Synthesis and fungicidal activity of new fluorine-containing mandelic acid amide compounds

Article abstract of DOI:10.1016/j.jfluchem.2012.02.011

A series of novel fluorine-containing mandelic acid amide compounds were designed and synthesized by a facile method, and their structures were characterized by ¹H nuclear magnetic resonance (NMR) and high-resolution mass spectrometry. The preliminary in vivo bioassays indicated that some of the title compounds showed excellent fungicidal activities in vivo against Pseudoperonospora cubensis at the dosage of 25 mg L^-1, which were comparable with the control (Mandipropamid).

Full text of DOI:10.1016/j.jfluchem.2012.02.011

Journal of Fluorine Chemistry 137 (2012) 108–112
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Synthesis and fungicidal activity of new fluorine-containing mandelic acid
amide compounds
Shuai Li a, Can Cui a, Man-Yi Wang a, Shui-Jing Yu a, Yan-Xia Shi b, Xiao Zhang a,
Zheng-Ming Li a, Wei-Guang Zhao a, , Bao-Ju Li
*
b,**
a State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, China
b Institute of Vegetables and Flowers, Chinese Academy of Agricultural Science, Beijing, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel fluorine-containing mandelic acid amide compounds were designed and synthesized by
a facile method, and their structures were characterized by 1H nuclear magnetic resonance (NMR) and
high-resolution mass spectrometry. The preliminary in vivo bioassays indicated that some of the title
compounds showed excellent fungicidal activities in vivo against Pseudoperonospora cubensis at the
dosage of 25 mg LÀ1, which were comparable with the control (Mandipropamid).
ß 2012 Elsevier B.V. All rights reserved.
Received 19 October 2011
Received in revised form 19 February 2012
Accepted 26 February 2012
Available online 8 March 2012
Keywords:
Fluorinated mandelic acid amide
Fungicidal activities
Synthesis
1. Introduction
taking into account the above-mentioned important contributions,
our main interest was to enhance the hydrophobicity of mandelic
Mandipropamid developed by Syngenta is the first mandelic
acid amide fungicide [1] on the market. It is belongs to the
Carboxylic Acid Amide (CAA) group of fungicides. It exhibited a
high level of activity against most foliar Oomycetes pathogens,
such as Plasmopara viticola in grapes, Phytophthora infestans in
potatoes and tomatoes and Pseudoperonospora cubensis in cucur-
bits [2]. Blum et al. have reported that the mode of action of
Mandipropamid is directly linked to the inhibition of the cellulose
synthase-like in the Oomycete plant pathogen [3].
acid amide compounds by introducing fluorine atoms.
Thus, in this paper, we designed and prepared a series of
fluorine-containing mandelic acid amide compounds in which the
methyl moiety of catecholamine was replaced by 1,1,1-trifluor-
omethyl moiety. Among them, compounds 5d, 5e, 8a, 8b and 8c
displayed excellent fungicidal activity, which were comparable
with the control (Mandipropamid) (Fig. 1).
2. Results and discussion
It is well known that the huge success of fluorine-containing
drugs will stimulate continued research on fluorine in medicinal
chemistry for drug discovery [4] because of the unique properties
of fluorine atom, such as the highest electronegativity, high
thermal stability and lipophilicity. Bioisosteric substitution for
hydrogen by fluorine has become an important strategy [5] for
electronic modulation [6], lipophilic modulation [7] and steric
parameters [8]. 14C-labeled Mandipropamid showed that the
fungicide acts on the cell wall without entering into the cell [3].
Therefore high hydrophobicity may force the immersion of the
pesticide into the wax layer of plant surface, which results in long-
lasting activity, and does not diminish its fungicidal activity. By
2.1. Synthesis
The intermediate 1 was prepared by Duff’s reaction [9], with
hexamethylenetetramine (HMTA) in trifluoroacetic acid (TFA). And
the intermediates 2a–c, which were easily obtained from
compound 1 by alkylation, were converted to intermediates 3a–
c by Henry Condensation reaction [10]. The intermediates 3a–c
were reduced with lithium aluminum hydride to the correspond-
ing amines, which were then converted into amides 4a and b by
treating with ester. The amides 4a and b, which were key
intermediates could be transformed by O-alkylation with alkyl-
ation reagent into the title mandelamides 5a–e (Scheme 1).
