Synthesis, crystal structure, DFT analysis and fungicidal activity of a novel series O-substituted trifluoroatrolactamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2016.09.020

A series of O-substituted trifluoroatrolactamide derivatives has been synthesized and fully characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR, HRMS and X-ray diffraction analyses. The fungicidal activity of these compounds was evaluated and the results showed that some of them exhibited potent in?vitro fungicidal activity against Erysiphe graminis and Pyricularia oryzae. Their structure-property relationships were investigated using density functional theory calculations. The X-ray crystal structure of one of these compounds adopted a monoclinic space group with the following unit cell parameters: a?=?24.285 (13) ?, b?=?9.006 (5) ?, c?=?9.794 (5) ?, β?=?92.110 (9)o, V?=?2140.6 (19) ?3 and Z?=?4. A comparison of these experimental results with the theoretical values revealed that there was good agreement between the two sets of data. The subsequent biological evaluation of these compounds showed that some of them exhibited potent in?vitro fungicidal activity against Erysiphe graminis and Pyricularia oryzae.

Full text of DOI:10.1016/j.molstruc.2016.09.020

Accepted Manuscript
Synthesis, crystal structure, DFT analysis and fungicidal activity of a novel series O-
substituted trifluoroatrolactamide derivatives
Hui-Hui Yang, Can Cui, Cong Zhu, Jian-Qiang Li, Rui Wu, Lei Tian, Wei-Guang Zhao
PII:
S0022-2860(16)30934-6
10.1016/j.molstruc.2016.09.020
MOLSTR 22932
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 25 October 2015
Revised Date: 18 August 2016
Accepted Date: 6 September 2016
Please cite this article as: H.-H. Yang, C. Cui, C. Zhu, J.-Q. Li, R. Wu, L. Tian, W.-G. Zhao,
Synthesis, crystal structure, DFT analysis and fungicidal activity of a novel series O-substituted
trifluoroatrolactamide derivatives, Journal of Molecular Structure (2016), doi: 10.1016/
j.molstruc.2016.09.020.
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ACCEPTED MANUSCRIPT
Synthesis, crystal structure, DFT analysis and fungicidal activity of a novel series
O-substituted trifluoroatrolactamide derivatives

