1H, CHMe2), 0.79–0.86 (m, 6H, 2 × CH3). 13C NMR (75 MHz, CDCl3): δ
162.7, 159.7, 159.5, 137.3, 137.2, 131.6, 131.5, 124,4, 122.8, 122.7, 109.6, 109.2, 107.7,
97.5, 97.2, 74.5, 44.0, 38.5, 25.5, 22.7, 22.2. IR (cm−1): 2958, 1600, 1264, 1232, 1152,
1035, 836, 738. Anal. Calcd. for C15H17FN2S (276.11): C 65.19, H 6.20, N 10.14. Found:
C 65.31, H 6.47, N 10.08.
2-[6-Fluoroindole-2-yl]-4-benzylthiazoline (9d). Pale oil; yield 64%. 1H NMR
(300 MHz, CDCl3): δ 9.73 (s, 1H, NH), 7.55 (dd, J = 5.40, 8.70 Hz, 1H, ArH), 7.22–7.30

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L. LIU ET AL.
(m, 5H, ArH), 6.84–7.01 (m, 3H, ArH), 4.88–4.93 (m, 1H, CHN ), 3.40 (dd, J = 7.80,
11.10 Hz, 1H, one of CH2S), 3.15–3.22 (m, 2H, one of CH2S and one of CH2Ph), 2.86
(dd, J = 8.40, 13.20 Hz, 1H, one of CH2Ph). 13C NMR (75MHz, CDCl3): δ 162.9, 160.0,
159.7, 138.2, 137.2, 137.0, 131.4, 131.4, 129.2, 129.1, 128.8, 128.5, 126.5, 124.5, 122.9,
122.2, 109.8, 109.4, 107.9, 97.7, 97.4, 77.7, 40.3, 37.5. IR (cm−1): 2916, 1560, 1264, 1222,
1108, 1033, 835, 738. Anal. Calcd. for C19H15FN2S (310.09): C 69.65, H 4.87, N 9.03.
Found: C 69.83, H 4.71, N 9.28.
2-[6-Fluoroindole-2-yl]-4-phenylthiazoline (9e). Pale oil; yield 70%. 1H NMR
(300 MHz, CDCl3): δ 9.34 (s, 1H, NH), 7.48–7.59 (m, 1H, ArH), 7.29–7.39 (m, 5H, ArH),
6.86–7.01 (m, 3H, ArH), 5.65 (t, J = 9.0Hz, 1H, CHN ), 3.83 (dd, J = 8.40, 11.40 Hz,
1H, one of CH2S), 3.36 (dd, J = 9.30, 11.40 Hz, 1H, one of CH2S). 13C NMR (75 MHz,
CDCl3): δ 162.9, 160.8, 159.7, 141.4, 137.1, 136.9, 131.2, 131.2, 128.7, 127.8, 127.0,
126.6, 124.5, 123.0, 122.8, 109.9, 109.6, 108.0, 97.7, 97.4, 79.7, 41.0. IR (cm−1): 3124,
1603, 1518, 1270, 1250, 1158, 1073, 726, 714. Anal. Calcd. for C17H13FN2S (296.08): C
68.90, H 4.42, N 9.45. Found: C 68.86, H 4.57, N 9.56.
2-[6-Chloroindole-2-yl]-4-methylthiazoline (10a). Colorless crystals; yield
1
55%; mp: 51–52◦C. H NMR (300 MHz, CDCl3): δ 10.80 (s, 1H, NH), 7.50 (d, J =
8.40Hz, 1H, ArH), 7.24 (s, 1H, ArH), 7.03 (dd, J = 1.80, 3.90 Hz, 1H, ArH), 6.88 (d,
J = 1.05 Hz, 1H, ArH), 4.70–4.81 (m, 1H, CHN ), 3.56 (dd, J = 8.10, 10.80 Hz, 1H,
one of CH2S), 3.07 (dd, J = 6.90, 11.10 Hz, 1H, one of CH2S), 1.32 (d, J = 6.66
Hz, 3H, CH3). 13C-NMR (75MHz, CDCl3): δ 159.8, 137.4, 131.5, 130.1, 126.3, 122.6,
121.1, 111.3, 107.6, 71.6, 39.8, 20.1. IR (cm−1): 2959, 1307, 1160, 1037, 950, 820. Anal.
Calcd. for C12H11ClN2S (250.03): C 57.48, H 14.14, N 11.17. Found: C 57.77, H 14.30,
N 11.22.
2-[6-Chloroindole-2-yl]-4-iso-propylthiazoline (10b). Colorless crystals;
yield 52%; mp: 59–61◦C.1H NMR (300 MHz, CDCl3): δ 9.68 (s, 1H, NH), 7.53(d, J =
8.40 Hz, 1H, ArH), 7.30 (t, J = 0.90 Hz, 3H, ArH), 7.08 (d, J = 1.80 Hz, 1H, ArH), 6.86
(d, J = 0.90 Hz, 1H, ArH), 4.70–4.81(m, 1H, CHN ), 3.47 (dd, J = 8.58, 10.80 Hz,
1H, one of CH2S), 3.21 (dd, J = 9.00, 11.40 Hz, 1H, one of CH2S), 2.02–2.09 (m, 1H,
CHMe2), 1.09 (d, J = 6.90 Hz, 3H, CH3), 1.01 (d, J = 6.78 Hz, 3H, CH3). 13C NMR (75
MHz, CDCl3): δ 158.9, 137.1, 131.6, 130.4, 126.5, 122.7, 121.3, 111.2, 107.2, 83.2, 35.6,
33.2, 19.7, 19.1. IR (cm−1): 2961, 2929, 1602, 1306, 1160, 1039, 846, 818. Anal. Calcd.
for C14H15ClN2S (278.06): C 60.31, H 5.42, N 10.05. Found: C 60.47, H 5.20, N 10.01.