After synthesizing a series of mandelamides, we wanted to
synthesize some mandelamides containing two propargyl groups.
* Corresponding author. Tel.: +86 22 23498368; fax: +86 22 23595948.
** Co-corresponding author. Tel.: +86 10 62197975; fax: +86 10 62174123.
E-mail addresses: zwg@nankai.edu.cn, zhaoweiguang@foxmail.com,
nkzhwg@gmail.com (W.-G. Zhao), libj@mail.caas.net.cn (B.-J. Li).
Unexpectedly, the
b-nitrostyrene 3c could be reduced to not only
the desired phenylethylamine, but also the propargyl cleavage
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.02.011

S. Li et al. / Journal of Fluorine Chemistry 137 (2012) 108–112
109
Fig. 1. Structures of Mandipropamid and fluorine-containing mandelic acid amide compounds.
Scheme 1. Synthesis of compounds 5.
compound. Due to the difficulty of the purification of the mixture 6,
it is immediately used in the next step without further purification.
After propargylation in the last step, the title mandelamides 8 were
prepared and isolated easily (Scheme 2).
with P. cubensis by spraying a sporangial suspension. Disease
incidence was assessed after an incubation period of 5 days in a
greenhouse. Mandipropamid was chosen as the comparison
fungicide. The results of the fungicidal experiments are presented
in Table 1.
2.2. Biological activities
The SAR picture of fluorine-containing mandelic acid amide
compounds is completely different from that of mandelic acid
amide compounds. The alkylation of the phenol in the para
position of the catecholamine moiety has a negative effect on the
To determine the efficacy of the new fluorine-containing
compounds as a potential fungicide, the upper leaf surfaces of
three-week-old cucumber plants were treated with the test
compounds in a spray chamber. Each test compound was prepared
at a terminal concentration of 100, 50 and 25 mg LÀ1, respectively.
One day later, the treated and controlled plants were inoculated
fungicidal efficacy, and leads to inactive compounds at 100 mg LÀ1
,
as 5a, 5b and 5c. A comparison between the ethylated title
compounds (5a, 5b and 5c) and their propargyl and benzyl
derivatives reveals that the biological activitives are closely related
Scheme 2. Synthesis of compounds 8.

110
S. Li et al. / Journal of Fluorine Chemistry 137 (2012) 108–112
Table 1
acetate and the combined organic extract was dried over
Fungicidal activities of title compounds.
magnesium sulfate, and concentrated. The residue was purified
by flash chromatography on silica gel [elution solvent:ethyl
acetate/petroleum ether (60–90 8C), 1:10 (v/v)] to afford com-
pound 1. White solid, m.p. 74–75 8C (76–78 8C [11]), yield 45%. 1H
No.
Pseudoperonospora cubensis
100 mg LÀ1
50 mg LÀ1
25 mg LÀ1
5a
0
0
0
0
0
0
NMR (400 MHz, CDCl3): d 11.25 (s, 1H, OH), 9.95 (s, 1H, CHO), 7.57–
5b
5c
0
0
0
7.50 (m, 2H, Ar–H), 7.07–7.03 (m, 1H, Ar–H).
5d
98
98
98
98
98
98
90
90
98
98
98
85
85
90
95
90
90
75
5e
5.2. General synthetic procedures for 3-trifluoromethoxy-4-
8a
alkoxylbenzaldehyde (2a–c)
8b
8c
Mandipropamid
The
4-hydroxy-3-(trifluoromethoxy)benzaldehyde
(2.0 g,
9.7 mmol), 1-bromopropane (1.3 g, 10.7 mmol), and anhydrous
K2CO3 (2.0 g, 14.6 mmol) were stirred together under reflux in
30 mL dry acetone for 6 h. The mixture was filtered, and the filtrate
was concentrated under vacuum. The residue was purified by flash
chromatography on silica gel [elution solvent:ethyl acetate/
petroleum ether (60–90 8C), 1:20 (v/v)] to afford compound 2a.