ACCEPTED MANUSCRIPT
Synthesis, crystal structure, DFT analysis and fungicidal activity of
a novel series O-substituted trifluoroatrolactamide derivatives
Hui-Hui Yang, Can Cui, Cong Zhu, Jian-Qiang Li, Rui Wu, Lei Tian, Wei-Guang Zhao*
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
China
*Corresponding author
Tel: + 86 222 350 4279; Fax: + 86 222 350 4279. E-mail: zwg@nankai.edu.cn.
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ABSTRACT
A series of O-substituted trifluoroatrolactamide derivatives has been synthesized and fully
1
characterized by H NMR, 13C NMR, 19F NMR, HRMS and X-ray diffraction analyses. The
fungicidal activity of these compounds was evaluated and the results showed that some of them
exhibited potent in vitro fungicidal activity against Erysiphe graminis and Pyricularia oryzae.
Their structure-property relationships were investigated using density functional theory
calculations. The X-ray crystal structure of one of these compounds adopted a monoclinic space
group with the following unit cell parameters: a = 24.285(13) Å, b = 9.006(5) Å, c = 9.794(5) Å,
β = 92.110(9)º, V = 2140.6(19) Å3 and Z = 4. A comparison of these experimental results with
the theoretical values revealed that there was good agreement between the two sets of data. The
subsequent biological evaluation of these compounds showed that some of them exhibited potent
in vitro fungicidal activity against Erysiphe graminis and Pyricularia oryzae.
Keywords: Trifluoroatrolactamide; Crystal structure; Density Functional Theory; Fungicidal
activity
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Introduction
α-Hydroxyacetic acids represent an interesting structural class that has recently received
considerable interest from researchers working in a number of different areas. Atrolactic acid is
an important α-hydroxyacetic acid with numerous applications in the field of medicine, where it
has been used to good effect as a chiral derivatizing agent [1]. Themisone, which is also known
as atrolactamide, was discovered to be a potent anticonvulsant in the 1950s [2]. The
trifluorinated analogue of themisone, compound 1, offered increased duration of action with
similar activity to phenytoin and no observed toxicity [3]. We recently developed a rapid, eco-
friendly and high-yielding procedure for the synthesis of trifluoroatrolactamide using a Passerini
reaction under ultrasound irradiation conditions [4]. We also developed an ultrasound-promoted
one-pot Passerini/hydrolysis reaction sequence for the rapid generation of a combinatorial library
of trifluoroatrolactamides 2, which possessed excellent broad-spectrum fungicidal activities [5].
In the early 1990s, the α-hydroxy acetamides 3 [6, 7] and 4 [8] were reported to show inhibitory
activity against a number of different plant pathogens (in particular, oomycetes diseases). The
subsequent alkylation of the hydroxyl group of compound 3 led to the discovery of
mandipropamid, which was the first mandelamide-based fungicide to be developed against foliar
diseases caused by Oomycetes [9]. Herein, we describe our recent efforts towards the
development of a novel series of atrolactamide-based compounds 5 with higher fungicidal
activities by the alkylation of the corresponding hydroxyl compounds 2.
Experimental
Materials and methods
1H, 13C and 19F NMR spectra were measured on a Bruker AC-P500 instrument (Bruker,
Fallanden, Switzerland) using CDCl3 as a solvent with TMS as an internal reference standard.
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Melting points were determined on an X-4 binocular microscope melting point apparatus
(Beijing Tech Instruments, Beijing, China) and were uncorrected. HRMS were recorded on an
Ionspec 7.0-T Fourier-transform ion-cyclotron resonance mass spectrometer (Bruker, Billerica,
MA, USA). The ultrasonic irradiation experiments were conducted on a Nanjing SL2010-N
ultrasonic processor (Shunliu, Nanjin, China). All of the reagents used in the current study were
purchased as the analytical grade.
Typical Procedure for the Preparation of Trifluoroatrolactamide 2.
Compound 2 was synthesized by an ultrasound-promoted one-pot Passerini/hydrolysis
reaction sequence between 2,2,2-trifluoroacetophenone 7 and isonitrile 8 according to the
literature procedure [5]. All of the products were purified by column chromatography.
Typical Procedure for the Preparation of the N-substituted benzyl (or phenethyl)-2-(alkyloxy)-
3,3,3-trifluoro-2-(substituted phenyl)propanamides 5 and 6.
NaH (60% dispersion in mineral oil, 0.09 g, 2.22 mmol) was added to a solution of compound
2 (2.59 mmol) and a catalytic amount of tetrabutylammonium bromide in THF (10 mL) at room
temperature, and the resulting mixture was stirred for 15 min. Alkyl bromide (3.88 mmol) was
then added to the reaction in a dropwise manner, and the resulting mixture was heated at reflux
for 2 h. The mixture was cooled to ambient room temperature and the solvent removed in vacuo
to give a residue, which was dissolved in EtOAc (30 mL). The organic solution was washed with
brine and dried over MgSO4 before being evaporated to dryness in vacuo to give a solid, which
was recrystallized from EtOH to give compounds 5 and 6.
The data for compounds 5-1~28 and 6-1~4 can be found in the Supporting Information.
Determination of the crystal structure
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Crystals suitable for X-ray crystallography were obtained by the slow evaporation of ethanol
solutions of the desired compounds at room temperature. The X-ray intensity data for compound
5-28 were collected with a Rigaku MM-007 rotating anode diffractometer equipped with a
Saturn CCD Area Detector System using monochromated Mo-Kα radiation at T = 113(2) K. The
structures were solved by direct methods with SHELX-97 [10] and subsequently refined using
the same software [11]. All non-hydrogen atoms were refined with anisotropic thermal
parameters. All of the hydrogen atoms were placed in their calculated positions. Details of the
data collection conditions and the parameters of the refinement process are shown in Table 1.