2-[6-Chloroindole-2-yl]-4-iso-butylthiazoline (10c). Pale oil; yield 61%. 1H-
NMR (300 MHz, CDCl3): δ 10.74 (s, 1H, NH), 7.50 (d, J = 8.40Hz, 1H, ArH), 7.23 (s,
1H, ArH), 7.01–7.05 (m, 1H, ArH), 6.57 (d, J = 1.08Hz, 1H, ArH), 4.71–4.76 (m, 1H,
CHN ), 3.56 (dd, J = 8.16, 10.80 Hz, 1H, one of CH2S), 3.09 (dd, J = 6.84, 10.80 Hz,
1H, one of CH2S), 1.65–1.84 (m, 2H, CH2), 1.35–1.44 (m, 1H, CHMe2), 0.81–0.91 (m,
6H, 2 × CH3). 13C NMR (75 MHz, CDCl3): δ 159.7, 137.4, 131.6, 130.1, 126.3, 122.6,
121.0, 111.2, 107.6, 74.6, 43.9, 38.5, 25.5, 22.7, 22.2. IR (cm−1): 2957, 2929, 1309, 1165,
1056, 925, 817. Anal. Calcd. for C15H17ClN2S (292.08): C 61.52, H 5.85, N 9.57. Found:
C 61.71, H 5.60, N 9.34.
2-[6-Chloroindole-2-yl]-4-benzylthiazoline (10d). Pale oil; yield 56%. 1H
NMR (300 MHz, CDCl3): δ 9.49 (s, 1H, NH), 7.57 (dd, J = 0.42, 8.70 Hz, 1H, ArH),
7.21–7.33 (m, 6H, ArH), 7.14 (dd, J = 1.50, 8.40 Hz, 1H, ArH), 4.80–4.86 (m, 1H, CHN ),
3.43 (dd, J = 8.40, 11.10 Hz, 1H, one of CH2S), 3.16–3.24 (m, 2H, one of CH2S and one of
CH2Ph), 2.83 (dd, J = 8.40, 13.50 Hz, 1H, one of CH2Ph). 13C NMR (75MHz, CDCl3): δ
158.8, 137.9, 135.1, 131.6, 129.0, 128.4, 127.1, 124.7, 120.4, 111.3, 111.1, 75.7, 40.4, 37.8.

THIAZOLINES WITH HALOGENATED INDOLYL MOIETY
1799
IR (cm−1): 3028, 1582, 1319, 1221, 1204, 1101, 926, 639. Anal. Calcd. for C18H15ClN2S
(326.06): C 66.15, H 4.63, N 8.57. Found: C 66.36, H 4.79, N 8.77.
2-[6-Chloroindole-2-yl]-4-phenythiazoline (10e). Pale oil; yield 70%. 1H
NMR (300 MHz, CDCl3): δ 9.85 (s, 1H, NH), 7.50 (dd, J = 8.52 Hz, 1H, ArH), 7.23–7.31
(m, 5H, ArH), 7.20 (s, 1H, ArH), 7.03–7.06 (m, 1H, ArH), 6.91 (d, J = 1.20 Hz, ArH), 5.63
(t, J = 8.79 Hz, 1H, CHN ), 3.78 (dd, J = 8.61, 11.70 Hz, 1H, one of CH2S), 3.32 (dd, J
= 9.0, 11.10 Hz, 1H, one of CH2S). 13C NMR (75 MHz, CDCl3): δ 160.9, 141.2, 137.2,
131.3, 130.4, 128.7, 127.8, 126.5, 122.6, 121,3, 111.3, 107.9, 79.7, 41.0. IR (cm−1): 1601,
1512, 1308, 1210, 1159, 1060, 1039, 859, 710. Anal. Calcd. for C17H13ClN2S (312.05): C
65.27, H 4.19, N 8.96. Found: C 65.60, H 4.32, N 8.68.
X-Ray Diffraction
The crystal of compound 7a was obtained from a solution of petroleum ether–ethyl
acetate, and its structure was determined by X-ray diffraction analysis. The X-ray inten-
sity data were recorded on a Bruker Smart 1000 CCD diffraction meter using graphite
monochromated Mo Kα radiation (λ 0.71073 Å). In the range of 1.71< θ <25.33deg,
4385 independent reflections were obtained. All calculations were refined anisotropically.
All hydrogen atoms were located from a difference Fourier map, were placed at calculated
positions, and were included in the refinements in the riding mode with isotropic thermal
parameters.
Crystal data can be obtained from the Crystallographic Data Centre as supplementary
publication number CCDC 790194. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk.
Bioassay of Fungicidal Activities
¨
Fungicidal activities of the title compounds against Rhizoctonia solani kuhn, Botrytis
cinerea Pers, Sclerotinia sclerotiorum (Lib) de Bary, Phomopsis asparagi (Sacc.) Bubak,
Cytospora sp, Phytophthora capsici, Phytophthora parasitica Dast, and Pyricularia oryzae
Cav. were evaluated using the mycelium growth rate test.18 The detailed bioassay procedures
are shown in the Supplemental Materials.
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