Compounds 2b and 2c were prepared through the same process,
the alkylation reagent was benzyl bromide and 3-bromopropyne,
respectively. Data for 2a. Colorless oil, yield 60%. 1H NMR
to the degree of unsaturation of the substituent groups, and
propargylation here leads to the best result. For example,
compounds 5d, 5e and 8a exhibited 85, 90 and 95% inhibition
effect against P. cubenis, at 25 mg LÀ1 respectively. The propargyl
substitution of the free hydroxyl function of mandelic acid
generally leads to higher fungicidal activity than the benzyl
substitution.
The fungicidal activity of compound 8c, whose methoxyl is
introduced into the para position of the mandelic acid phenyl ring,
was equivalent to that of the unsubstituted compound 8b. The 4-
chloro substituent (8a) gave the best results.
(300 MHz, CDCl3): d 9.79 (s, 1H, O55C–H), 7.83–7.60 (m, 2H, Ar–
H), 7.02 (d, J = 8.3 Hz, 1H, Ar–H), 4.12 (q, J = 7.0 Hz, 2H, CH2CH3),
1.41 (t, J = 7.0 Hz, 3H, CH2CH3).
Data for 2b. White solid, m.p. 57–59 8C, yield 51%. 1H NMR
(300 MHz, CDCl3):
d 9.87 (s, 1H, CHO), 7.88–7.71 (m, 2H, Ar–H),
3. Conclusion
7.59–7.32 (m, 5H, Ph–H), 7.14 (d, J = 8.4 Hz, 1H, Ar–H), 5.25 (s, 2H,
O–CH2).
A series of novel fluorine-containing mandelic acid amide
compounds were designed based on the theory of bioisoterism.
Some of the title compounds showed excellent fungicidal activities
in vivo against P. cubensis at the dosage of 25 mg LÀ1, which were
comparable with the control (Mandipropamid). After introducing
of fluorine atoms into the catecholamine moiety, their fungicidal
activities had close relation with the degree of unsaturation of the
substituent R1. The compounds where R1 is either propargyl or
benzyl have good fungicidal activities, whereas compounds 5a–c
(R2 is ethyl) are inactive.
Data for 2c. Yellow oil. Yield 62.2%. 1H NMR (400 MHz, CDCl3):
d
9.90 (s, 1H, CHO), 7.91–7.74 (m, 2H, Ph–H), 7.30 (d, J = 8.6 Hz, 1H,
Ph–H), 4.89 (s, 2H, OCH2), 2.61 (s, 1H, CBB CH).
5.3. General synthetic procedures for 3-trifluoromethoxy-4-alkoxy-
b
-nitrostyrene (3a–c)
A mixture of 4-ethoxy-3-trifluoromethoxybenzaldehyde (2a,
3.3 g, 14.1 mmol), nitromethane (2.6 g, 42.3 mmol), glacial acetic
acid (14 mL) and ammonium acetate (1.1 g, 14.1 mmol) was
refluxed for 6 h. Upon cooling to room temperature, the crude
product was filtrated as a yellow solid, then recrystallized from
ethanol to give 3a. Compounds 3b and 3c were prepared through
the same process.
4. Experimental
1H NMR spectra were obtained at 400 MHz, 19F NMR spectra
were obtained at 376 MHz, 13C NMR spectra were obtained at
100 MHz on a Bruker Avance 400 spectrometer with tetramethyl-
silane (TMS) as an internal standard. 1H NMR spectra of some
intermediates were obtained at 300 MHz on a Bruker AV300
spectrometer with tetramethylsilane (TMS) as an internal stan-
dard. High resolution mass spectrometry (HRMS) data were
obtained on a VG ZAB HS instrument. CEM Discover focused
microwave (2450 MHz, 300 W) were used wherever mentioned.