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 1429628 for this compound.
Theoretical calculations
Compounds 5-21 and 5-28 were selected as suitable representatives of the compound series
and their structures were optimized by density functional theory (DFT) calculations using the
B3LYP/6-31++G (d, p) basis sets with the Gaussian software package[12, 13]. Vibrational
analysis showed that the optimized structures were in accordance with the minimum points on
the potential energy surfaces. All of the convergent precision values used in the current study
were the system default values, and all of the calculations were carried out on a DELL computer.
Fungicidal Activities
The fungicidal activities of the compounds synthesized in the current study were evaluated
against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia sorghi Schw (in vivo) and
Pyricularia oryzae (in vitro) using previously described methods from the literature [14, 15]. The
results of these experiments are summarized in Tables 2 and 3.
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Results and discussion
Chemistry synthesis
The O-substituted trifluoroatrolactamides reported in the current study were prepared via a
facile and efficient three-step procedure, which is described below (see Scheme 1).
The trifluoroatrolactamides 2 were prepared according to our previously reported ultrasound-
promoted method [4, 5]. Briefly, trifluoroacetophenones were reacted with acetic acid and
isonitriles under ultrasonic irradiation and solvent-free conditions at 40 °C for 20 min to give a
mixture of O-acetyl trifluoroatrolactamides 9a and the corresponding cyclized products 9b. It is
noteworthy that the nature of the substituents on the phenyl rings of the isonitrile and
phenylethanone substrates had a significant impact on the ratio of the products (i.e., 9a to 9b).
The reaction mixtures, which were not isolated, were directly hydrolyzed in 15 min by the
addition of aqueous sodium hydroxide and methanol at room temperature to give the
corresponding trifluoroatrolactamides 2 in good yields. The hydroxyl group of these compounds
was subsequently alkylated with various alkyl halides using NaH in THF to furnish the O-
substituted trifluoroatrolactamides 5 and 6. The structures of all of the compounds prepared in
1
the current study were confirmed by H NMR, 13C NMR, 19F NMR and high resolution mass
spectrometry analyses. The structure of compound 5-28 was further confirmed by single crystal
X-ray diffraction analysis.
X-ray crystal structure
Compound 5-28 was recrystallized from ethanol to give colorless needles, which were
subjected to X-ray diffraction analysis. The single X-ray crystal structure of compound 5-28 is
shown in Fig. 1. The results revealed that compound 5-28 crystallized in a monoclinic system
with a P2(1)/c space group. The single C(1)-C(8) bond (1.515(4) Å) was shorter in length than
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any of the other C-C bonds in the molecule, including the C(9)-C(10) (1.531(4) Å), C(10)-C(13)
(1.534(4) Å) and C(10)-C(11) (1.539(5) Å) bonds. The dihedral angle between the planes of the
methoxyl-phenyl ring (C(13)-C(18)) and benzene ring (C(19)-C(24)) was 70.7°. The dihedral
angle between the planes of the methoxyl-phenyl ring (C(1)-C(6)) and benzene ring (C(19)-
C(24)) was 24.8°. The C8-N1-C9-C10-C11 bonds were almost coplanar based on the torsion
angles of the C8-N1-C9-C10 (169.5(3)°) and N1-C9-C10-C11 (178.0(3)°) bonds.
The packing of compound 5-28 in the crystalline state is shown in Fig. 3. The crystal structure
revealed the presence of intermolecular hydrogen bonding interactions between neighboring
molecules with N(1)-H(1)...O(2) distances of 2.07(2) Å that stabilized the molecular structure.
Fungicidal activity
The fungicidal activities of all of the compounds prepared in the current study were tested
against Pseudoperonospora cubensis, Erysiphe graminis and Puccinia sorghi Schw (in vivo) at a
concentration of 400 mg L−1. These compounds were also tested against Pyricularia oryzae (in
vitro) at 25 mg L−1. Some of the compounds exhibited good fungicidal activities. Under
equivalent dosage conditions of 25 µgꢀmL−1, compounds 5-4, 5-5, 5-21, 6-2 and 6-4 displayed
complete control (i.e., 100% inhibition) against Pyricularia oryzae. Under equivalent dosage
conditions of 400 µgꢀmL−1, compounds 5-10, 6-1 and 6-4 exhibited high levels of control (i.e.,
95% inhibition) against Puccinia sorghi Schw; compounds 5-5 and 5-13 exhibited 95 and 98%
inhibition against Pseudoperonospora cubensis; and compounds 5-1, 5-10, 5-12, 5-21 and 5-23
exhibited 100, 100, 98, 100 and 100% inhibition against Erysiphe graminis. The nature of the
substituents on the phenyl rings of the products had a significant impact on their fungicidal
activities. The alkylation of the trifluoroatrolactamides 2 led to an increase in their fungicidal
activity, with the Me, Et and allyl units proving to be particularly effective in this regard. The
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introduction of substituents at the ortho-position of the benzylamine group generally led to a
decrease in the fungicidal activity. However, the introduction of a methyl group at the para-
position of the benzylamine group was an exception to this general trend, with compounds 5-4
and 5-5 exhibiting significant levels of control against Pyricularia oryzae. Interestingly,
compound 5-21 bearing a 2-Cl group at its R2 position, exhibited complete control (i.e., 100%
percent inhibition) against Erysiphe graminis and Pyricularia oryzae whilst compound 5-10
bearing an electron-donating methoxy group at the same position only exhibited complete
control against Pyricularia oryzae. Increasing the alkyl chain length of the compound (i.e., n = 2)
compounds 6-2 and 6-4 displayed high levels of fungicidal activity against Pyricularia oryzae.
The activities of the most active compounds were measured at a variety of different
concentrations using a four-fold serial dilution. As shown in Table 2, compound 5-21 inhibited
the growth of Erysiphe graminis by 80% at a concentration of 6.25 ꢁg mL−1, as well as inhibiting
the growth of Pyricularia oryzae by 100% at a concentration of 8.3 ꢁg mL−1. Compounds 5-4, 5-
5 and 6-4 displayed all inhibited the growth of Pyricularia oryzae by 50% at a concentration of
8.3 ꢁg mL−1.
Theoretical calculations
The total molecular and frontier molecular orbital energy levels of compounds 5-21 and 5-28
are listed in Table 3. The energy gap between the highest occupied molecular orbital (HOMO)
and lowest occupied molecular orbital (LUMO) was calculated at the B3LYP level using DFT.
According to the frontier molecular orbital theory, the energy levels of the HOMO and LUMO
can have a significant impact on the bioactivity of a compound. The HOMO and LUMO can
donate and accept electrons, respectively. Studying the frontier molecular orbital energy levels in
this way can therefore provide useful information about the biological mechanism of action of a
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compound. Fig. 4 shows that there were noticeable differences in the electron density
distributions of the frontier molecular orbitals of compounds 5-21 and 5-28 and that the electron
densities of the LUMO and HOMO orbitals were also different from each other. These
differences were attributed to differences in the location and quantity of the electron density in
these compounds. The results in Fig. 4 clearly show that the HOMO of compound 5-21 was
mainly located across the two benzene rings and the amide group, whilst the LUMO was mainly
located on only one of the benzene rings and the amide group. This result therefore showed that
the electrons were being transferred from the benzene ring to the amide group. In contrast, the
HOMO of compound 5-28 was mainly located across the three benzene rings and the amide
group, while the LUMO was mainly located on the PhO-benzene ring and amide group. This
result indicated that there was an electron transfer from the EtO-benzene ring to the amide group.
The main difference between these two molecules was therefore determined to be the direction
of the electron transfer process, with the electrons moving in the opposite direction in both cases.
This difference in the direct of the electron transfer could explain the difference in the fungicidal
activities of these compounds.
Conclusion
We have synthesized a series of O-substituted trifluoroatrolactamides, which were fully
characterized by spectroscopic analyses (1H NMR, 13C NMR, 19F NMR, HRMS) and single
crystal X-ray diffraction. The structural properties of these compounds were calculated by DFT
using the B3LYP/6-31++G(d, p) basis sets. The fungicidal activities of these compounds were
tested against four phytopathogenic fungi. The X-ray crystallography data revealed that these
compounds were stabilized by hydrogen bonding interactions between the N(1)-H(1)...O(2)
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groups of two individual molecules. Notably, some of these compounds exhibited good in vitro
fungicidal activity against E. graminis and P. oryzae.
Acknowledgment
We are grateful for financial support for this work from the National Natural Science Foundation
of China (21172124).
Appendix A. Supplementary material
Further details of the crystal structure investigations may be obtained from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif on quoting the
depository number CCDC 1429628. Copies of the data can be obtained, free of charge, on
application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Tel: 044-01223-762910;
fax: 044-01223-336033; email:deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk.
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j. molstruc.
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Table 1.
Crystal data and experimental and refinement parameters of compound 5-28.
Empirical formula
Formula weight
C24 H22 F3 N O4
445.43
Temperature
113(2) K
Wavelength
0.71073 A
Crystal system, space group
a (Å 3)
Monoclinic, P2(1)/c
24.285(13)
b (Å 3)
9.006(5)
c (Å 3)
9.794(5)
α (º)
90
β (º)
92.110(9)
γ (º)
90
Volume (Å 3)
2140.6(19)
Z, Calculated density y (g cm-3 )
Absorption coefficient (mm-1)
F(000)
4, 1.382
0.111
928
Crystal size
0.20 x 0.18 x 0.12 mm
1.68 to 25.02 deg.
-28<=h<=28, -10<=k<=10, -11<=l<=11
18899 / 3782 [R(int) = 0.1436]
100.0 %
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 25.02
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F^2
Final R indices [I>2sigma(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole (e. Å 3)
Semi-empirical from equivalents
0.9868 and 0.9781
Full-matrix least-squares on F^2
3782 / 1 / 296
1.062
R1 = 0.0753, wR2 = 0.1758
R1 = 0.1023, wR2 = 0.1957
0.0054(16)
0.299 and -0.297
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Table 2
Fungicidal activities of compounds 5 and 6 (percentage inhibition) against Pseudoperonospora
cubensis, Erysiphe graminis, Puccinia sorghi Schw (in vivo) and Pyricularia oryzae (in vitro)
P. cubensis E. graminis P. sorghi Schw P. oryzae
No.
R1
R2
R3
n
400 mg/L
25 mg/L
5-1
5-2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
Et
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
0
100
0
0
0
0
0
CH2C≡CC2H5
5-3
H
Bn
0
0
0
0
5-4
4-Me
Me
0
0
0
100
100
50
0
5-5
4-Me
Et
95
0
60
0
0
5-6
4-Me
CH2=CHCH2
0
5-7
4-Me
CH2C≡CCH3
0
0
0
5-8
4-Me
CH2-C≡CC2H5
0
0
0
0
5-9
4-Me
Bn
0
0
0
0
5-10
5-11
5-12
5-13
5-14
5-15
5-16
5-17
5-18
5-19
5-20
5-21
5-22
5-23
5-24
5-25
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
4-MeO
4-MeO
4-MeO
4-F
Me
0
100
85
98
60
0
95
0
50
0
Et
50
0
Pr
0
80
0
CH2=CHCH2
98
0
0
Bn
75
0
0
Me
0
70
0
0
CH2C≡CC2H5
0
0
0
Bn
0
0
0
0
Me
0
0
0
80
50
0
4-F
CH2=CHCH2
0
85
0
0
4-F
Bn
0
0
2-Cl
Me
0
100
0
0
100
0
2-Cl
Pr
0
0
2-Cl
CH2=CHCH2
0
100
0
0
50
0
2-Cl
Bn
0
70
0
4-MeO
4-MeO
4-MeO
4-MeO
3,4-diMeO
3,4-diMeO
3,4-diMeO
3,4-diMeO
3,4-diMeO
Me
0
0
80
0
5-26 MeO
5-27 Ph
5-28 OPh
Me
0
0
0
Me
0
0
0
0
Me
0
0
0
0
6-1
6-2
6-3
6-4
6-5
H
H
H
H
H
Me
0
0
95
0
0
Et
0
0
100
0
Pr
CH2=CHCH2
Bn
0
0
0
0
0
95
0
100
0
0
0
14