Melting points were determined on an X-4 binocular microscope
melting point apparatus (Beijing Tech Instruments Co., Beijing,
China) and were uncorrected. Yields were not optimized. All
chemicals or reagents were purchased from standard commercial
suppliers. All solvents and liquid reagents were dried by standard
methods in advance and distilled before use.
Data for 3a. Yellow solid, m.p. 101–103 8C, yield 53.8%. 1H NMR
(400 MHz, CDCl3):
d 7.86 (d, J = 13.6 Hz, 1H, C55C–H), 7.43 (d,
J = 13.6 Hz, 1H, C55C–H), 7.42–6.95 (m, 3H, Ar–H), 4.10 (q,
J = 7.0 Hz, 2H, CH2CH3), 1.41 (t, J = 7.0 Hz, 3H, CH2CH3).
Data for 3b. Yellow solid, m.p. 97–99 8C, yield 43.3%. 1H NMR
(300 MHz, CDCl3):
d 7.93 (d, J = 13.6 Hz, 1H, C55C–H), 7.50 (d,
J = 13.6 Hz, 1H, C55C–H), 7.45–7.06 (m, 8H, Ar–H), 5.23 (s, 2H,
OCH2).
Data for 3c. Yellow solid, m.p. 80–81 8C, yield 31.0%. 1H NMR
(300 MHz, CDCl3):
d 7.95 (d, J = 13.7 Hz, 1H, C55C–H), 7.52 (d,
J = 13.7 Hz, 1H, C55C–H), 7.52–7.21 (m, 3H, Ar–H), 4.85 (d,
J = 2.4 Hz, 2H, OCH2), 2.59 (t, J = 2.4 Hz, 1H, CBB CH).
5.4. General synthetic procedures for 2-(4-chlorophenyl)-N-(4-
alkoxy-3-(trifluoromethoxy)phenethyl)-2-hydroxyacetamide (4a and
b)
5. Chemistry
5.1. Synthesis of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (1)
To a stirred solution of LiAlH4 (1.1 g, 30.0 mmol) in dry THF
(35 mL) was slowly added a solution of 3-(trifluoromethoxy)-4-
A solution of 2-(trifluoromethoxy)phenol (10 g, 56.1 mmol) and
hexamethylenetetramine (16 g, 112.3 mmol) in trifluoroacetic
acid (50 mL) was heated at 65 8C for 10 h. Then the mixture was
(ethoxy)-b-nitrostyrene (3a, 2.8 g, 10.0 mmol) in dry THF (15 mL).
The solution was refluxed for 7 h. The mixture was cooled to 0 8C
and quenched carefully with water (3 mL), 15% aqueous NaOH
(3 mL), and then water (6 mL). The solution was stirred 30 min at
room temperature. After removal of white precipitates by
concentrated and diluted with
a 2 N aqueous solution of
hydrochloric acid. The acid phase was extracted twice with ethyl

S. Li et al. / Journal of Fluorine Chemistry 137 (2012) 108–112
111
filtration, the filtrate was dried over K2CO3, and evaporated under
reduced pressure to afford colorless oil, which was used in the
subsequent step without further purification.
H), 6.93–6.79 (m, 2H, Ar–H), 6.71 (s, 1H, NH), 4.89 (s, 1H, NH), 4.11
(dd, J = 15.8, 2.4 Hz, 1H, CH–CBB CH), 3.98 (q, J = 7.0 Hz, 2H,
CH3CH2), 3.88 (dd, J = 15.8, 2.4 Hz, 1H, CH–CBB CH), 3.57–3.29 (m,
2H, CH2CH2), 2.68 (td, J = 6.9, 2.6 Hz, 2H, CH2CH2), 2.40 (t,
J = 2.4 Hz, 1H, CBB CH), 1.34 (t, J = 7.0 Hz, 3H, CH3CH2). 13C NMR
The mixture of methyl 2-(4-chlorophenyl)-2-hydroxyacetate
(2.0 g, 10.0 mmol) and the crude product obtained above was
heated under microwave condition (120 8C, 135 W) for 1 h. Upon
cooling to room temperature, the mixture was diluted with CH2Cl2
(20 mL), and then washed with water (10 mL), dried over
magnesium sulfate and concentrated. The residue was purified
by flash chromatography on silica gel [elution solvent:ethyl
acetate/petroleum ether (60–90 8C), 1:2 (v/v)] to afford compound
4a. Compound 4b was prepared through the same process.
Data for 4a. White solid, m.p. 83–84 8C, yield 62.5%. Rf = 0.39
(100 MHz, CDCl3)
d 169.59, 150.07, 134.64, 131.08, 128.85, 128.66,
127.94, 123.49, 114.26, 79.59, 78.05, 75.85, 64.69, 56.39, 40.12,
34.59, 14.67. 19F NMR (376 MHz, CDCl3)
d
À58.10 (3F). HRMS (ESI)
m/z Calcd for C22H21ClF3NO4Na+ [M+Na+] 478.1003, found
478.1006.
Data for 5d. White solid, m.p. 72–73 8C, yield 65.6%. Rf = 0.32
(PE:EA = 2:1). 1H NMR (400 MHz, CDCl3):
d 7.49–7.23 (m, 9H, Ar–
H), 7.06 (s, 1H, Ar–H), 6.97–6.90 (m, 2H, Ar–H), 6.78 (s, 1H, NH),
5.12 (s, 2H, Ph–CH2), 4.65 (s, 1H, CH), 3.55–3.37 (m, 4H,
CH2CH2 + CH3CH2), 2.75 (t, J = 6.8 Hz, 2H, CH2CH2), 1.17 (t,
(PE:EA = 1:1). 1H NMR (400 MHz, CDCl3):
d 7.43–7.20 (m, 4H, Ar–
H), 6.97 (s, 1H, Ar–H), 6.87–6.81 (m, 2H, Ar–H), 6.16 (s, 1H, NH),
4.95 (s, 1H, CH), 4.07 (q, J = 6.8 Hz, 2H, CH2CH3), 3.59–3.33 (m, 2H,
CH2CH2), 2.70 (m, 2H, CH2CH2), 1.43 (t, J = 6.8 Hz, 3H, CH2CH3).
HRMS (ESI) m/z Calcd for C19H19ClF3NO4Na+ [M+Na+] 440.0847,
found 440.0850.
J = 6.9 Hz, 3H, CH3CH2). 13C NMR (100 MHz, CDCl3):
d 170.48,
149.72, 138.28, 136.45, 136.10, 134.11, 131.74, 128.64,
128.09,128.04, 127.99, 127.02, 126.98, 123.59, 114.83, 81.19,
70.82, 65.39, 39.97, 34.59, 15.10. 19F NMR (376 MHz, CDCl3):
À57.99 (3F). HRMS (ESI) m/z Calcd for C26H25ClF3NO4Na+ [M+Na+]
530.1316, found 530.1313.