ACCEPTED MANUSCRIPT
Table 3
Fungicidal activities of compounds 5 and 6 (percentage inhibition) against Pseudoperonospora
cubensis, Erysiphe graminis, Puccinia sorghi Schw (in vivo) and Pyricularia oryzae (in vitro)
P. cubensis
E. graminis
P. sorghi Schw
P. oryzae
No.
400 100 400 100 25 6.25 400
100
-
25 8.3 2.8 0.9
0
95
0
-
20
-
0
-
-
-
-
-
-
0
0
100 80
100 80
50
50
-
0
0
-
5-4
5-5
60
-
100 30
100 95
100 60
-
-
95
0
0
50
-
5-10
5-21
5-23
6-1
0
-
90
40
-
80
0
-
--
-
100 100
0
0
-
0
-
0
50
0
-
-
-
0
-
0
0
0
-
-
-
95
0
50
-
-
-
0
-
-
-
100 50
100 80
-
-
6-2
0
-
-
-
95
100
70
50
0
6-4
fenaminstrobin 100 100 100 100 100 100
100 100 100 100 80
15

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Table 4
Total and frontier molecular orbital energies of compounds 5-21 and 5-28.
5-21
5-28
Etotal/Hartreeb -1621.42379522 -1582.54682774
EHOMO/Hartree
LUMO/Hartree
ꢂEa/Hartree
0.24965
-0.02695
-0.2766
-0.22219
-0.01699
0.2052
E
aꢂE= ELUMO- EHOMO; b 1 Hartree = 4.35974417×10−18J = 27.2113845ev
16

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Fig. 1. Structures of some compounds containing an α-hydroxyacetamide moiety and the design
of the target compounds based on compound 2
17

ACCEPTED MANUSCRIPT
Fig. 2. Crystal structure of compound 5-28 showing the atom numbering scheme.
18

ACCEPTED MANUSCRIPT
Fig. 3. Crystal Packing diagram of compound 5-28.
19

ACCEPTED MANUSCRIPT
Fig. 4. Frontier molecular orbitals of compounds 5-21 and 5-28.
20

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of compounds 5 and 6
21

ACCEPTED MANUSCRIPT
Highlights
A series of O-substituted trifluoroatrolactamide derivatives were synthesized.
Their structures were characterized by NMR, MS, IR, X-ray.
Some molecular properties were calculated by density functional theory
calculations.
Good fungicidal activities were observed.