Data for 5e. Colorless oil, yield 79.2%. Rf = 0.24 (PE:EA = 3:1). 1H
NMR (400 MHz, CDCl3): d 7.51–7.23 (m, 9H, Ar–H), 7.07 (s, 1H, Ar–
H), 6.99–6.91 (m, 2H, Ar–H), 6.73 (s, 1H, NH), 5.13 (s, 2H, Ph–CH2),
4.96 (s, 1H, CH), 4.19 (d, J = 15.8 Hz, 1H, CH–CBB CH), 3.96 (d,
J = 15.8 Hz, 1H, CH–CBB CH), 3.74–3.36 (m, 2H, CH2CH2), 2.77 (t,
J = 6.9 Hz, 2H, CH2CH2), 2.46 (s, 1H, CBB CH). 13C NMR (100 MHz,
Data for 4b. White solid, m.p. 87–88 8C, yield 56.2%. Rf = 0.22
(PE:EA = 3:1). 1H NMR (400 MHz, CDCl3):
d 7.50–7.21 (m, 9H, Ar–
H), 7.00 (s, 1H, Ar–H), 6.87–6.79 (m, 2H, Ar–H), 6.13 (s, 1H, NH),
5.13 (s, 2H, Ph–CH2), 4.96 (s, 1H, CH), 3.40–3.55 (m, 2H, CH2CH2),
2.80–2.60 (m, 2H, CH2CH2). HRMS (ESI) m/z Calcd for
C24H21ClF3NO4Na+ [M+Na+] 502.1030, found 502.0997.
5.5. General synthetic procedures for 2-(4-chlorophenyl)-2-alkoxy-N-
(4-alkoxy-3-(trifluoromethoxy)phenethyl)acetamide (5a–e)
CDCl3)
d 169.64, 149.75, 136.45, 134.66, 131.67, 128.86, 128.66,
128.64, 128.04, 128.00, 127.04, 123.62, 114.87, 79.59, 78.04, 75.87,
1-Bromopropane (3 mmol) was added slowly at room temper-
ature to a mixture of 5a (0.5 g, 1.2 mmol), 30% aqueous sodium
hydroxide solution (0.8 g, 6 mmol) and catalytic amounts of
tetrabutylammonium bromide (TBAB) in 10 mL of dichloro-
methane. The reaction mixture was stirred for 16 h at 40 8C. The
mixture was concentrated under vancum. Water was added,
dichloromethane (3 Â 50) was used to extract the crude product.
The combines organic layers were dried over magnesium sulfate
and evaporated to give a crude product, which was purified by
flash chromatography on silica gel [elution solvent:ethyl acetate/
petroleum ether (60–90 8C), 1:1 (v/v)] to afford compound 5a.
Compounds 5b, 5c, 5d, and 5e were prepared through the same
process, using benzyl bromide, 3-bromopropyne, 3-bromopropyne
and diethyl sulfate separately. Data for 5a. Colorless oil, yield
70.83, 56.40, 40.12, 34.59. 19F NMR (376 MHz, CDCl3)
d
À57.97
(3F). HRMS (ESI) m/z Calcd for C27H23ClF3NO4Na+ [M+Na+]
540.1160, found 540.1162.
5.6. General synthetic procedures for 2-(4-substituted phenyl)-2-
(prop-2-ynyloxy)-N-(4-(prop-2-ynyloxy)-3-
(trifluoromethoxy)phenethyl)acetamide (8a–c)
To a stirred solution of LiAlH4 (1.1 g, 30.0 mmol) in dry THF
(50 mL) was slowly added a solution of 3-(trifluoromethoxy)-4-
(propynyloxy)-b-nitrostyrene 3c (2.9 g, 10.0 mmol) in dry THF
(35 mL). The solution was refluxed for 7 h. The mixture was cooled
to 0 8C and quenched carefully with water (3 mL), 15% aqueous
NaOH (3 mL), and then water (6 mL). The solution was stirred
30 min at room temperature. After removal of white precipitates
by filtration, the filtrate was dried over K2CO3, and evaporated
under reduced pressure to afford colorless oil, which was used in
the subsequent step without further purification. This mixture 6
was 4-propynyloxy-3-trifluoromethoxyphenethylamine and the
propargyl cleavage product 4-hydroxy-3-trifluoromethoxyphe-
nethylamine.
55.9%. Rf = 0.28 (PE:EA = 3:1). 1H NMR (400 MHz, CDCl3):
d 7.21 (s,
4H, Ar–H), 6.95 (s, 1H, Ar–H), 6.92–6.78 (m, 2H, Ar–H), 6.75 (s, 1H,
NH), 4.57 (s, 1H, CH), 3.98 (q, J = 7.0 Hz, 2H, CH3CH2), 3.46–3.31 (m,
4H, CH3CH2 + CH2CH2), 2.67 (t, J = 6.9 Hz, 2H, CH2CH2), 1.34 (t,
J = 7.0 Hz, 3H, CH3CH2), 1.09 (t, J = 7.0 Hz, 3H, CH3CH2). 13C NMR
(100 MHz, CDCl3):
d 170.46, 150.04, 138.12, 136.11, 134.10,
131.16, 128.63, 128.10, 127.94, 123.44, 121.94, 119.38, 114.24,
81.20, 65.38, 64.71, 39.98, 34.58, 15.09, 14.65. 19F NMR (376 MHz,
CDCl3): À58.12 (3F). HRMS (ESI) m/z Calcd for C21H23ClF3NO4Na+
[M+Na+] 468.1160, found 468.1165.
To
a
cooled (À20 8C) solution of compound 6a (2.9 g,
12.9 mmol) in anhydrous THF (100 mL) was added 4-methylmor-
pholine (1.4 g, 13.8 mmol) during 20 min. After 10 min isobutyl
chloroformate (1.8 g, 13.2 mmol) was added at the same temper-
ature during 10 min. After 20 min, the crude product obtained
above was added. The resulting mixture was stirred for an
additional 12 h at room temperature. The mixture was concen-
trated under reduced pressure, the residue was diluted with H2O
(10 mL) and extracted twice with ethyl acetate and the combined
organic extract dried over magnesium sulfate and concentrated.
The residue was purified by flash chromatography on silica gel
[elution solvent:ethyl acetate/petroleum ether (60–90 8C), 1:3 (v/
v)] to afford a mixture. The mixture cannot be separated further,
because both compounds had the same retention times on TLC.
This mixture can be converted to pure title compound 8 by further
propargylation.
Data for 5b. White solid, m.p. 94–96 8C, yield 75.8%. Rf = 0.31
(PE:EA = 3:1). 1H NMR (400 MHz, CDCl3):
d 7.38–7.20 (m, 9H, Ar–
H), 7.03 (s, 1H, Ar–H), 6.99–6.82 (m, 2H, Ar–H), 6.83 (s, 1H, NH),
4.76 (s, 1H, CH), 4.51 (d, J = 11.5 Hz, 1H, Ph–CH2), 4.37 (d,
J = 11.5 Hz, 1H, Ph–CH2), 4.05 (q, J = 7.0 Hz, 2H, CH3CH2), 3.58–3.40
(m, 2H, CH2CH2), 2.74 (t, J = 6.9 Hz, 2H, CH2CH2), 1.43 (t, J = 7.0 Hz,
3H, CH3CH2). 13C NMR (100 MHz, CDCl3):
d 170.11, 150.06, 138.13,
136.64, 135.60, 134.35, 131.07, 128.79, 128.63, 128.59, 128.37,
128.27, 127.96, 123.44, 114.19, 80.47, 71.35, 64.67, 40.00, 34.54,
14.67. 19F NMR (376 MHz, CDCl3): À58.08 (3F). HRMS (ESI) m/z
Calcd for C26H25ClF3NO4Na+ [M+Na+] 530.1316, found 530.1321.
Data for 5c. Colorless oil, yield 82.3%. Rf = 0.22 (PE:EA = 3:1). 1H
NMR (400 MHz, CDCl3): d 7.29–7.15 (m, 4H, Ar–H), 6.95 (s, 1H, Ar–

112
S. Li et al. / Journal of Fluorine Chemistry 137 (2012) 108–112
Propargyl bromide (1.4 g, 12.0 mmol) was added slowly at
170.34, 159.99, 148.49, 138.41, 132.75, 128.79, 128.04, 127.87,
123.49, 121.67, 115.22, 114.14, 79.92, 78.46, 77.96, 76.20, 75.46,
56.81, 55.86, 55.31, 40.08, 34.72. 19F NMR (376 MHz,ÀCDCl3): -
58.03 (3F). HRMS (ESI) m/z Calcd for C24H21ClF3NO5 [MÀH]À
460.1377, found 460.1369.
room temperature to the mixture obtained above, 30% aqueous
sodium hydroxide solution (3.2 g, 24.0 mmol) and catalytic
amounts of tetrabutylammonium bromide in 150 mL of dichlor-
omethane. The reaction mixture was stirred for 16 h at 40 8C. The
mixture was concentrated under vacuum. Ethyl acetate
(3 Â 50 mL) was used to extract the product; then, the combined
organic layers were washed with brine, dried (MgSO4), and
evaporated to give a crude product, which was purified by flash
chromatography on silica gel [elution solvent:ethyl acetate/
petroleum ether (60–90 8C), 1:3 (v/v)] to afford compound 8a.
Compounds 8b and 8c were prepared through the same process.
Data for 8a. White solid, m.p. 80–81 8C, yield 60.6%. Rf = 0.21
Acknowledgments
We are grateful to the financial support for this work from the
National Natural Science Foundation of China (21172124), the
National Basic Research Science Foundation of China
(2010CB126105) for financial support of this research and the
National Key Technologies R&D Program (2011BAE06B05).We
thank you in advance for your kindest consideration, and look
forward to hearing from you soon.
(PE:EA = 3:1). 1H NMR (400 MHz, CDCl3):
d 7.34–7.26 (m, 4H, Ar–
H), 7.09–7.03 (m, 3H, Ar–H), 6.76 (s, 1H, NH), 4.97 (s, 1H, OCH), 4.76
(s, 2H, CH2–CBB CH), 4.21 (d, J = 15.8 Hz, 1H, CH–CBB CH), 3.97 (d,
J = 15.8 Hz, 1H, CH–CBB CH), 3.62–3.43 (m, 2H, CH2CH2), 2.79 (t,
J = 7.0 Hz, 2H, CH2CH2), 2.54 (s, 1H, CBB CH), 2.48 (s, 1H, CBB CH). 13
C
Appendix A. Supplementary data
NMR (100 MHz, CDCl3):
d 169.64, 148.53, 134.67, 134.62, 132.56,
128.88, 128.67, 127.84, 123.45, 115.20, 79.58, 76.21, 75.89, 56.79,
56.39, 40.09, 34.64. 19F NMR (376 MHz, CDCl3): À58.04 (3F). HRMS
(ESI) m/z Calcd for C23H19ClF3NO4Na+ [M+Na]+ 488.0847, found
488.0840.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2012.02.011.
Data for 8b. Colorless oil, yield 64.2%. Rf = 0.29 (PE:EA = 2:1). 1H
References
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d 7.38–7.31 (m, 5H, Ar–H), 7.08–7.04 (m,
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3H, Ar–H), 6.80 (s, 1H, NH), 5.00 (s, 1H, CH), 4.75 (s, 2H, CH2–
CBB CH), 4.20 (d, J = 15.8 Hz, 1H, CH–CBB CH), 3.97 (d, J = 15.8 Hz, 1H,
CH–CBB CH), 3.57–3.43 (m, 2H, CH2CH2), 2.79 (t, J = 7.0 Hz, 2H,
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d 170.08, 148.49, 136.05, 132.73, 128.77,
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4.95 (s, 1H, CH), 4.75 (s, 2H, CH2–CBB CH), 4.17 (d, J = 15.8 Hz, 1H,
CH–CBB CH), 3.94 (d, J = 15.8 Hz, 1H, CH–CBB CH), 3.80 (s, 3H, OCH3),
3.63–3.43 (m, 2H, CH2CH2), 2.80 (t, J = 7.0 Hz, 2H, CH2CH2), 2.54 (s,
1H, CBB CH), 2.46 (s, 1H, CBB CH). 13C NMR (100 MHz, CDCl3):
d